Tetrahydropyrazolo-pyrazinyl-dihydroimidazolide or tetrahydropyrazolo-pyridinyl-dihydroimidazolide compounds and their usage methods

Abstract

This application relates to compounds of formula (I) that modulate the activity of GLP-1 receptors, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof; pharmaceutical compositions comprising compounds of formula (I); and methods for treating or preventing diseases in which GLP-1 receptors function.

Description

[0001] Related applications

[0002] This application claims the benefit and priority of International Application No. PCT / CN2020 / 102955, filed on July 20, 2020, and International Application No. PCT / CN2021 / 070120, filed on January 4, 2021, the entire contents of each of which are incorporated herein by reference in their entirety.

[0003] background

[0004] Glucagon-like peptide-1 (GLP-1) is an incretin consisting of 30 or 31 amino acids, secreted by L cells in the small intestine. GLP-1 exerts a wide range of effects through the GLP-1 receptor, such as promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and suppressing appetite. Therefore, GLP-1 analogs have shown efficacy in reducing HbA1c and weight loss and have been developed as effective therapeutic agents for the treatment of diabetes and obesity. GLP-1 analogs have also demonstrated efficacy in improving cardiovascular outcomes and preserving renal function in patients with diabetes, thus providing therapeutic opportunities for a variety of metabolic disorders and related comorbidities. Recently, liraglutide and semaglutide have shown reductions in hepatic steatosis and promoted NASH regression in clinical trials, indicating potential utility against 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 analogs is challenging, likely due to their peptide nature.

[0005] Currently, there are no approved small molecule GLP-1 receptor agonists for treating diabetes or other metabolic disorders in which the GLP-1 receptor plays a role. Therefore, there is a need for small molecule GLP-1 receptor agonists as a therapeutic option for treating these disorders. This application addresses that need.

[0006] Overview

[0007] This application provides a novel GLP-1 receptor ligand that can be used to treat diseases or disorders in which the GLP-1 receptor functions, such as those described herein, including but not limited to diabetes, obesity, overweight, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, hypertension, stroke, coronary heart disease, congestive heart failure, arrhythmia, diabetic nephropathy, dementia, Parkinson's disease, Alzheimer's disease, and liver diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0008] The first aspect of this application relates to compounds of formula (I):

[0009]

[0010] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein A, X, Y, T, L, R2 and R4 are described in detail below.

[0011] Another aspect of this application relates to 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.

[0012] Another aspect of this application relates to a method for treating or preventing GLP-1 receptor-mediated diseases or disorders (e.g., diseases or disorders in which GLP-1 receptors function or are associated with regulation of GLP-1 receptors), said diseases or disorders as described herein (e.g., diabetes, obesity, overweight, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, hypertension, stroke, coronary heart disease, congestive heart failure, arrhythmia, diabetic nephropathy, dementia, Parkinson's disease, Alzheimer's disease, and liver diseases such as NAFLD and NASH). The method includes administering to a subject requiring 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 therapeutically effective amount of 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.

[0013] Another aspect of this application relates to a method of modulating (e.g., activating or stimulating) a GLP-1 receptor. The method comprises administering to a subject requiring such modulation 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 therapeutically effective amount of 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.

[0014] Another aspect of this 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 the treatment or prevention of GLP-1 receptor-mediated diseases or disorders, or in methods of modulating (e.g., activating or stimulating) GLP-1 receptors.

[0015] Another aspect of this application relates to the use 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, in the manufacture of a medicament for treating or preventing GLP-1 receptor-mediated diseases or disorders, or for modulating (e.g., activating or stimulating) GLP-1 receptors.

[0016] This application provides modulators (e.g., agonists) of the GLP-1 receptor, which are therapeutic agents for treating diseases such as diabetes, obesity, metabolic diseases, cardiovascular diseases, liver diseases, NASH, kidney diseases, neurodegenerative diseases, and other diseases or disorders related to the regulation of the GLP-1 receptor.

[0017] This application also provides compounds and compositions that have improved therapeutic profiles (e.g., potency, pharmacodynamics, safety) relative 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, kidney diseases, neurodegenerative diseases, and other diseases associated with the regulation of GLP-1 receptors.

[0018] Detailed Explanation

[0019] The compounds of this application

[0020] This application relates to compounds and compositions thereof capable of modulating the activity of GLP-1 receptors. The application is characterized by a method of treating, preventing, or alleviating diseases or disorders in which GLP-1 receptors function by administering a therapeutically effective amount of the compound of this application or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof to a subject with appropriate need. The compounds of this application can be used to treat a variety of GLP-1-mediated diseases and disorders by stimulating GLP-1 receptors. Activation or stimulation of GLP-1 receptors provides treatment, prevention, or alleviation of diseases, including but not limited to diabetes, obesity, metabolic diseases, cardiovascular diseases, liver diseases, non-alcoholic steatohepatitis (NASH), and other diseases associated with the regulation of GLP-1 receptors.

[0021] In the first aspect of this application, compounds of formula (I) are described:

[0022]

[0023] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer, wherein:

[0024] yes

[0025] R1 is (CR) C R C ) 0-2 -C3-C6 cyclic hydrocarbon group, (CR C R C ) 0-2 -Phenyl or (CR) containing a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S. C R C ) 0-2 - Heteroaryl, wherein the cyclic hydrocarbon, phenyl or heteroaryl group is optionally substituted by one or more substituents independently selected from the following: 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 cyclic hydrocarbon, wherein the cyclic hydrocarbon is a spirocyclic hydrocarbon, a bridged cyclic hydrocarbon or a monocyclic hydrocarbon;

[0026] Each R C It is independently H, C1-C3 alkyl, or C1-C3 haloalkyl;

[0027] R2 is C3-C 10Cycloalkyl, phenyl, heterocyclic group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, or heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, wherein the cycloalkyl, phenyl, heterocyclic or heteroaryl group is 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, wherein the cycloalkyl group is a spirocyclic alkyl group, a bridged cycloalkyl group or a monocyclic alkyl group;

[0028] It is selected from the following bicyclic heteroaryl rings:

[0029] Each R3 is independently a halogen, C3-C 10 Cycloalkyl, phenyl, heterocyclic group comprising one or two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, or heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, wherein the cycloalkyl, phenyl, heterocyclic or heteroaryl group is 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, wherein the cycloalkyl group is a spirocyclic cycloalkyl, a bridged cycloalkyl or a monocyclic cycloalkyl, provided that at least one R3 is a cycloalkyl, phenyl, heterocyclic or heteroaryl group;

[0030] R4 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2 or CN;

[0031] L is Or phenylene, wherein the phenylene is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and halogen, or wherein when the phenylene is substituted by two substituents attached to adjacent carbon atoms in the phenylene ring, the two substituents together with the carbon atoms to which they are attached can form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing 1 to 3 heteroatoms selected from N, O and S;

[0032] 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 atoms to which they are attached form a C3-C6 cyclic hydrocarbon group, said C3-C6 cyclic hydrocarbon group optionally being substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen; and

[0033] T is C(O)OH, (CH2)NHS(O)2-(C1-C6 alkyl), or a heteroaryl group comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, or oxo, and when L is When T is not C(O)OH, or when L is a phenylene ring substituted with two substituents attached to adjacent carbon atoms, and said two substituents together with the carbon atoms to which they are attached form a 5- or 6-membered ring, T is H.

[0034] The condition is when yes yes T is an oxadiazolone group, each R3 is independently F, a heterocyclic group comprising one or two 3- to 6-membered rings and 1-3 heteroatoms selected from N, O, and S, or a heteroaryl group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic group or heteroaryl group is optionally substituted, and L is Furthermore, when R5 and R6 together with the carbon atoms to which they are attached form a C3-C6 cyclic hydrocarbon group, the C3-C6 cyclic hydrocarbon group is not substituted;

[0035] The condition is when yes yes T stands for oxadiazolone group, L is... R5 and R6 together with the carbon atoms to which they are attached form unsubstituted C3-C6 cyclic hydrocarbon groups, and R3 is substituted when it is a heterocyclic group containing a 6-membered ring and 1-3 heteroatoms selected from N, O and S.

[0036] The condition is when yes yes T stands for oxadiazolone group, L is... Furthermore, if R5 and R6 are both methyl groups, then R3 is not a heteroaryl group containing a 6-membered ring and 1-3 heteroatoms selected from N, O, and S; and

[0037] The condition is when yes yes L is When R5 and R6 are each H, and R3 is a heterocyclic group containing a 6-membered ring and 1-3 heteroatoms selected from N, O and S, then R3 is substituted.

[0038] In some embodiments, the compound of formula (I) has formula (Ia1), formula (Ia2), formula (Ia3), formula (Ia4), formula (Ia5), formula (Ia6), formula (Ia7), formula (Ia8), formula (Ia9), formula (Ia10), or formula (Ia11):

[0039]

[0040]

[0041] Or the structure of its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer.

[0042] in:

[0043] Each R7 is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; and

[0044] Each R 11 It is independently a 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 cyclic hydrocarbon group.

[0045] In some embodiments, the compound of formula (I) has formula (Ib1), formula (Ib2), formula (Ib3), formula (Ib4), formula (Ib5), formula (Ib6), formula (Ib7), formula (Ib8), formula (Ib9), formula (Ib10), or formula (Ib11):

[0046]

[0047]

[0048] Or the structure of a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer, wherein:

[0049] Each R7 is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; and

[0050] Each R11 It is independently a 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 cyclic hydrocarbon group.

[0051] For each of the formulas described in this paper, where applicable:

[0052] In some implementation schemes, yes

[0053] In some implementation schemes, yes

[0054] In some embodiments, R1 is substituted by one or more substituents independently selected from the following (CR... C R C ) 0-2 -Phenyl: Straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 Halogenated alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), CN, NO2, and C3-C6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0055] In some embodiments, R1 is substituted by one or more substituents independently selected from the following (CR... C R C ) 0-2-Phenyl: Straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, each of which is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), straight-chain C1-C4 haloalkoxy or branched C3-C4 Halogenated alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C4 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), N(C1-C4 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), CN, NO2, and C3-C6 cyclic hydrocarbon groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0056] In some embodiments, R1 is substituted by one or more substituents independently selected from the following (CR... C R C ) 0-2 -Phenyl: Straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, each of which is substituted with one or more halogens (e.g., F, Cl)), straight-chain C1-C4 alkoxy or branched C3- C4 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), straight-chain C1-C4 haloalkoxy groups or branched C3-C4 haloalkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy groups, each of which is substituted by one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br, or I).

[0057] In some implementations, R1 is substituted with one, two, or three substituents as described herein (CR). C R C ) 0-2 -Phenyl.

[0058] In some embodiments, R1 is substituted with one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl (CR C R C ) 0-2 -Phenyl.

[0059] In some implementations, R1 is substituted by one or more substituents as described herein (CR). C R C ) 0-1 -Phenyl.

[0060] In some implementations, R1 is substituted with one, two, or three substituents as described herein (CR). C R C ) 0-1 -Phenyl.

[0061] In some embodiments, R1 is substituted with one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl (CR C R C ) 0-1 -Phenyl.

[0062] In some embodiments, R1 is a phenyl group substituted with one or more substituents as described herein.

[0063] In some embodiments, R1 is a phenyl group substituted with one, two, or three substituents as described herein.

[0064] In some embodiments, R1 is a phenyl group substituted with one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl.

[0065] In some embodiments, R1 is a CR substituted with one or more substituents as described herein. C R C -Phenyl.

[0066] In some implementations, R1 is a CR substituted with one, two, or three substituents as described herein. C R C -Phenyl.

[0067] In some embodiments, R1 is a CR substituted with one, two, or three substituents selected from methyl, CF3, F, and Cl. C R C -Phenyl.

[0068] In some embodiments, R1 is optionally substituted by one or more substituents independently selected from the following (CR... C R C )0-2 -C3-C6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dicyclobutyl, dicyclopentyl, or dicyclohexyl): straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted by one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy). (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), CN, NO2, and C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0069] In some embodiments, R1 is optionally substituted by one or more substituents independently selected from the following (CR... C R C ) 0-2-C3-C6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dicyclobutyl, dicyclopentyl, or dicyclohexyl): straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, each of which is substituted by one or more halogens (e.g., F, Cl)), straight-chain C1-C4 alkoxy or branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy). (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C4 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), N(C1-C4 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), CN, NO2, and C3-C6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0070] In some embodiments, R1 is optionally substituted with one, two, or three substituents as described herein (CR). C R C ) 0-2 -C3-C6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl).

[0071] In some embodiments, 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 groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl).

[0072] In some embodiments, R1 is optionally substituted with one or more substituents as described herein (CR). C R C ) 0-1 -C3-C6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl).

[0073] In some embodiments, R1 is optionally substituted with one, two, or three substituents as described herein (CR). C R C ) 0-1 -C3-C6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl).

[0074] In some embodiments, R1 is optionally substituted with one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl (CR C R C ) 0-1 -C3-C6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl).

[0075] In some embodiments, R1 is cyclohexyl or bicyclopentyl, wherein each is optionally substituted by one or more substituents as described herein.

[0076] In some embodiments, R1 is cyclohexyl or bicyclopentyl, wherein each is optionally substituted by one, two or three substituents as described herein.

[0077] In some embodiments, R1 is cyclohexyl or bicyclopentyl, wherein each is optionally substituted by one, two or three substituents selected from methyl, methoxy, CF3, F and Cl.

[0078] In some embodiments, R1 is a (CR) ring comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S. C R C ) 0-2 - Heteroaryl, the (CR) C R C ) 0-2-The heteroaryl group is optionally substituted by one or more substituents independently selected from the following: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted by one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkyl, tert-butoxy, pentoxy, or hexyl, etc. Alkyl or branched C3-C6 haloalkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), CN, NO2, and C3-C6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0079] In some embodiments, R1 is a (CR) ring comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S. C R C ) 0-2 - Heteroaryl, the (CR) C R C ) 0-2-The heteroaryl group is optionally substituted by one or more substituents independently selected from the following: straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, each of which is substituted by one or more halogens (e.g., F, Cl)), straight-chain C1-C4 alkoxy or branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), straight-chain C1-C4 haloalkyl, methyl ... Alkyl or branched C3-C4 haloalkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C4 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), N(C1-C4 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), CN, NO2, and C3-C6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0080] In some implementations, R1 is a (CR) ring comprising a 5-membered ring and 1-3 heteroatoms selected from N, O, and S. C R C ) 0-2 - Heteroaryl, the (CR) C R C ) 0-2 -The heteroaryl group may optionally be substituted as described herein.

[0081] In some implementations, R1 is a (CR) ring comprising a 5-membered ring and 1-3 heteroatoms selected from N, O, and S. C R C ) 0-1 - Heteroaryl, the (CR) C R C ) 0-1 -The heteroaryl group may optionally be substituted as described herein.

[0082] In some embodiments, R1 is a heteroaryl group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted as described herein.

[0083] In some implementations, R1 is a heteroatom consisting of a 6-membered ring and 1-3 heteroatoms selected from N, O, and S (CR). C R C )0-2 - Heteroaryl, the (CR) C R C ) 0-2 -The heteroaryl group may optionally be substituted as described herein.

[0084] In some implementations, R1 is a heteroatom consisting of a 6-membered ring and 1-3 heteroatoms selected from N, O, and S (CR). C R C ) 0-1 - Heteroaryl, the (CR) C R C ) 0-1 -The heteroaryl group may optionally be substituted as described herein.

[0085] In some embodiments, R1 is a heteroaryl group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted as described herein.

[0086] In some implementations, each R C It's H.

[0087] In some implementations, at least one R C It is a C1-C3 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) or a C1-C3 haloalkyl (e.g., methyl, ethyl, propyl, or isopropyl, wherein each is substituted with one or more halogens (e.g., F, Cl).

[0088] In some implementations, each R C Independently, it is a C1-C3 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) or a C1-C3 haloalkyl (e.g., methyl, ethyl, propyl, or isopropyl, wherein each is substituted with one or more halogens (e.g., F, Cl).

[0089] In some embodiments, R2 is a heterocyclic group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, or a heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group or heteroaryl group is optionally substituted by one or more substituents independently selected from: optionally by straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, ...). C1-C6 alkyl groups substituted with isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl groups, or branched C3-C6 haloalkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, each of which is substituted with one or more halogens). (e.g., F, Cl) substitution), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, their Each of these is replaced by one or more halogens (e.g., F, Cl), OH, halogens (e.g., F, Cl, Br or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl), CN and NO2.

[0090] In some embodiments, R2 is a heterocyclic group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentoxy, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl groups or branched C3-C6 haloalkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), CN, and NO2.

[0091] In some embodiments, R2 is a heterocyclic group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted with one or more substituents as described herein.

[0092] In some embodiments, R2 is a heterocyclic group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more substituents as described herein.

[0093] In some embodiments, R2 is a heterocyclic group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more substituents as described herein.

[0094] In some embodiments, R2 is a heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentoxy, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl groups or branched C3-C6 haloalkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), CN, and NO2.

[0095] In some embodiments, R2 is a heteroaryl group comprising two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with one or more substituents as described herein.

[0096] In some embodiments, R2 is a heteroaryl group comprising two 5- or 6-membered rings and one to three heteroatoms selected from N and O, wherein the heteroaryl group is optionally substituted by one or more substituents as described herein.

[0097] In some embodiments, R2 is a heteroaryl group comprising two 5- or 6-membered rings and one to three heteroatoms selected from N, wherein the heteroaryl group is optionally substituted with one or more substituents as described herein.

[0098] In some embodiments, R2 is a heteroaryl group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with one or more substituents as described herein.

[0099] In some embodiments, R2 is a heteroaryl group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with one or more substituents as described herein.

[0100] In some embodiments, R2 is a heteroaryl group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with one or more substituents as described herein.

[0101] In some embodiments, R2 is an indazole or imidazopyridyl group, wherein each is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentoxy, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl groups or branched C3-C6 haloalkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted with one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy groups or branched C3-C6 alkoxy groups. The following compounds are used: alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy groups or branched C3-C6 haloalkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), CN, and NO2.

[0102] In some embodiments, R2 is an indazole or imidazopyridyl group, wherein each is optionally substituted with one or more substituents independently selected from: C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentoxy, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutyl, tert-butyl, pentoxy, or hexyl), straight-chain C1-C6 haloalkyl groups or branched C3-C6 haloalkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, or hexyl), or straight-chain C1-C6 haloalkyl groups or branched C3-C6 haloalkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, ... tert-butyl, pentyl, or hexyl, each of which is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted with one or more halogens (e.g., F, Cl), OH, and halogens (e.g., F, Cl, Br, or I).

[0103] In some embodiments, R2 is an indazole or imidazopyridyl group, wherein each is optionally substituted with one or more substituents independently selected from the following: C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentoxy, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl groups or branched C3-C6 haloalkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted with one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br, or I).

[0104] In some embodiments, R2 is an indazole or imidazopyridyl, wherein each is optionally substituted with one, two or three substituents as described herein.

[0105] In some embodiments, R2 is a spiroC3-C ... 10 Cyclic hydrocarbon groups, bridging C3-C 10 Cyclic hydrocarbon group or single C3-C 10Cyclic hydrocarbon group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which may be a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group): C1-C6 alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy) Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl; straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, each of which is substituted with one or more halogens (e.g., F, Cl)); straight-chain C1-C6 alkoxy or branched C3-C6 Alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy groups or branched C3-C6 haloalkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy groups, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), CN, and NO2.

[0106] In some embodiments, R2 is a bicyclooctyl group independently substituted with one or more substituents selected from the following: C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutyl, tert-butyl, pentyl, or hexyl); straight-chain C1-C6 haloalkyl groups or branched C3-C6 haloalkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted with one or more halogens (e.g., F, Cl)); straight-chain C1-C6 alkoxy groups or branched C3-C6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted with one or more halogens (e.g., F, Cl)); straight-chain C1-C6 alkoxy groups or branched C3-C6 alkoxy groups (e.g., methoxy, ethoxy, prop ... The following compounds are substituted for alkyl, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, linear C1-C6 alkyl halogens or branched C3-C6 alkyl halogens (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), CN, and NO2.

[0107] In some embodiments, R2 is a phenyl group independently substituted with one or more substituents selected from the following: C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentoxy, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl); straight-chain C1-C6 haloalkyl groups or branched C3-C6 haloalkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted with one or more halogens (e.g., F, Cl)); straight-chain C1-C6 alkoxy groups or branched C3-C6 alkoxy groups (e.g., methoxy). The following substances may be substituted for halogens: ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy; straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl); OH; halogens (e.g., F, Cl, Br, or I); NH2; NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl); N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl); CN; and NO2.

[0108] In some embodiments, R2 is indazole, imidazopyridyl, phenyl, or bicyclooctyl, wherein each is optionally independently substituted by one or more substituents independently selected from: C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl groups or branched C3-C6 haloalkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted by one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy groups or branched C3-C6 alkoxy groups, wherein each is substituted by one or more halogens (e.g., F, Cl)), and C1-C6 alkoxy groups or branched C3-C6 alkoxy groups. 3-C6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy groups or branched C3-C6 haloalkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy groups, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), CN, and NO2.

[0109] In some embodiments, R2 is indazole, imidazopyridyl, phenyl, or bicyclooctyl, wherein each is optionally independently substituted by one or more substituents independently selected from: C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl groups, or branched C3-C6 haloalkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl... The following compounds may be used: alkyl, sec-butyl, tert-butyl, pentyl, or hexyl, each of which is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy); straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted with one or more halogens (e.g., F, Cl); OH; and halogens (e.g., F, Cl, Br, or I).

[0110] In some embodiments, R2 is indazole, imidazopyridyl, phenyl, or bicyclooctyl, wherein each is optionally independently substituted by one, two, or three substituents as described herein.

[0111] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings: In some implementation schemes, It is selected from the following bicyclic heteroaryl rings: In some implementation schemes, It is selected from the following bicyclic heteroaryl rings: In some implementation schemes, It is selected from the following bicyclic heteroaryl rings: In some implementation schemes, It is selected from the following bicyclic heteroaryl rings: In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0112] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0113] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings: In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0114] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0115] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0116] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0117] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0118] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0119] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0120]

[0121]

[0122] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0123] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0124] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0125] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0126] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0127] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0128] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0129] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings: In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0130] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0131] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0132] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0133] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0134] In some implementation schemes, It is selected from the following bicyclic heteroaryl rings:

[0135] In some embodiments, at least one R3 is a spiroC3-C molecule optionally substituted with one or more substituents independently selected from the following: 10 Cyclic hydrocarbon groups, bridging C3-C10 Cyclic hydrocarbon group or single C3-C 10 Cyclic hydrocarbon groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which may be a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group): straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, each of which is substituted by one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy). The following compounds are used to replace alkyl groups: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl; OH, halogens (e.g., F, Cl, Br, or I); NH2; NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl); N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl); CN; and NO2.

[0136] In some embodiments, at least one R3 is a spiroC3-C molecule optionally substituted with one or more substituents independently selected from the following: 10 Cyclic hydrocarbon groups, bridging C3-C 10 Cyclic hydrocarbon group or single C3-C 10Cyclic alkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which may be a spirocyclic alkyl group, a bridged cyclic alkyl group, or a monocyclic alkyl group): straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, each of which is diffused by one or more halogens (e.g., F). Alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 halogenated alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), and halogens (e.g., F, Cl, Br, or I).

[0137] In some embodiments, at least one R3 is a spiroC3-C molecule optionally substituted with one or more substituents independently selected from the following: 10 Cyclic hydrocarbon groups, bridging C3-C 10 Cyclic hydrocarbon group or single C3-C 10 Cyclic alkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which may be a spirocyclic alkyl group, a bridged cyclic alkyl group, or a monocyclic alkyl group): straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, each of which is diffused by one or more halogens (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclooct ...hexyl, cyclooctyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclo The halogens are 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), straight-chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, each of which is substituted with one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br or I).

[0138] In some embodiments, at least one R3 is a spiroC3-C molecule optionally substituted with one or more substituents independently selected from the following: 10 Cyclic hydrocarbon groups, bridging C3-C 10Cyclic hydrocarbon group or single C3-C 10 Cyclic hydrocarbon groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which may be a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group): straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, each of which is substituted by one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br, or I).

[0139] In some embodiments, at least one R3 is a spiroC3-C substituted with one or two substituents as described herein. 10 Cyclic hydrocarbon groups, bridging C3-C 10 Cyclic hydrocarbon group or single C3-C 10 Cyclic hydrocarbon groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which may be a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group).

[0140] In some embodiments, at least one R3 is a phenyl group optionally substituted with one or more substituents independently selected from: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, ... The following are substituted for halogens: tert-butoxy, pentoxy, or hexoxy; straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl); OH; halogens (e.g., F, Cl, Br, or I); NH2; NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl); N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl); CN; and NO2.

[0141] In some embodiments, at least one R3 is a phenyl group optionally substituted with one or more substituents independently selected from: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br, or I).

[0142] In some embodiments, at least one R3 is a phenyl group 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, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, wherein each is substituted with one or more halogens (e.g., F, Cl). (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), straight-chain C1-C4 alkoxy or branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, each of which is substituted by one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br, or I).

[0143] In some embodiments, at least one R3 is a phenyl group optionally substituted with one or more substituents independently selected from the following: straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, each of which is substituted with one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br, or I).

[0144] In some embodiments, at least one R3 is a phenyl group optionally substituted with one or two substituents as described herein.

[0145] In some embodiments, at least one R3 is a phenyl group substituted with one or two substituents as described herein.

[0146] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted by one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyl). The heterocyclic group containing two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S can be a spirocyclic heterocyclic group or a fused-ring heterocyclic group. The heterocyclic group may contain two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S.

[0147] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted by one or more halogens (e.g., F, Cl)), straight-chain C1 -C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br, or I), wherein the heterocyclic group containing two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S can be a spirocyclic heterocyclic group or a fused-ring heterocyclic group.

[0148] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, wherein each is substituted by one or more halogens (e.g., F, Cl)), straight-chain C1-C4 alkoxy or branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), straight-chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, each of which is substituted by one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br, or I), wherein the heterocyclic group containing two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S can be a spirocyclic heterocyclic group or a fused-ring heterocyclic group.

[0149] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, wherein each is substituted by one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br, or I), wherein the heterocyclic group comprising two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S may be a spirocyclic heterocyclic group or a fused-ring heterocyclic group.

[0150] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted with one or two substituents as described herein, and the heterocyclic group comprising two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S can be a spirocyclic heterocyclic group or a fused-ring heterocyclic group.

[0151] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is substituted by one or two substituents as described herein, and the heterocyclic group comprising two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S can be a spirocyclic heterocyclic group or a fused-ring heterocyclic group.

[0152] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted by one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropyl... The following substances are present: oxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy; straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)); OH; halogens (e.g., F, Cl, Br, or I); NH2; NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl); N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl); CN; and NO2.

[0153] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted by one or more substituents selected from: (e.g., F, Cl) substituted with one or more halogens, straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy or hexoxy, each of which is substituted with one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br or I).

[0154] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, wherein each of The halogens are 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), straight-chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, each of which is substituted with one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br or I).

[0155] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, wherein each is substituted by one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br, or I).

[0156] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, said heterocyclic group optionally being substituted with one or two substituents as described herein.

[0157] In some embodiments, at least one R3 is a heterocyclic group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, said heterocyclic group being substituted with one or two substituents as described herein.

[0158] In some embodiments, at least one R3 is a heterocyclic group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, said heterocyclic group optionally being substituted with one or more substituents as described herein.

[0159] In some embodiments, at least one R3 is a heterocyclic group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, said heterocyclic group optionally being substituted with one or two substituents as described herein.

[0160] In some embodiments, at least one R3 is a heterocyclic group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, said heterocyclic group being substituted with one or two substituents as described herein.

[0161] In some embodiments, at least one R3 is a heterocyclic group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group optionally being substituted with one or more substituents as described herein.

[0162] In some embodiments, at least one R3 is a heterocyclic group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group optionally being substituted with one or two substituents as described herein.

[0163] In some embodiments, at least one R3 is a heterocyclic group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group being substituted with one or two substituents as described herein.

[0164] In some embodiments, at least one R3 is a heterocyclic group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group optionally being substituted with one or more substituents as described herein.

[0165] In some embodiments, at least one R3 is a heterocyclic group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group optionally being substituted with one or two substituents as described herein.

[0166] In some embodiments, at least one R3 is a heterocyclic group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group being substituted with one or two substituents as described herein.

[0167] In some embodiments, at least one R3 is a tetrahydropyranyl group optionally substituted with one or more substituents as described herein.

[0168] In some embodiments, at least one R3 is a tetrahydropyranyl group optionally substituted with one or two substituents as described herein.

[0169] In some embodiments, at least one R3 is a tetrahydropyranyl group substituted with one or two substituents as described herein.

[0170] In some embodiments, at least one R3 is a heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted by one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropyl... The following substances are present: oxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy; straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)); OH; halogens (e.g., F, Cl, Br, or I); NH2; NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl); N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl); CN; and NO2.

[0171] In some embodiments, at least one R3 is a heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted by one or more substituents selected from: (e.g., F, Cl) substituted with one or more halogens, straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy or hexoxy, each of which is substituted with one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br or I).

[0172] In some embodiments, at least one R3 is a heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, wherein each of The halogens are 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), straight-chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, each of which is substituted with one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br or I).

[0173] In some embodiments, at least one R3 is a heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, wherein each is substituted by one or more halogens (e.g., F, Cl)) and halogens (e.g., F, Cl, Br, or I).

[0174] In some embodiments, at least one R3 is a heteroaryl group comprising one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with one or two substituents as described herein.

[0175] In some embodiments, at least one R3 is a heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, said heteroaryl group being substituted with one or two substituents as described herein.

[0176] In some embodiments, at least one R3 is a heteroaryl group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with one or more substituents as described herein.

[0177] In some embodiments, at least one R3 is a heteroaryl group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with one or two substituents as described herein.

[0178] In some embodiments, at least one R3 is a heteroaryl group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, said heteroaryl group being substituted with one or two substituents as described herein.

[0179] In some embodiments, at least one R3 is a heteroaryl group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally being substituted with one or more substituents as described herein.

[0180] In some embodiments, at least one R3 is a heteroaryl group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally being substituted by one or two substituents as described herein.

[0181] In some embodiments, at least one R3 is a heteroaryl group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group being substituted with one or two substituents as described herein.

[0182] In some embodiments, at least one R3 is a heteroaryl group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally being substituted with one or more substituents as described herein.

[0183] In some embodiments, at least one R3 is a heteroaryl group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally being substituted by one or two substituents as described herein.

[0184] In some embodiments, at least one R3 is a heteroaryl group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group being substituted with one or two substituents as described herein.

[0185] In some embodiments, at least one R3 is a pyridyl group optionally substituted with one or more substituents as described herein.

[0186] In some embodiments, at least one R3 is a pyridyl group optionally substituted with one or two substituents as described herein.

[0187] In some embodiments, at least one R3 is a pyridyl group substituted with one or two substituents as described herein.

[0188] In some embodiments, R4 is a straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, or a halogen (e.g., F, Cl, Br, or I).

[0189] In some embodiments, R4 is a straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted with one or more halogens (e.g., F, Cl)) or a halogen (e.g., F, Cl, Br, or I).

[0190] In some embodiments, R4 is a straight-chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0191] In some embodiments, R4 is a straight-chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0192] In some implementations, L is

[0193] In some embodiments, L is a phenylene group optionally substituted with one or more substituents independently selected from: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, and halogens (e.g., F, Cl, Br, or I).

[0194] In some embodiments, L is a phenylene ring substituted with two substituents attached to an adjacent carbon atom in the phenylene ring, and the two substituents together with the carbon atom to which they are attached can form a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing 1 to 3 heteroatoms selected from N, O and S.

[0195] In some implementations, R5 and R6 are each H.

[0196] 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, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is substituted with one or more halogens (e.g., F, Cl)), a straight-chain C1-C6 alkoxy, or a branched C3-C6 alkyl. Chain C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched-chain C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, or halogens (e.g., F, Cl, Br, or I).

[0197] In some embodiments, R5 and R6, together with the carbon atoms to which they are attached, form a C3-C6 cyclic hydrocarbon group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted by one or more substituents independently selected from: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each The halogens may be 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted with one or more halogens (e.g., F, Cl), OH, and halogens (e.g., F, Cl, Br, or I).

[0198] In some embodiments, R5 and R6, together with the carbon atoms to which they are attached, form a C3-C6 cyclic hydrocarbon group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted by one or more substituents independently selected from: straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, etc.). Each of the following is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, each of which is substituted with one or more halogens (e.g., F, Cl)); OH and halogens (e.g., F, Cl, Br or I).

[0199] In some embodiments, R5 and R6 together with the carbon atoms to which they are attached form a C3-C6 cyclic hydrocarbon group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted with one or more straight-chain C1-C4 alkyl or branched C3-C4 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0200] In some embodiments, R5 and R6 together with the carbon atoms to which they are attached form a cyclopropyl group, which is optionally substituted with one or two straight-chain C1-C6 alkyl or branched C3-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl).

[0201] In some embodiments, R5 and R6 together with the carbon atoms to which they are attached form a cyclopropyl group, which is optionally substituted with one or two straight-chain C1-C4 alkyl groups or branched C3-C4 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0202] In some implementations, R5 and R6 together with the carbon atoms to which they are attached form a cyclopropyl group.

[0203] In some implementations, T is C(O)OH.

[0204] In some implementations, T is (CH2)NHS(O)2-(C1-C6 alkyl).

[0205] In some embodiments, T is a heteroaryl group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), wherein each is substituted by one or more halogens (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, ... Alkoxy groups can be substituted with one or more halogens (e.g., F, Cl), straight-chain C1-C6 alkoxy groups or branched C3-C6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy groups or branched C3-C6 haloalkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted with one or more halogens (e.g., F, Cl), OH, halogens (e.g., F, Cl, Br, or I), and oxo (i.e., =O).

[0206] In some embodiments, T is a heteroaryl group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted by one or more substituents independently selected from: straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, wherein each is substituted by one or more halogens ( For example, substituted F, Cl), straight-chain C1-C4 alkoxy or branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), straight-chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogens (e.g., F, Cl, Br or I) and oxo (i.e. = O).

[0207] In some embodiments, T is a heteroaryl group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with one or more substituents as described herein.

[0208] In some embodiments, T is a heteroaryl group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with one or more substituents as described herein.

[0209] In some embodiments, T is a heteroaryl group selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, oxadiazolone, and thiazolyl, wherein each is optionally substituted by one or more substituents as described herein.

[0210] In some embodiments, at least one R7 is a straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, or halogens (e.g., F, Cl, Br, or I).

[0211] In some embodiments, at least one R7 is a straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), a straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, wherein each is substituted with one or more halogens (e.g., F, Cl)), a straight-chain C1-C4 alkoxy, or a branched C3-C4 alkyl. Chain C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), straight-chain C1-C4 haloalkoxy or branched-chain C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, or halogens (e.g., F, Cl, Br, or I).

[0212] In some embodiments, at least one R7 is a straight-chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0213] In some implementations, at least one R 11 It is a straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), a straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkyl. Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, each of which is substituted by 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, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), CN, NO2, or C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0214] In some implementations, at least one R 11It is a straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), a straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, each of which is 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), a straight-chain C1-C4 haloalkoxy or branched C3-C4 haloalkyl. Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, each of which is substituted by one or more halogens (e.g., F, Cl)), OH, halogen (e.g., F, Cl, Br, or I), NH2, NH-(C1-C4 alkyl) (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), N(C1-C4 alkyl)2 (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), CN, NO2, or C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0215] In some implementations, at least one R 11 It is a straight-chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), a straight-chain C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, each of which is substituted by 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, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), straight-chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, each of which is substituted by one or more halogens (e.g., F, Cl)) or halogens (e.g., F, Cl, Br, or I).

[0216] In some implementations, at least one R 11 It is F.

[0217] In some implementations, at least one R 11 It is F, and at least one R 11 It is a methyl group.

[0218] This article is for L, T, R1, RC R 11 Any part of the description in R1, R2, R3, R4, R5, R6, and R7 can be related to the present document for... L, T, R1, R C R 11 Any combination of one or more of the remaining parts of R2, R3, R4, R5, R6, and R7.

[0219] In some implementation schemes, L, T, R1, R C R 11 R2, R3, R4, R5, R6, and R7 can be combined as follows:

[0220] (A-1') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0221] (A-1) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0222] (A-2) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0223] (A-3') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0224] (A-3) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0225]

[0226] (A-4) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0227] (A-5') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0228] (A-5) In some implementation schemes, yes and It is selected from the following bicyclic heteroaryl rings:

[0229] (A-6) In some implementation schemes, yes and It is selected from the following bicyclic heteroaryl rings:

[0230] (A-7) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0231] (A-8) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0232] (A-9) In some implementation schemes, yes and It is selected from the following bicyclic heteroaryl rings:

[0233] (A-10) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0234] (A-11) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0235] (A-12) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0236] (A-13) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0237] (A-14) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0238] (A-15) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0239] (A-16') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0240] (A-16) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0241] (A-17') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0242] (A-17) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0243] (A-18') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0244] (A-18) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0245] (B-1') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0246] (B-1) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0247] (B-2') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0248] (B-2) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0249] (B-3') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0250]

[0251] (B-3) In some implementation schemes, yes and It is selected from the following bicyclic heteroaryl rings:

[0252] (B-4) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0253] (B-5) In some implementation schemes, yes and It is selected from the following bicyclic heteroaryl rings:

[0254] (B-6) In some implementation schemes, yes and It is selected from the following bicyclic heteroaryl rings:

[0255] (B-7) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0256] (B-8) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0257] (B-9) In some implementation schemes, yes and It is selected from the following bicyclic heteroaryl rings:

[0258] (B-10') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0259] (B-10) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0260] (B-11') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0261] (B-11) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0262] (B-12') In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0263] (B-12) In some implementations, yes and It is selected from the following bicyclic heteroaryl rings:

[0264] (C-1) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is substituted by one or more substituents as described herein (CR). C R C ) 0-2 -Phenyl.

[0265] (C-2) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is substituted by one, two, or three substituents as described herein (CR). C R C ) 0-2 -Phenyl.

[0266] (C-3) In some implementation schemes, It is as described in any of (A-1')-(B-12), and R1 is substituted by one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl (CR C R C ) 0-2 -Phenyl.

[0267] (C-4) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is a phenyl group substituted with one or more substituents as described herein.

[0268] (C-5) In some implementation schemes, It is as described in any of (A-1')-(B-12), and R1 is a phenyl group substituted with one, two or three substituents as described herein.

[0269] (C-6) In some implementation schemes, It is as described in any of (A-1')-(B-12), and R1 is a phenyl group substituted with one, two or three substituents selected from methyl, methoxy, CF3, F and Cl.

[0270] (C-7) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is a CR substituted with one or more substituents as described herein. C R C -Phenyl.

[0271] (C-8) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is a CR substituted with one, two, or three substituents as described herein. C R C -Phenyl.

[0272] (C-9) In some implementation schemes, It is as described in any of (A-1')-(B-12), and R1 is a CR substituted with one, two, or three substituents selected from methyl, CF3, F, and Cl. C R C -Phenyl.

[0273] (C-10) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is optionally substituted with one or more substituents as described herein (CR). C R C ) 0-2 -C3-C6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl).

[0274] (C-11) In some implementations, It is as described in any of (A-1')-(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 groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl).

[0275] (C-12) In some implementations, It is as described in any of (A-1')-(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 groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl).

[0276] (C-13) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is cyclohexyl or bicyclopentyl, wherein each is optionally substituted by one or more substituents as described herein.

[0277] (C-14) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is cyclohexyl or bicyclopentyl, wherein each is optionally substituted by one, two or three substituents as described herein.

[0278] (C-15) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is cyclohexyl or bicyclopentyl, wherein each is optionally substituted by one, two or three substituents selected from methyl, methoxy, CF3, F and Cl.

[0279] (C-16) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is a (CR) ring containing a 5-membered ring and 1-3 heteroatoms selected from N, O and S. C R C ) 0-2 - Heteroaryl, the (CR) C R C ) 0-2 -The heteroaryl group may optionally be substituted as described herein.

[0280] (C-17) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is a heteroaryl group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O and S, wherein the heteroaryl group is optionally substituted as described herein.

[0281] (C-18) In some implementations, It is as described in any of (A-1')-(B-12), and R1 is a (CR) ring containing a 6-membered ring and 1-3 heteroatoms selected from N, O and S. C R C ) 0-2 - Heteroaryl, the (CR) C R C ) 0-2 -The heteroaryl group may optionally be substituted as described herein.

[0282] (C-19) In some implementation schemes, It is as described in any of (A-1')-(B-12), and R1 is a heteroaryl group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O and S, wherein the heteroaryl group is optionally substituted as described herein.

[0283] (D-1) In some implementations, R1 is as described in any of (A-1')-(C-19) where applicable, and R2 is a heterocyclic group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group optionally being substituted with one or more substituents as described herein.

[0284] (D-2) In some implementations, R1 is as described in any of (A-1')-(C-19) where applicable, and R2 is a heterocyclic group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group optionally substituted with one or more substituents as described herein.

[0285] (D-3) In some implementation schemes, R1 is as described in any of (A-1')-(C-19) where applicable, and R2 is a heterocyclic group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group optionally substituted with one or more substituents as described herein.

[0286] (D-4) In some implementations, R1 is as described in any of (A-1')-(C-19) where applicable, and R2 is a heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally substituted with one or more substituents as described herein.

[0287] (D-5) In some implementation schemes, R1 is as described in any of (A-1')-(C-19) where applicable, and R2 is a heteroaryl group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally substituted with one or more substituents as described herein.

[0288] (D-6) In some implementation schemes, R1 is as described in any of (A-1')-(C-19) where applicable, and R2 is a heteroaryl group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally substituted with one or more substituents as described herein.

[0289] (D-7) In some implementations. R1 is as described in any of (A-1')-(C-19) where applicable, and R2 is a heteroaryl group comprising two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, said heteroaryl group optionally substituted with one or more substituents as described herein.

[0290] (D-8) In some implementations, R1 is as described in any of (A-1')-(C-19) where applicable, and R2 is indazole or imidazopyridyl, wherein each is optionally substituted by one or more substituents as described herein.

[0291] (D-9) In some implementation schemes R1 is as described in any of (A-1')-(C-19) where applicable, and R2 is a spiroC3-C ... 10 Cyclic hydrocarbon groups, bridging C3-C 10 Cyclic hydrocarbon group or single C3-C 10 Cyclic hydrocarbon groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which may be a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group).

[0292] (D-10) In some implementations, R1 is as described in any of (A-1')-(C-19) where applicable, and R2 is a bicyclooctyl group optionally substituted with one or more substituents as described herein.

[0293] (D-11) In some implementations, R1 is as described in any of (A-1')-(C-19) where applicable, and R2 is a phenyl group optionally substituted with one or more substituents as described herein.

[0294] (E-1) In some implementations, R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a spiroC3-C substituted with one or more substituents as described herein. 10 Cyclic hydrocarbon groups, bridging C3-C 10 Cyclic hydrocarbon group or single C3-C 10 Cyclic hydrocarbon groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which may be a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group).

[0295] (E-2) In some implementations, R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a phenyl group optionally substituted with one or more substituents as described herein.

[0296] (E-3) In some implementations, R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a heterocyclic group comprising one or two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group optionally being substituted with one or more substituents as described herein.

[0297] (E-4) In some implementations, R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a heterocyclic group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group optionally being substituted with one or more substituents as described herein.

[0298] (E-5) In some implementations, R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a heterocyclic group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group optionally substituted with one or more substituents as described herein.

[0299] (E-6) In some implementations, R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a heterocyclic group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heterocyclic group optionally substituted with one or more substituents as described herein.

[0300] (E-7) In some implementations. R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a tetrahydropyranyl group optionally substituted with one or more substituents as described herein.

[0301] (E-8) In some implementations, R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a heteroaryl group comprising one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally substituted with one or more substituents as described herein.

[0302] (E-9) In some implementations. R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a heteroaryl group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally substituted with one or more substituents as described herein.

[0303] (E-10) In some implementations, R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a heteroaryl group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally substituted with one or more substituents as described herein.

[0304] (E-11) In some implementations, R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a heteroaryl group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally substituted with one or more substituents as described herein.

[0305] (E-12) In some implementations, R1 and R2 are as described in any of (A-1')-(D-11) where applicable, and at least one R3 is a pyridyl group optionally substituted with one or more substituents as described herein.

[0306] (F-1) In some implementations, R1, R2, and R3 are as described in any of (A-1')-(E-12) where applicable, and L is Furthermore, R5 and R6 are each H.

[0307] (F-2) In some implementations, R1, R2, and R3 are as described in any of (A-1')-(E-12) where applicable, and L is Furthermore, R5 and R6 together with the carbon atoms to which they are attached form C3-C6 cyclic hydrocarbon groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) that are optionally substituted with one or more substituents as described herein.

[0308] (F-3) In some implementations, R1, R2, and R3 are as described in any of (A-1')-(E-12) where applicable, and L is Furthermore, R5 and R6, together with the carbon atoms to which they are attached, form a cyclopropyl group that is optionally substituted with one or more substituents as described herein.

[0309] (G-1) In some implementations, R1, R2, R3, R5, R6 and L are as described in any of (A-1')-(F-3) where applicable, and T is a heteroaryl group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally substituted with one or more substituents as described herein.

[0310] (G-2) In some implementations, R1, R2, R3, R5, R6 and L are as described in any of (A-1')-(F-3) where applicable, and T is a heteroaryl group comprising a 5-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally substituted with one or more substituents as described herein.

[0311] (G-3) In some implementations, R1, R2, R3, R5, R6 and L are as described in any of (A-1')-(F-3) where applicable, and T is a heteroaryl group comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl group optionally substituted with one or more substituents as described herein.

[0312] (G-4) In some implementations, R1, R2, R3, R5, R6 and L are as described in any of (A-1')-(F-3) where applicable, and T is a heteroaryl group selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, oxadiazolonel and thiazolyl, wherein each is optionally substituted by one or more substituents as described herein.

[0313] Non-limiting illustrative compounds of this application are listed in Table A. As shown in Table A throughout this application, other tables of compounds, examples, schemes and compounds, “or 1” (or “Or 1”) and “or 2” (or “Or 2”) indicate a single stereoisomer configuration, although the absolute stereochemistry of the indicated chiral carbon atom is not determined, and “&1” indicates a mixture of stereoisomers of the indicated chiral carbon atom.

[0314] Table A

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351] Compared to known compounds such as known GLP-1 agonists, the compounds of this application possess advantageous properties. For example, the compounds of this application exhibit more potent GLP-1 agonist activity and more favorable pharmacokinetic properties (e.g., as indicated by C...). 最大 T 最大 The compounds of this application exhibit fewer interactions with other cellular targets (e.g., hepatocyte transporters such as OATP1B1) and correspondingly improved safety (e.g., drug-drug interactions). These beneficial properties of the compounds can be measured using methods commonly available in the art, such as those exemplified herein.

[0352] Due to the presence of double bonds, the compounds of this application can be in cis or trans configuration, or Z or E configuration. It should be understood that although one configuration may be depicted in the structure of the compounds or formulas of this application, this application also covers another configuration. For example, the compounds or formulas of this application may be depicted in cis or trans configuration, or Z or E configuration.

[0353] In one embodiment, the compound of this application (e.g., any compound of any kind disclosed herein or any single compound) is a pharmaceutically acceptable salt. In another embodiment, the compound of this application (e.g., any compound of any kind disclosed herein or any single compound) is a solvate. In yet another embodiment, the compound of this application (e.g., any compound of any kind disclosed herein or any single compound) is a hydrate.

[0354] Details of this application are set forth in the description which follows. While methods and materials similar to or equivalent to those described herein may be used to practice or test this application, illustrative methods and materials are described hereafter. Other features, objects, and advantages of this application will be apparent from the description and claims. In this specification and the appended claims, the singular form also includes the plural form unless the context clearly indicates otherwise. Unless otherwise defined, 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 pertains. All patents and publications referenced in this specification are incorporated herein by reference in their entirety.

[0355] definition

[0356] The articles “a” and “an” are used in this application to refer to one or more (i.e., at least one) grammatical objects of the article. By way of instance, “an element” means one or more elements.

[0357] Unless otherwise indicated, the term “and / or” is used in this application to mean “and” or “or”.

[0358] This application also includes pharmaceutical compositions comprising an effective amount of the compounds of this application (e.g., compounds of any form disclosed herein or any single compound) and a pharmaceutically acceptable carrier.

[0359] As used herein, the term "alkyl" refers to a saturated, straight-chain, or branched hydrocarbon group comprising one to six carbon atoms in some embodiments. 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.

[0360] As used herein, the term "alkenyl" means a monovalent group derived from a hydrocarbon moiety comprising two to six carbon atoms and having at least one carbon-carbon double bond in some embodiments. The double bond may or may not be an attachment point to another group. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and similar groups.

[0361] The term "alkoxy" refers to an -O-alkyl group.

[0362] As used herein, the terms “hal,” “halo,” and “halogen” refer to atoms selected from fluorine, chlorine, bromine, and iodine.

[0363] As used herein, the term "aryl" refers to a monocyclic or polycyclic carbocyclic system having one or more fused or non-fused aromatic rings, including but not limited to phenyl, naphthyl, tetrahydronaphthyl, indenyl, indenyl and similar groups.

[0364] As used herein, the term "aralkyl" refers to an alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl, and similar groups.

[0365] As used herein, the term "cycloalkyl group" refers to a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic compound (fused ring, bridged ring, or spiro ring). Examples of C3-C8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; and C3-C 12 Examples of cycloalkyl groups 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 compounds having at least one carbon-carbon double bond by removing a single hydrogen atom are also contemplated. Examples of such groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and similar groups.

[0366] As used herein, the term "heteroaryl" refers to a fused or non-fused group or ring system having at least one aromatic ring, having five to ten ring atoms (one of which is selected from S, O, and N; zero, one, or two of which are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon) of either a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more rings). Heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrroleyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxolinyl, and similar groups.

[0367] As used herein, the term "heteroaryl" refers to an alkyl residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridylmethyl, pyrimidinylethyl, and similar groups.

[0368] As used herein, the term “heterocyclic group” or “heterocyclic hydrocarbon group” refers to a saturated or unsaturated non-aromatic 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic ring system, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring system (fused ring, bridged ring, or spirocyclic ring), or an 11-, 12-, 13-, or 14-membered tricyclic ring system (fused ring, bridged ring, or spirocyclic ring), wherein (i) each ring contains one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds, and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen heteroatom and sulfur heteroatom may optionally be oxidized, and (iv) the nitrogen heteroatom may optionally be quaternized. Representative heterocyclic hydrocarbon groups include, but are not limited to, [1,3]dioxacyclopentyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, imidazolinyl, imidazolinyl, piperidinyl, piperazinyl, 2-pyridinone, oxazolyl, isoxazolyl, morpholinyl, tetrahydropyranyl, thiazolinyl, isothiazolyl, tetrahydrofuranyl, dioxacyclohexyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[ 3.3] Heptyl, 1,4-dioxa-8-azaspiro[4.5] Decyl, 2-azaspiro[3.3] Hept-5-amine, 1-azaspiro[3.3] Hept-5-amine, 1-oxa-6-azaspiro[3.3] Hept-3-amine, 2-azaspiro[3.3] Hept-6-amine, 1-azaspiro[3.3] Hept-6-amine, 6-azaspiro[3.4] Oct-2-amine, 5-azaspiro[3.4] Oct-2 -amine, 6-azaspiro[3.4]oct-1-amine, 5-azaspiro[3.4]oct-1-amine, 5-oxa-2-azaspiro[3.4]oct-7-amine, 7-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide, 5-oxa-2-azaspiro[3.4]oct-8-amine, 8-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide and similar groups.

[0369] The term "alkylamino" refers to a group having a structure such as NH (C1-C6 alkyl), where C1-C6 alkyl is as previously defined.

[0370] The term "dialkylamino" refers to a group having a structure such as N(C1-C6 alkyl)2, where C1-C6 alkyl is as previously defined.

[0371] According to this application, any one of the aryl, substituted aryl, heteroaryl, and substituted heteroaryl groups described herein can be any aromatic group. The aromatic group can be substituted or unsubstituted.

[0372] As described herein, the compounds of this application may optionally be substituted with one or more substituents, as generally stated above, or as exemplified by the specific class, subclass, and type of this application. It will be understood that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” Generally, the term “substituted,” whether or not preceded by the term “optionally,” refers to the replacement of a hydrogen group in a given structure with a group containing the specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substituted position of that group, and when more than one position in any given structure may be substituted by more than one substituent selected from the specified group, the substituent 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 heteroaryl,” “optionally substituted heterocycloalkyl,” and any other optionally substituted group refer to a group that is substituted or unsubstituted by independently replacing one, two, three, or more hydrogen atoms thereon with substituents including, but not limited to, the following: -F, -Cl, -Br, -I, -OH, protected hydroxyl, -NO2, -CN, -NH2, protected amino, -NH-Cl-C 12 -alkyl, -NH-C2-C 12 -Alkenyl, -NH-C2-C 12 -alkynyl group, -NH-C3-C 12 -cyclic hydrocarbon group, -NH-aryl group, -NH-heteroaryl group, -NH-heterocyclic hydrocarbon group, -dialkylamino group, -diarylamino group, -diheteroarylamino group, -O-Cl-C 12 -alkyl, -O-C2-C 12 -Alkenyl, -O-C2-C 12 -alkynyl group, -O-C3-C 12 -cyclic hydrocarbon group, -O-aryl group, -O-heteroaryl group, -O-heterocyclic hydrocarbon group, -C(O)-C1-C 12 -alkyl, -C(O)-C2-C 12 -Alkenyl, -C(O)-C2-C 12 -alkynyl group, -C(O)-C3-C 12-Cycloalkyl group, -C(O)-aryl group, -C(O)-heteroaryl group, -C(O)-heterocyclic alkyl group, -CONH2 group, -CONH-C1-C 12 -alkyl, -CONH-C2-C 12 -Alkenyl, -CONH-C2-C 12 -alkynyl group, -CONH-C3-C 12 -cyclic hydrocarbon group, -CONH-aryl group, -CONH-heteroaryl group, -CONH-heterocyclic hydrocarbon group, -OCO2-C1-C 12 -alkyl, -OCO2-C2-C 12 -Alkenyl, -OCO2-C2-C 12 -alkynyl group, -OCO2-C3-C 12 -cyclic hydrocarbon group, -OCO2-aryl group, -OCO2-heteroaryl group, -OCO2-heterocyclic hydrocarbon group, -OCONH2 group, -OCONH-C1-C 12 -alkyl, -OCONH-C2-C 12 -Alkenyl, -OCONH-C2-C 12 -Alkyne group, -OCONH-C3-C 12 -cyclic hydrocarbon group, -OCONH-aryl group, -OCONH-heteroaryl group, -OCONH-heterocyclic hydrocarbon group, -NHC(O)-C1-C 12 -alkyl, -NHC(O)-C2-C 12 -Alkenyl, -NHC(O)-C2-C 12 -Alynyl group, -NHC(O)-C3-C 12 -cyclic hydrocarbon group, -NHC(O)-aryl group, -NHC(O)-heteroaryl group, -NHC(O)-heterocyclic hydrocarbon group, -NHCO2-C1-C 12 -alkyl, -NHCO2-C2-C 12 -Alkenyl, -NHCO2-C2-C 12 -Alkyne group, -NHCO2-C3-C 12 -cyclic hydrocarbon group, -NHCO2-aryl group, -NHCO2-heteroaryl group, -NHCO2-heterocyclic hydrocarbon group, -NHC(O)NH2 group, -NHC(O)NH-C1-C 12 -alkyl, -NHC(O)NH-C2-C 12 -Alkenyl, -NHC(O)NH-C2-C 12 -Alynyl group, -NHC(O)NH-C3-C 12 -cyclic hydrocarbon group, -NHC(O)NH-aryl group, -NHC(O)NH-heteroaryl group, -NHC(O)NH-heterocyclic hydrocarbon group, -NHC(S)NH2 group, -NHC(S)NH-C1-C 12-alkyl, -NHC(S)NH-C2-C 12 -Alkenyl, -NHC(S)NH-C2-C 12 -Alynyl group, -NHC(S)NH-C3-C 12 -cyclic hydrocarbon group, -NHC(S)NH-aryl group, -NHC(S)NH-heteroaryl group, -NHC(S)NH-heterocyclic hydrocarbon group, -NHC(NH)NH2 group, -NHC(NH)NH-C1-C 12 -alkyl, -NHC(NH)NH-C2-C 12 -Alkenyl, -NHC(NH)NH-C2-C 12 -Alkyne group, -NHC(NH)NH-C3-C 12 -cyclic hydrocarbon group, -NHC(NH)NH-aryl group, -NHC(NH)NH-heteroaryl group, -NHC(NH)NH-heterocyclic hydrocarbon group, -NHC(NH)-C1-C 12 -alkyl, -NHC(NH)-C2-C 12 -Alkenyl, -NHC(NH)-C2-C 12 -Alynyl group, -NHC(NH)-C3-C 12 -cyclic hydrocarbon group, -NHC(NH)-aryl group, -NHC(NH)-heteroaryl group, -NHC(NH)-heterocyclic hydrocarbon group, -C(NH)NH-C1-C 12 -alkyl group, -C(NH)NH-C2-C 12 -Alkenyl, -C(NH)NH-C2-C 12 -Alynyl group, C(NH)NH-C3-C 12 -cyclic hydrocarbon group, -C(NH)NH-aryl group, -C(NH)NH-heteroaryl group, -C(NH)NH-heterocyclic hydrocarbon group, -S(O)-C1-C 12 -alkyl, -S(O)-C2-C 12 -Alkenyl, -S(O)-C2-C 12 -alkynyl group, -S(O)-C3-C 12 -cyclic hydrocarbon group, -S(O)-aryl group, -S(O)-heteroaryl group, -S(O)-heterocyclic hydrocarbon group -SO2NH2, -SO2NH-C1-C 12 -alkyl, -SO2NH-C2-C 12 -Alkenyl, -SO2NH-C2-C 12 -alkynyl group, -SO2NH-C3-C 12 -cyclic hydrocarbon group, -SO2NH-aryl group, -SO2NH-heteroaryl group, -SO2NH-heterocyclic hydrocarbon group, -NHSO2-C1-C 12 -alkyl, -NHSO2-C2-C 12-Alkenyl, -NHSO2-C2-C 12 -Alkyne group, -NHSO2-C3-C 12 -cyclic hydrocarbon group, -NHSO2-aryl group, -NHSO2-heteroaryl group, -NHSO2-heterocyclic hydrocarbon group, -CH2NH2 group, -CH2SO2CH3 group, -aryl group, -arylalkyl group, -heteroaryl group, -heteroarylalkyl group, -heterocyclic hydrocarbon group, -C3-C 12 -cyclic hydrocarbon group, polyalkoxyalkyl group, polyalkoxy group, -methoxymethoxy group, -methoxyethoxy group, -SH group, -S-Cl-C group 12 -alkyl, -S-C2-C 12 -Alkenyl, -S-C2-C 12 -alkynyl group, -S-C3-C 12 -cyclic hydrocarbon group, -S-aryl group, -S-heteroaryl group, -S-heterocyclic hydrocarbon group or methylthiomethyl group.

[0373] As used in this application, the term "carrier" encompasses carriers, excipients, and diluents, and means a material, composition, or medium relating to carrying or delivering a pharmaceutical agent from one organ or part of a subject's body to another organ or part of the subject's body, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials.

[0374] The compounds of this application can form salts, which are also within the scope of this application. Unless otherwise indicated, references to compounds of formula herein should be understood to include references to their salts.

[0375] Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetates, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium salts, calcium edetate, camsylate, carbonates, chlorides, citrates, clavulariate, dihydrochlorides, edetate, ethanedisulfonate, etolate, ethanesulfonate, fumarate, fumarate, gluconate, gluconate, glutamate, glycolyllarsanilate, hexafluorophosphate, hexylresorcinate, hyaluronic acid, hydrobromide, etc. Hydrochloride, hydroxynaphthylcarboxylate, iodide, hydroxyethyl sulfonate, lactate, lacturonate, laurate, magnesium salt, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalene sulfonate, nitrate, N-methylglucosamine ammonium salt, 3-hydroxy-2-naphthylcarboxylate, oleate, oxalate, palmitate, papoate (1,1-methylene-bis-2-hydroxy-3-naphthylcarboxylate, einbonate), pantothenate, phosphate / bisphosphonate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, toluenesulfonate, triethyliodide, and valerate.

[0376] The compounds of this application, such as pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers of the compounds, may exist in a solvated or non-solventized form with other solvent molecules.

[0377] "Solvate" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds or salts have a tendency to trap a fixed molar ratio of solvent molecules in their crystalline solid state, thus forming a solvate. If the solvent is water, the formed solvate is a hydrate, and if the solvent is an alcohol, the formed solvate is an alcohol. Hydrates are formed by the combination of one or more water molecules with one molecule of the substance, where the water retains its molecular state as H₂O.

[0378] All stereoisomers (e.g., geometric isomers, optical isomers, and similar isomers) of the compounds herein (including salts, solvates, esters, and prodrugs of the compounds, as well as salts, solvates, and esters of prodrugs), such as those that may exist due to asymmetric carbons on multiple substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotational isomeric forms, trans-blocked isomers, and diastereomeric forms, are contemplated within the scope of this application, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). For example, if a compound of formula (I) incorporates a double bond or a fused ring, both the cis and trans forms, as well as mixtures thereof, are included within the scope of this application. Individual stereoisomers of the compounds of this application may, for example, be substantially free of other isomers, or may, for example, be racemic or mixed with all other stereoisomers or other selected stereoisomers. The chiral center of this application may have an S-configuration or an R-configuration as defined by IUPAC 1974 Recommendations. The terms “salt,” “solvent,” “ester,” “prodrug,” and similar terms are intended equally to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemates, or prodrugs of the compounds of this invention.

[0379] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. Structural differences may lie in their configuration (geometric isomers) or ability to rotate the plane of polarization (stereoisomers). Regarding stereoisomers, the compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, or as individual enantiomers or diastereomers.

[0380] In this specification, the structural formulas of compounds are used in some cases to represent certain isomers for convenience, but this application includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers and similar isomers.

[0381] "Isomericness" refers to compounds that have the same molecular formula but differ in the order of their atomic bonding or in the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomers with opposite chirality is called a "racemic mixture."

[0382] The compounds of this application may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of this application, as well as mixtures thereof, including racemic mixtures, constitute a part of this application. Furthermore, this application includes all geometrical and positional isomers. For example, if a compound of this application incorporates a double bond or a fused ring, both the cis and trans forms, as well as mixtures thereof, are included within the scope of this application. Each compound disclosed herein includes all enantiomers conforming to the general structure of the compound. Compounds may be in racemic form or enantiomerically pure form, or any other stereochemical form. Measurement results may reflect data collected for the racemic form, the enantiomerically pure form, or any other stereochemical form.

[0383] A carbon atom bonded to four different substituents is called a "chiral center".

[0384] "Chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center may exist as individual diastereomers or as mixtures of diastereomers (referred to as "diastereomer mixtures"). When a chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are arranged according to the sequence rules of Cahn, Ingold, and Prelog. (Cahn et al., Angew. Chem. Inter. ed. 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).

[0385] "Geometric isomers" refers to diastereomers whose existence is attributable to hindered rotation around the double bond. These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, which indicate whether the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rule.

[0386] In another embodiment of this application, the compounds of this application (e.g., any compound of any formula disclosed herein or any single compound) are enantiomers. In some embodiments, the compound is an (S)-enantiomer. In other embodiments, the compound is an (R)-enantiomer. In still other embodiments, the compounds of this application (e.g., any compound of any formula disclosed herein or any single compound) may be (+) or (-) enantiomers. The compound may contain more than one stereocenter.

[0387] In another embodiment of this application, the compound of this application (e.g., any compound of any formula disclosed herein or any single compound) is a diastereomer. In some embodiments, the compound is a syn diastereomer. In other embodiments, the compound is an antidiastereomer.

[0388] A mixture of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or a Mosher acid chloride), converting the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to their corresponding pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0389] It is also possible that the compounds of this application may exist in different tautomer forms, and all such forms are included within the scope of this application. Furthermore, for example, all keto-enol forms and imine-enamine forms of the compounds are included in this application.

[0390] A tautomer is one of two or more structural isomers that exist in equilibrium and readily transform from one isomer to another. This transformation results in the migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer groups in solution. In solid form, one tautomer is usually dominant. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The precise ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerization is called tautomerism.

[0391] Of the many possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, simultaneous transfer of electrons and hydrogen atoms occurs. Ring-chain tautomerism arises from the reaction of an aldehyde group (-CHO) in a sugar molecule with one of a hydroxyl group (-OH) in the same molecule to give it its cyclic (ring) form, as seen in glucose.

[0392] Common tautomer pairs are: keto-enol, amide-nitrile, lactam-lactamimide, amide-imine tautomerism in heterocycles (e.g., in nucleobases such as guanine, thymine, and cytosine), amine-enamine, and enamine-imide.

[0393] This application relates to compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof capable of modulating (e.g., activating or stimulating) the GLP-1 receptor, which may be used to treat diseases and disorders associated with the regulation of the GLP-1 receptor. This application also relates to compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, which may be used to modulate (e.g., activate or stimulate) 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.

[0394] In some embodiments, this application provides compounds of this application (e.g., compounds of any form disclosed herein or any single compound) wherein, compared to one or more known GLP-1 receptor ligands (e.g., incretins or small molecule GLP-1 receptor agonists), the compounds have advantageous properties such as increased potency, improved oral bioavailability, or desirable pharmacodynamic / pharmacokinetic profile.

[0395] The efficacy of agonists / activators / stimulants can be measured by EC. 50 The value is determined. For example, under broadly similar conditions, a lower EC value is determined. 50 Compounds with higher EC values ​​relative to those with higher EC values 50 The compound with the highest value is a more effective agonist / activator / stimulant.

[0396] The compounds of this application can be converted into N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (m-CPBA) and / or hydrogen peroxide) to provide other compounds of this application. Therefore, all nitrogen-containing compounds shown and claimed, where valence and structure permit, are considered to include the compounds as shown and their N-oxide derivatives (which may be specified as N→O or N…). + -O - Both. Furthermore, in other cases, the nitrogen in the compounds of this application can be converted to an N-hydroxy compound or an N-alkoxy compound. For example, an N-hydroxy compound can be prepared by oxidizing the parent amine via an oxidizing agent such as m-CPBA. All nitrogen-containing compounds shown and claimed are also considered to cover both the compounds shown and their N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, where R is a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3-14 membered carbide ring, or 3-14 membered heterocyclic ring) derivatives, where valence and structure permit.

[0397] As used in this application, the term "prodrug" means a compound that can be converted into the disclosed compound in vivo by metabolic means (e.g., by hydrolysis).

[0398] Because prodrugs are known to enhance many desirable qualities of a drug (e.g., solubility, bioavailability, manufacturing, etc.), the compounds of this application (e.g., any compound of any kind disclosed herein or any single compound) or their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers can be delivered in prodrug form. Therefore, this application is intended to cover prodrugs of the compounds of this application (e.g., any compound of any kind disclosed herein or any single compound) or their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers, methods of delivery thereof, and compositions comprising them. "Prodrug" is intended to include any covalently bonded carrier that, when administered to a mammalian subject, releases the active parent drug of this application in vivo. Prodrugs are prepared by modifying functional groups present in the compound in such a manner that the modification is cleaved into the parent compound during conventional manipulation or in vivo. Prodrugs include compounds of this application in which a hydroxyl or amino group is bonded to any group, wherein when a prodrug of this application is administered to a mammalian subject, any group cleaves to form a free hydroxyl group or a free amino group, respectively. Examples of prodrugs include, but are not limited to, compounds of each formula described herein or their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers or tautomers, acetate / salt derivatives, formate / salt derivatives and benzoate / salt derivatives of alcohol and amine functional groups.

[0399] The terms "crystalline polymorph," "polymorph," or "crystalline form" refer to crystalline structures in which a compound (or its salts or solvates) can crystallize in different crystalline packing arrangements, all with the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to become dominant.

[0400] As used herein, the term "analogue" refers to a compound that is structurally similar to another compound but has a slightly different composition (e.g., an atom is replaced by an atom of a different element, or a specific functional group is present, or a functional group is replaced by another functional group). Therefore, an analogue is a compound that is functionally similar to or equivalent to a reference compound, but structurally dissimilar to or not equivalent to a reference compound in terms of origin.

[0401] This application also includes isotopically labeled compounds that are identical to those listed in each formula described herein, but in fact, one or more atoms are replaced by atoms having atomic masses or mass numbers different from those most commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, and fluorine, such as... 3 H, 11 C 14 C 2 H and 18 F.

[0402] Compounds of this application containing the isotopes mentioned above and / or other isotopes of other atoms (e.g., compounds of any formula disclosed herein or any single compound) or their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers are within the scope of this application. Isotope-labeled compounds of this application, such as radioisotopes such as… 3 H, 14 Those C values ​​incorporated into this group can be used for drug and / or substrate tissue distribution assays. Tritiumization is... 3 H isotopes and carbon-14, i.e. 14 C isotopes are useful because they are easy to prepare and detectable. 11 C isotopes and 18 The fluorine isotope is useful in PET (positron emission tomography). PET is also useful in brain imaging. Furthermore, heavier isotopes such as deuterium are also used. 2 H substitution can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and is therefore preferred in some cases. The isotopically labeled compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents by implementing the procedures disclosed in the schemes described herein and / or the examples. In one embodiment, the compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers are not isotopically labeled.

[0403] As used in this application, the terms “administer,” “administering,” or “administration” mean the direct administration of the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound to a subject, or the administration of a prodrug, derivative, or analog of the compound or a pharmaceutically acceptable salt or composition of the compound to a subject, which may form an equivalent amount of the active compound in the subject’s body.

[0404] "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0405] When used in combination with a compound or pharmaceutical composition, an "effective amount" or "therapeutic effective amount" is an amount that is effective in treating or preventing a disease in a subject as described herein.

[0406] The term "treatment" in relation to a subject refers to the improvement of at least one symptom of the subject's disorder. Treatment includes curing, improving, or at least partially alleviating the disorder.

[0407] The compounds of this application, or their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers, may also be used for the prevention of diseases, conditions, or disorders. As used herein, “preventing” or “prevent” describes reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.

[0408] Unless otherwise indicated, the term “disorder” is used in this application to mean the term disease, condition or ailment, and is used interchangeably with the term disease, condition or ailment.

[0409] As used herein, the term "GLP-1 receptor-mediated" disease or disorder means any disease or other harmful condition in which a GLP-1 receptor or its mutants are known to play a role. Therefore, another embodiment of this application relates to treating one or more diseases in which a GLP-1 receptor or its mutants are known to play a role, or to reducing the severity of said one or more diseases. Specifically, this application relates to methods of treating or reducing the severity of diseases or conditions as described herein, said methods comprising administering to a subject with appropriate need a compound of this application (e.g., a compound of any form disclosed herein or any single compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer, or composition according to this application thereof.

[0410] Methods for preparing compounds

[0411] The compounds of this application can be prepared by a variety of methods, including standard chemistry. Suitable synthetic routes are described in the schemes given below.

[0412] The compounds of this application (e.g., any compound of any formula disclosed herein or any single compound) can be prepared by methods known in the field of organic synthesis, as illustrated in part by the synthetic schemes described below. In the schemes described below, it will be readily understood that protecting groups of sensitive or reactive groups are employed as necessary, based on general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (TW Greene and PGM Uts, "Protective Groups in Organic Synthesis", 3rd ed., Wiley, New York 1999). These groups are removed at convenient stages of compound synthesis using methods readily apparent to those skilled in the art. The selection of processes, reaction conditions, and their order of execution should be consistent with the preparation of the compounds of this application.

[0413] Those skilled in the art will recognize the presence of a stereochemical center in the compounds of this application (e.g., compounds of any formula disclosed herein or any single compound). Therefore, this application includes two possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but also individual enantiomers and / or diastereomers. When a compound is required as a single enantiomer or diastereomer, it can be obtained by stereooriented synthesis or by the resolution of the final product or any convenient intermediate. The resolution of the final product, intermediate, or starting material can be influenced by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Leel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0414] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0415] The compounds of this application can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of this application can be synthesized using the methods described below in conjunction with synthetic methods known in the field of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The compounds of this application (e.g., compounds of any formula disclosed herein or any individual compound) can be synthesized by following the steps outlined in the examples, schemes, procedures and / or syntheses described herein (e.g., examples). Starting materials are commercially available or prepared by known procedures in reported literature or as described.

[0416] The mixture of enantiomers, diastereomers, and cis / trans isomers produced by the process described above can be separated into their individual components by chiral salt techniques, chromatography using normal-phase, reverse-phase, or chiral columns, depending on the nature of the separation.

[0417] Analytical methods, materials and instruments

[0418] 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 given in ppm (δ), and the coupling constant J is reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC / MS) was performed using a SHIMADZU LCMS-2020EV or an Agilent 1260-6125B LCMS. Purity and low-resolution mass spectrometry data were measured using an Agilent 1260-6125B LCMS system (with a diode array detector and an Agilent G6125BA mass spectrometer) or a Waters Acquity UPLC system (with a diode array detector and a Waters 3100 mass detector). Purity was characterized by UV wavelengths at 214 nm, 220 nm, 254 nm, and ESI. Column: Poroshell 120EC-C18 2.7μm 4.6×100mm; flow rate 0.8mL / min; solvent A (100 / 0.1 water / formic acid), solvent B (100 acetonitrile); gradient: hold 5% B for 0.3min, 5%-95% B from 0.3min to 2min, hold 95% B for 4.8min, 95%-5% B from 4.8min to 5.4min, then hold 5% B for 6.5min. Alternatively, column: Acquity UPLC BEH C18 1.7μm 2.1×50mm; flow rate 0.5mL / min; solvent A (water containing 0.1% formic acid), solvent B (acetonitrile); gradient: hold 5% B for 0.2min, 5%-95% B from 0.2min to 2.0min, hold 95% B for 3.1min, then hold 5% B for 3.5min.

[0419] The abbreviations used in the following embodiments and elsewhere in this document are:

[0420] DIEA N,N-Diisopropylethylamine

[0421] DMF N,N-dimethylformamide

[0422] DMA N,N-dimethylacetamide

[0423] DMSO (dimethyl sulfoxide)

[0424] DEAD Diethyl azodicarbonate

[0425] EA (ethyl acetate)

[0426] IPA isopropanol

[0427] IPE diisopropyl ether

[0428] MeCN Acetonitrile

[0429] THF Tetrahydrofuran

[0430] m-CPBA 3-chloroperoxybenzoic acid

[0431] DCM dichloromethane

[0432] LC / MS (Liquid Chromatography-Mass Spectrometry)

[0433] MeOH (methanol)

[0434] MS mass spectrometry

[0435] PE petroleum ether

[0436] NMP N-methylpyrrolidone

[0437] NMR (Nuclear Magnetic Resonance)

[0438] ppm (parts per million)

[0439] TEA Triethylamine

[0440] Biological assay

[0441] The biological activity of the compounds of this application can be evaluated using methods and assays known in the art. Exemplary methods, such as GLP1R cAMP assay and human GLP-1 activity assay, are described in the examples.

[0442] Compared to known small-molecule GLP-1 receptor agonists, the compounds of this application also possess favorable pharmacokinetic properties and / or activity profiles against hepatic drug transporters (e.g., OATP1B1, OATP1B3). These properties can be evaluated using methods and assays available in the art, such as those described and / or illustrated herein.

[0443] Methods using compounds

[0444] The compounds of this application can be used to regulate (e.g., activate or stimulate) GLP-1 receptors. Therefore, the compounds of this application can be used to treat 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 regulation 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 nephropathy.

[0445] "Diabetes" is a condition or disease in which the metabolism of glucose production and use becomes inadequate due to the body's inability to maintain adequate blood glucose levels, and it encompasses insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes).

[0446] "Dementia" includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia.

[0447] "Diabetic complications" are those resulting from diabetes or hyperglycemia, including ketoacidosis, infectious diseases (e.g., skin infections, soft tissue infections, biliary tract infections, respiratory infections, urinary tract infections), microvascular complications (e.g., nephropathy, retinopathy), neuropathy (e.g., sensory nerve disorders, motor nerve disorders, autonomic nerve disorders), and gangrene. The major diabetic complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0448] Liver diseases (e.g., liver diseases related to GLP-1 receptors) include, but are not limited to, NASH, NAFLD, liver inflammation, liver fibrosis, cirrhosis, liver autoimmune diseases, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, and alcoholic liver disease.

[0449] Another aspect of this application relates to a method for treating, preventing, inhibiting, or eliminating a disease or disorder associated with the regulation of the GLP-1 receptor (e.g., activation or stimulation of the GLP-1 receptor). The method comprises administering to a subject requiring treatment for a disease or disorder associated with the regulation of the GLP-1 receptor an effective amount of a compound of this application (e.g., any compound of any formula disclosed herein or any single compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition of a compound of this application (e.g., any compound of any formula disclosed herein or any single compound). In one embodiment, the GLP-1 receptor-mediated disorder is the 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.

[0450] Another aspect of this application relates to a method of modulating a GLP-1 receptor, the method comprising administering to a subject with a corresponding need a therapeutically effective amount of a compound of this application (e.g., a compound of any form disclosed herein or any single compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition of a compound of this application (e.g., a compound of any form disclosed herein or any single compound). In one embodiment, modulating the GLP-1 receptor is activating 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.

[0451] Another aspect of this application relates to compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, for use in methods of treating GLP-1 receptor-mediated diseases or disorders. In one embodiment, the GLP-1 receptor-mediated disorder is the 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.

[0452] In another aspect, this application relates to pharmaceutical compositions of compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, for use in methods of treating GLP-1 receptor-mediated diseases or disorders. In one embodiment, the GLP-1 receptor-mediated disorder is the 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.

[0453] Another aspect of this application relates to compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof for use in modulating a GLP-1 receptor. In one embodiment, modulating the GLP-1 receptor is 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.

[0454] In another aspect, this application relates to pharmaceutical compositions of compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers 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.

[0455] Another aspect of this application relates to the use of compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof in the manufacture of a medicament for treating GLP-1 receptor-mediated diseases or disorders. In one embodiment, the GLP-1 receptor-mediated disorder is the 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.

[0456] In another aspect, this application relates to the use of compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof in the manufacture of a medicament for treating GLP-1 receptor-mediated diseases or disorders. In one embodiment, the GLP-1 receptor-mediated disorder is the 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.

[0457] Another aspect of this application relates to the use of compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers 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.

[0458] In another aspect, this application relates to the use of compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) or pharmaceutical compositions thereof, as pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers, in the manufacture of a medicament for modulating the GLP-1 receptor. In one embodiment, modulating the GLP-1 receptor is 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.

[0459] The compounds disclosed in this application can be administered in an effective amount for treating or preventing disorders and / or preventing the development of disorders in subjects.

[0460] The compounds of this application can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (drug combinations) or treatment modalities such as non-pharmacological therapies. For example, synergistic effects may occur with other antiproliferative, anticancer, immunomodulatory, or anti-inflammatory substances. In some embodiments, the compounds of this application (e.g., any compound of any form disclosed herein or any single compound) are administered in combination with additional therapeutic agents selected from: anti-inflammatory agents, immunomodulatory agents, chemotherapeutic agents, agents for treating cardiovascular diseases, agents for treating liver diseases, agents for treating lung diseases, agents for treating kidney diseases, agents for treating eye diseases, agents for treating skin diseases, antiviral agents, agents for treating blood disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders. When the compounds of this application are administered in combination with other therapies, the dosage of the co-administered compounds will naturally vary depending on the type of co-drug used, the specific drug used, the condition being treated, etc.

[0461] Combination therapy includes the administration of subject compounds in further combination with other bioactive ingredients (such as, but not limited to, anti-inflammatory agents, immunomodulators, chemotherapeutic agents, agents for treating cardiovascular diseases, agents for treating liver diseases, antiviral agents, agents for treating blood disorders, agents for treating diabetes, agents for treating immunodeficiency disorders, and agents for treating pain) and non-pharmacological therapies (such as, but not limited to, surgery or radiation therapy). For example, the compounds of this application may be used in combination with other pharmaceutically active compounds, preferably compounds capable of enhancing the effects of the compounds of this application. The compounds of this application may be administered simultaneously (as a single product or a separate product) or sequentially with other pharmaceutical therapies or modes of treatment. Generally, combination therapy envisions the administration of two or more drugs during a single cycle or course of therapy.

[0462] Pharmaceutical Composition

[0463] This application also provides pharmaceutical compositions comprising a compound of the present application (e.g., a compound of any of the forms disclosed herein or any single compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, in combination with at least one pharmaceutically acceptable excipient or carrier.

[0464] A “pharmaceutical composition” is a formulation comprising the compound of this application in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in a bulk dosage form or in a unit dosage form. A unit dosage form is any of a variety of forms, including, for example, capsules, IV bags, tablets, a single pump on an aerosol inhaler, or vials. 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 dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that it may sometimes be necessary to routinely vary the dosage according to the patient’s age and condition. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, percutaneous, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, sublingual, sublingual, intrapleural, intrathecal, intranasal, and similar routes. Dosage forms for topical or transdermal application of the compounds used in this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

[0465] As used herein, the phrase “pharmaceutically acceptable” refers to compounds, materials, compositions, carriers, and / or dosage forms that are suitable, to the extent of reasonable medical judgment, for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0466] "Pharmaceutical-acceptable excipient" means an excipient useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes excipients acceptable for veterinary use and human pharmaceutical use. As used in this specification and claims, "pharmaceutical-acceptable excipient" includes one or more such excipients.

[0467] The pharmaceutical compositions of this application are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral administration (e.g., intravenous, intradermal, subcutaneous), oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents, such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and agents for adjusting tension, such as sodium chloride or dextrose. The pH may be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral products may be encapsulated in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0468] The compounds or pharmaceutical compositions of this application may be administered to a subject using many well-known methods currently used for chemotherapy. The selected dose should be sufficient to constitute an effective treatment, but not high enough to cause unacceptable side effects. The patient's disease condition and health status should preferably be closely monitored during treatment and for a reasonable period after treatment.

[0469] As used herein, the term "therapeutic effective amount" refers to the amount of a medicine used to treat, alleviate, or prevent an identified disease or condition, or to produce a detectable therapeutic or moderating effect. This effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the choice of the therapeutic agent or combination of therapeutic agents to be administered. The therapeutic effective amount for a given situation can be determined through routine experimentation within the skill and judgment of a clinician. In one embodiment, the disease or disorder is the one described herein.

[0470] For any compound, the therapeutically effective amount can initially be estimated in cell culture assays (e.g., cell culture assays of proliferative cells) or in animal models (typically rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine the dose and route of administration that is useful for human use. Therapeutic / prophylactic efficacy and toxicity can be determined in cell cultures or laboratory animals using standard pharmaceutical procedures, such as ED. 50 (The dose that is effective in 50% of the population) and LD50 50 (The dose that is 50% lethal to the population). The dose ratio between toxic effects and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD50. 50 / ED 50 Pharmaceutical compositions exhibiting a high therapeutic index are preferred. The dosage can vary within this range, depending on the dosage form used, patient sensitivity, and route of administration.

[0471] Adjust the dosage and administration to provide sufficient levels of active agent or maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's general health, the subject's age, weight and sex, diet, timing and frequency of administration, drug combination, sensitivity to response, and tolerance / response to the therapy. Long-acting drug compositions may be administered every 3 to 4 days, weekly, or every two weeks, depending on the half-life and clearance of the specific formulation.

[0472] The pharmaceutical compositions comprising the active compound (i.e., the compounds of this application (e.g., any compound of any formula disclosed herein or any single compound)) can be manufactured in a manner commonly known, such as by means of conventional mixing processes, dissolving processes, granulation processes, dragee-making processes, levigating processes, emulsification processes, encapsulation processes, embedding processes, or lyophilization processes. The pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or adjuvants, which facilitate the processing of the active compound into an article suitable for pharmaceutical use. Of course, the appropriate formulation depends on the chosen route of administration.

[0473] Suitable pharmaceutical compositions for injectable applications include sterile aqueous solutions (in the water-soluble case) or dispersions, as well as sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, Cremophor EL... TM(BASF, Parsippany, NJ) or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be a fluid sufficient for injection. It must be stable under manufacturing and storage conditions and must be preserved against contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol and the like), and suitable mixtures thereof. Suitable flowability can be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. Microbial inhibition can be achieved by a variety of antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferred to include isotonic agents in the composition, such as sugars, polyols such as mannitol, sorbitol, and sodium chloride. Extended absorption of the injectable composition can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0474] Sterile injectable solutions can be prepared by incorporating the active compound in the desired amount into a suitable solvent (which, if desired, contains one or a combination of the components listed above), followed by filtration and sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile medium containing an alkaline dispersion medium and other desired components from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, the preparation method is vacuum drying and freeze-drying, which produce a powder from its previously sterile filtered solution containing the active ingredient plus any other desired components.

[0475] Oral compositions typically contain an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be incorporated together with excipients and administered in tablet, lozenge, or capsule form. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is administered orally and is swished and spat out or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginate, Primogel, or corn starch; lubricants such as magnesium stearate or sterote; flow aids such as colloidal silica; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring.

[0476] For administration by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser that contains a suitable propellant, such as a gas like carbon dioxide, or a sprayer.

[0477] Systemic application can also be achieved via mucosal or transdermal means. For mucosal or transdermal application, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives used for mucosal application. Mucosal application can be achieved by using nasal sprays or suppositories. For transdermal application, as is generally known in the art, the active compound is formulated as an ointment, cream, gel, or lotion.

[0478] The active compound can be prepared with a pharmaceutically acceptable carrier that protects the compound from rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art. The materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting 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. Patent No. 4,522,811.

[0479] It is particularly advantageous to formulate oral or parenteral compositions in a dosage unit format that is easy to administer and has a uniform dosage. As used herein, a dosage unit format refers to a physically discrete unit suitable as a unit dose for use in a subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect, along with the required drug carrier. The specifications of the dosage unit format used in this application are determined by and directly depend on the unique properties of the active compound and the specific therapeutic effect to be achieved.

[0480] In therapeutic applications, the dosage of the pharmaceutical composition used according to this application varies depending on the agent, the recipient patient's age, weight, and clinical condition, the experience and judgment of the clinician or practitioner administering the therapy, and other factors influencing the chosen dosage. Dosages can range from about 0.01 mg / kg daily to about 5000 mg / kg daily. An effective amount of the agent is the amount that provides an objectively identifiable improvement as indicated by a clinician or other qualified observer. As used herein, the term "dosage-effective manner" refers to the amount of active compound that produces the desired biological effect in a subject or cells.

[0481] The pharmaceutical composition may be included in a container, package, or dispenser along with the instructions for use.

[0482] As used herein, "pharmaceutically acceptable salt" refers to a derivative of the compound of this application, wherein the parent compound is modified by preparing its acid salt or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali metal or organic salts of acidic residues such as carboxylic acids, and similar salts. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids, wherein the inorganic and organic acids are selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edemanic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylisophthalic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, and naphthylsulfonic acid. The following are listed as examples of amino acids: nitric acid, oxalic acid, dihydroxynaphthyl acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, basic acetic acid, succinic acid, aminosulfonic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and common amino acids such as glycine, alanine, phenylalanine, and arginine.

[0483] Other examples of pharmaceutically acceptable salts include salts of 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-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and similar acids. This application also covers salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, and the like.

[0484] It should be understood that all references to pharmaceutically acceptable salts include the same salt in its solvation form (solvent) or crystalline form (polymorph) as defined herein.

[0485] The compounds of this application can also be prepared as esters, such as pharmaceutically acceptable esters. For example, the carboxylic acid functional group in the compound can be converted into its corresponding ester, such as methyl ester, ethyl ester, or other esters. Furthermore, the alcohol group in the compound can be converted into its corresponding ester, such as acetate, propionate, or other esters.

[0486] The compounds of this application can also be prepared as prodrugs, such as pharmaceutically acceptable prodrugs. The terms "pro-drug" and "prodrug" are used interchangeably herein and refer to any compound that releases an active parent drug substance in vivo. Since prodrugs are known to enhance many desirable qualities of a drug substance (e.g., solubility, bioavailability, manufacturing, etc.), the compounds of this application can be delivered in prodrug form. Therefore, this application is intended to cover prodrugs of currently claimed compounds, methods of delivery thereof, and compositions comprising thereof. "Prodrug" is intended to include any covalently bonded carrier that, when administered to a subject, releases the active parent drug substance of this application in vivo. The prodrugs of this application are prepared by modifying functional groups present in the compound in such a manner that the modification is cleaved into the parent compound during conventional manipulation or in vivo. The prodrug includes the compounds of this application, wherein a hydroxyl group, an amino group, a thiol group, a carboxyl group, or a carbonyl group is bonded to any group that can be cleaved in vivo to form a free hydroxyl group, a free amino group, a free thiol group, a free carboxyl group, or a free carbonyl group, respectively.

[0487] Examples of prodrugs include, but are not limited to, esters (e.g., acetate derivatives, dialkylaminoacetate derivatives, formate derivatives, phosphate derivatives, sulfate derivatives, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of the compounds of this application, esters (e.g., ethyl esters, morpholinoethanol esters) of the carboxyl functional group, N-acyl derivatives (e.g., N-acetyl), N-Mannich bases, Schiff bases, and enamine ketones of the amino functional group, oximes, acetals, ketals, and enol esters of the ketone and aldehyde functional groups, and analogues, see Bundegaard, H., Design of Prodrugs, pp. 1-92, Elsevier, New York-Oxford (1985).

[0488] The compound or its pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs, or derivatives may be administered orally, nasally, transdermally, pulmonaryly, by inhalation, sublingually, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally. In one embodiment, the compound or its pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers may be administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0489] The dosage regimen for this compound is selected based on a number of factors, including: patient type, species, age, weight, sex, and medical condition; severity of the condition to be treated; route of administration; patient's renal and hepatic function; and the specific compound used or its pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers. A general practitioner or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counteract, or halt the progression of the condition.

[0490] Techniques for formulating and administering the disclosed compounds of this application can be found in Remington: The Science and Practice of Pharmacy, 19th Edition, Mack Publishing Co., Easton, PA (1995). In embodiments, the compounds described herein, and their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers, are combined with pharmaceutically acceptable carriers or diluents in pharmaceutical articles. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds, or their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers, will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0491] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of this application will become apparent from various examples. The examples provided illustrate different components and methods useful in practicing this application. These examples do not limit the claimed application. Based on this application, those skilled in the art can identify and employ other components and methods that can be used in practicing this application. Example

[0492] This application is further illustrated by the following embodiments and synthetic schemes, which are not to be construed as limiting the scope or spirit of this application to the specific procedures described herein. It should be understood that the embodiments are provided to illustrate certain implementations and are not intended to limit the scope of this application. It should also be understood that various other implementations, modifications, and equivalents that may be conceived by those skilled in the art may be employed without departing from the spirit of this application and / or the scope of the appended claims.

[0493] Example 1: Synthesis of Intermediate 1

[0494]

[0495] Step 1: 1-B

[0496] At 10 °C, NBS (31.3 g, 0.176 mol) was added in portions to a solution of 1-A (20.0 g, 0.16 mol) in MeCN (500 mL). The resulting mixture was heated to 25 °C and stirred for 30 min. After cooling to 10 °C, saturated aqueous Na₂S₂O₃ (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 × 3). The combined organic layers were washed with water (100 mL × 3) and brine (100 mL × 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).

[0497] Step 2: 1-C

[0498] At 10°C, NaNO₂ (7.39 g, 107 mmol) was added to a solution of 1-B (19.2 g, 89.3 mmol) in AcOH (600 mL). The mixture was stirred at 25°C for 4 hours. After cooling to 10°C, aqueous NaOH (50% w / w) was slowly added to the reaction mixture until pH = 7–8. The aqueous layer was extracted with ethyl acetate (500 mL × 3). The combined organic layers were washed with water (100 mL × 3) and brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (9% dichloromethane in ethyl acetate) to provide 1-C (9.2 g, 45.47% yield). MS: m / z = 215 (M+1).

[0499] Step 3: Intermediate 1

[0500] At 0 °C, t-BuOK (4.7 g, 42.0 mmol) was added to a solution of 1-C (9.2 g, 42.0 mmol) in DMF (50 mL). The resulting mixture was stirred at 25 °C for 40 min. CH3I (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 NH4Cl (200 mL), and the aqueous layer was extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL × 3), water (100 mL × 3), and brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (25% petroleum ether in ethyl acetate) to provide intermediate 1 (5.5 g, 56.12% yield). 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 7.45 (dd, J = 8.8, 6.2Hz, 1H), 7.07 (d, J = 8.8Hz, 1H), 4.07 (s, 3H) ppm; MS: m / z = 229 (M+1).

[0501] Example 2: Synthesis of Intermediate 2

[0502]

[0503] Step 1: 2-B

[0504] At 0 °C, (Boc)₂O (86.13 g, 0.395 mol) dissolved in ethyl acetate (200 mL) was added dropwise to a stirred mixture of 2-A (28.23 g, 0.375 mol) in ethyl acetate (200 mL) for 30 min. Then, TMEDA (59.6 mL, 0.395 mol) in ethyl acetate (50 mL) was added dropwise at 0 °C. Then, MsCl (30.6 mL, 0.395 mol) was added dropwise at 0 °C for 46 min. The reaction mixture was stirred at 0 °C for 3.2 h. After filtration, the filtrate was concentrated to about half its volume and poured into hexane (800 mL), and stirred at 0 °C for 2 h. After filtration, 2-B (79.6 g, 83.9% yield) was obtained. 1 H NMR (400MHz, CDCl3) δ 4.58 (m, 1H), 4.22 (m, 1H), 3.98 (m, 1H), 3.04 (s, 3H), 1.44 (s, 9H), 1.24 (d, J = 6.9Hz, 3H) ppm; MS: m / z = 254 (M+1).

[0505] Step 2: 2-C

[0506] TBAB (10.2 g, 31.3 mmol) was added to a stirred mixture of sodium cyanide (47.2 g, 0.407 mol) in DMF (500 mL), and the mixture was stirred at 35 °C for 2 h. Then 2-B (79.6 g, 0.313 mol) was added, and the mixture was stirred for another 48 h. Water (500 mL) was added, and the aqueous layer was extracted with ethyl acetate (1000 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to give 2-C (43 g, 74% yield). 1 H NMR (400MHz, CDCl3) δ4.68 (m, 1H), 3.95 (m, 1H), 2.80-2.63 (m, 1H), 1.45 (s, 9H), 1.31 (dd, J = 11.8, 6.0Hz, 3H) ppm; MS: m / z = 185 (M+1).

[0507] Step 3: 2-D

[0508] At 0°C, methanesulfonic acid (37.6 mL, 0.580 mol) was added to a mixture of 2-C (43 g, 0.232 mol) in THF (500 mL) 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 filter cake was dissolved in DCM (200 mL) and the mixture was adjusted to pH ~13 with hydrated 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). 1 H NMR (400MHz, CDCl3) δ3.39-3.26 (m, 1H), 2.40 (m, 2H), 1.24 (d, J = 6.4Hz, 3H) ppm; MS: m / z = 85 (M+1).

[0509] Step 4: 2-E

[0510] Ethyl acrylate (14.4 g, 144.2 mmol) and Et3N (20 mL, 144.2 mmol) were added to a solution of 2-D (10.1 g, 120.2 mmol) in ethanol (60 mL). The reaction solution was heated at 70 °C for 3 hours. After cooling to 25 °C, N-methylpiperazine (4 mL, 36.1 mmol) and (Boc)2O (33.1 mL, 144.2 mmol) were added, and the mixture was stirred at 25 °C for 14 hours. Water (100 mL) was added, and the aqueous layer was extracted with toluene (100 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to give 2-E (34.1 g, crude). MS: m / z = 285 (M+1).

[0511] Step 5: Intermediate 2

[0512] At 25°C, t-BuOK (13.5 g, 120.2 mmol) was added to a mixture of 2-E (34.1 g) and THF (500 mL), and the mixture was stirred for 2 hours. 2N HCl (90 mL) was added, and the mixture was stirred for 30 minutes. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give intermediate 2 (9.2 g, 32% yield). 1H NMR (400MHz, CDCl3) δ5.17-4.97(m,1H),4.36(m,1H),3.80(d,J=5.6Hz,1H),3.24 (m,1H),2.53-2.45(m,2H),1.49(s,9H),1.35-1.31(m,3H)ppm; MS: m / z=329(M+1).

[0513] Example 3: Synthesis of Intermediate 3

[0514]

[0515] Step 1: 3-B

[0516] At -78°C, n-BuLi (2.5M, 3.94mL, 9.85mmol) was added to a solution of 3-A (2g, 9.85mmol) in THF (20mL). The reaction mixture was stirred at -70°C for 1 hour. Di-tert-butyl-diazepine-1,2-dicarboxylate (2.27g, 9.85mmol) was added, and the reaction mixture was stirred at -40°C for 30 min and then heated to 25°C for another 2 hours. Aqueous NH4Cl (50mL) was added, and the aqueous layer was extracted with ethyl acetate (50mL × 2). The combined organic layers were dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 10 / 1) to give 3-B (2.58g, 74% yield). 1 HNMR (400MHz, CDCl3) δ7.17-6.92(m,2H),2.22(s,6H),1.53-1.46(m,18H)ppm; MS: m / z=439(M-1).

[0517] Step 2: 3-C

[0518] Methanesulfonic acid (1.40 g, 14.58 mmol) was added to a solution of 3-B (2.58 g, 7.29 mmol) in NMP (20 mL). The reaction mixture was heated to 80 °C and stirred for 12 hours. After cooling to room temperature, the reaction mixture was poured into toluene (20 mL), and the pH was adjusted to ~9 with aqueous K₂CO₃. 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 hour. The reaction mixture was poured into water (40 mL), and the pH was adjusted to ~9 with aqueous NaOH, followed by extraction with ethyl acetate (50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to give a residue, which was purified by silica gel column chromatography (PE / EA = 4 / 1) to give 3-C (1.80 g, 66% yield). MS: m / z = 375(M+1).

[0519] Step 3: 3-D

[0520] At 25 °C, t-BuOK (1.98 g, 17.65 mmol) was added to a solution of N-(2,2-dimethoxyethyl)imidazolium-1-carboxamide (1.29 g, 6.47 mmol) and 3-C (2.2 g, 5.88 mmol) in DMA (30 mL). 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 × 3). The organic layer was washed with brine (50 mL × 3), dried over sodium sulfate, and concentrated to give a residue, which was purified by silica gel column chromatography (DCM / EA = 3 / 1) to give 3-D (1.34 g, 45% yield). MS: m / z = 506 (M+1).

[0521] Step 4: 3-E

[0522] Methanesulfonic acid (196 mg, 2.04 mmol) was added to a solution of 3-D (1.29 g, 2.55 mmol) in THF (20 mL). The reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was then cooled and the pH was adjusted to ~9 with aqueous K3PO4. Boc2O (222.7 mg, 1.02 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 1 hour. 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 by silica gel column chromatography to give 3-E (729 mg, 65% yield). MS: m / z = 442 (M+1).

[0523] Step 5: 3-F

[0524] CuI (60.5 mg, 0.32 mmol) was added 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). 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 × 3). The organic layer was washed with brine (20 mL × 3), dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to give 3-F (774 mg, 82.6% yield). MS: m / z = 590 (M+1).

[0525] Step 6: Intermediate 3

[0526] At 25°C, HCl / dioxane (4M, 3mL) was added to a solution of 3-F (400mg, 678.39μmol) in DCM (3mL). The reaction mixture was stirred at 25°C for 2 hours. Excess solvent was removed under reduced pressure to give crude intermediate 3 (396mg, HCl salt). MS: m / z = 490 (M+1).

[0527] Example 4: Synthesis of intermediates 4 and 7

[0528] Intermediates 4 and 7 in Table 1 were prepared according to the procedure for intermediate 3.

[0529] Table 1

[0530]

[0531] Example 5: Synthesis of Intermediate 8

[0532]

[0533] Step 1: 8-B

[0534] 2-Aminoethanol (7.63 g, 124.89 mmol) was added to a solution of 8-A (10 g, 104.07 mmol) in methanol (60 mL), and the mixture was stirred for 1 hour. Sodium borohydride (4.72 g, 124.89 mmol) was then slowly added at 0 °C. The resulting mixture was stirred for another hour, then poured into water (100 mL), and benzyl chloroformate (21.29 g, 124.80 mmol) was added dropwise. The resulting mixture was stirred for another 2 hours. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated to give the residue. The residue was purified by rapid chromatography (DCM / MeOH = 10 / 1) to give 8-B (16 g, 55.88% yield). 1H NMR (300MHz, CDCl3): δ7.49(d,J=7.5Hz,1H),7.39-7.14(m,5H),6.20(d,J=52.6Hz ,1H),5.12(d,J=7.1Hz,2H),4.52(s,2H),3.89-3.70(m,2H),3.58(d,J=4.9Hz,2H).

[0535] Step 2: 8-C

[0536] At 0 °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 di-tert-butyl azodicarbonate (25.52 g, 110.8 mmol) in THF (200 mL). The resulting mixture was stirred for 16 hours. The mixture was concentrated, and the residue was dissolved in DCM (50 mL) and TFA (30 mL). After stirring for 0.5 hours, the mixture was concentrated, dissolved again in DCM (100 mL), and alkalized to pH 7–8 with saturated NaHCO3. After separation, the organic layer was washed with brine (50 mL) and concentrated to give a 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 rapid chromatography (PE / EA = 1 / 1) to give 8-C (10 g, 38.87 mmol, 71.33% yield). 1 HNMR (300MHz, CDCl3): δ7.51 (bs, 1H), 7.41-7.33 (m, 5H), 6.09 (d, J = 10.7Hz, 1H), 5. 18(s,2H),4.75(s,2H),4.30-4.19(m,2H),4.00-3.93(m,2H); MS: m / z=257.9(M+1).

[0537] Step 3: 8-D

[0538] At 0 °C, a solution of 8-C (6 g, 23.32 mmol) in MeCN (150 mL) was added dropwise to NIS (7.87 g, 34.98 mmol) in MeCN (150 mL). The mixture was stirred for 16 hours, then poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with saturated Na₂SO₃ solution (100 mL) and brine (100 mL) and concentrated to give 8-D (8.2 g, 91.76% yield). MS: m / z = 383.6 (M+1).

[0539] Step 4: 8-E

[0540] 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), Pd2(dba)3 (1.91 g, 2.09 mmol), and xantphos (2.42 g, 4.18 mmol) in toluene (100 mL) was stirred and refluxed for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by rapid chromatography (DCM / MeOH = 15 / 1) to give 1,1-diphenyl-N-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)methylimine (3.3 g). 1 ¹H NMR (400MHz, CDCl₃): δ 7.76–7.72 (m, 2H), 7.52–7.45 (m, 3H), 7.42–7.32 (m, 3H), 7.25–7.20 (m, 2H), 6.04 (s, 1H), 4.21 (s, 2H), 4.01 (t, J = 5.5 Hz, 2H), 3.31–3.23 (m, 2H); MS: m / z = 302.9 (M+1). The intermediate was dissolved in DCM (100 mL), and TEA (3.3 g, 32.7 mmol) was added, followed by dropwise addition of benzyl chloroformate (2 g, 11.7 mmol). After stirring for 1 hour, the mixture was washed with brine (100 mL), dried over sodium sulfate, and concentrated. The crude product was purified by rapid chromatography (PE / EA = 1 / 1) to give 8-E (3.9 g, 42.79% yield). MS: m / z = 436.7 (M+1).

[0541] Step 5: 8-F

[0542] A mixture of 8-E (2.16 g, 4.95 mmol), 1-bromo-4-fluorobenzene (1.73 g, 9.90 mmol), Pd(OAc)₂ (333.29 mg, 1.48 mmol), 1,10-phenanthroline (891.73 mg, 4.95 mmol), and Cs₂CO₃ (4.84 g, 14.85 mmol) in toluene (50 mL) was stirred at 140 °C for 12 hours. The reaction mixture was concentrated to give a crude product, which was purified by rapid chromatography (PE / EA = 1 / 1) to give 8-F (280 mg, 10.66% yield). MS: m / z = 558.7 (M+1).

[0543] Step 6: 8-G

[0544] HCl / dioxane (4M, 2 mL) was added to a solution of 8-F (160 mg, 301.55 μmol) in ethyl acetate (2 mL). The reaction mixture was stirred for 1 hour. 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 rapid chromatography (PE / EA = 1 / 1) to give 8-G (110 mg, 99.56% yield). MS: m / z = 367.2 (M+1).

[0545] Step 7: 8-H

[0546] At 0 °C, 8-G (110 mg, 300.23 μmol) in THF (5 mL) was added to a solution of triphosgene (90 mg, 300.23 μmol) in THF (10 mL), followed by TEA (152 mg, 1.50 mmol) in THF (5 mL). The reaction mixture was stirred for 1 hour. Then, 2,2-dimethoxyethylamine (158 mg, 1.50 mmol) in THF (5 mL) was added at 0 °C. The reaction mixture was stirred for another hour. 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).

[0547] Step 8: 8-I

[0548] HCl / dioxane (4M, 1mL) was added to a solution of 8-H (140 mg, 281.40 μmol) in DCM (2 mL). The resulting mixture was stirred for 2 hours. 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 a 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).

[0549] Step 9: 8-J

[0550] A mixture of 8-I (105 mg, 242.25 μmol), intermediate 1 (83 mg, 363.38 μmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (34 mg, 242.25 μmol), CuI (46 mg, 242.25 μmol), and K2CO3 (100 mg, 726.75 μmol) in dioxane (5 mL) was stirred at 100 °C for 16 hours. The reaction mixture was concentrated to give a crude product, which was purified by rapid chromatography (PE / EA = 1 / 1) to give 8-J (55 mg, 39.04% yield). MS: m / z = 582.1 (M+1).

[0551] Step 10: Intermediate 8

[0552] At 0 °C, a solution of boron trichloride in DCM (2 mL, 1 M) was added to a solution of 8-J (55 mg, 94.57 μmol) in DCM (2 mL), and the resulting mixture was stirred for 2 hours. 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).

[0553] Example 6a: Synthesis of Intermediate 9

[0554]

[0555] A mixture of 9-A (7.83 g, 58.38 mmol), tert-butyl N-carbamate (7.72 g, 58.38 mmol), and hexane (100 mL) was stirred under reflux for 1 hour. The white solid was filtered and washed with hexane. A 1 M borane solution in THF (58.35 mL) was added to the solid to obtain 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 vacuum and washed with THF to give intermediate 9 (9.36 g, 99% yield, HCl salt). 1 H NMR (400MHz, DMSO) δ7.15 (bs, 5H), 3.09 (t, J = 9.4Hz, 1H), 2.16-1.94 (m, 4H), 1.94-1.72 (m, 2H), 1.57 (m, 2H); MS: m / z = 151.0 (M+1).

[0556] Example 6b: Synthesis of Intermediate 10

[0557]

[0558] Step 1: 10-B

[0559] A solution of lithium methyl bromide complex in ether (1M, 161.72 mL) was slowly added to a stirred and cooled mixture (-50 °C) of 10-A (20 g, 67.38 mmol) in pentane (15 mL) and diethyl ether (3 mL) in 500 mL of 3-necked RBF (attached with a nitrogen line, thermometer, and addition funnel) at 150 mL. After the addition was complete, the mixture was allowed to heat to 0 °C. After 2 hours, the addition funnel was replaced with a distillation head attached to a 200 mL RBF bath at -78 °C. Vacuum was slowly applied to the system and the distillate was collected. A solution of 10-B (130 mL, approximately 0.3 M) in diethyl ether was obtained, which was used in the next step without further purification. 1 H NMR (300MHz, CDCl3) δ1.93 (s, 6H).

[0560] Step 2: 10-C

[0561] 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 (NE)-N-tert-butoxycarbonyliminocarbamate tert-butyl ester (12.43 g, 54.0 mmol) in DCM (200 mL) was added, followed by 10-B (0.3 M, 120 mL) in diethyl 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 chromatography (PE / EA = 10 / 1) to give 10-C (8.3 g, 77.27% yield). 1 H NMR (400MHz, DMSO-d6) δ9.00(s,1H),2.37(s,1H),1.92(s,6H),1.40(s,18H).

[0562] Step 3: Intermediate 10

[0563] At 25°C, HCl / dioxane (4M, 69.54mL) was added to a solution of 10-C (8.3g, 27.82mmol) in DCM (20mL). The reaction was stirred at 25°C for 16 hours. After filtration, the solid was collected and dried to give intermediate 10 (3.3g, 69.35% yield, HCl salt).

[0564] Example 7: Synthesis of Intermediate 11

[0565]

[0566] Step 1: 11-A

[0567] Intermediate 9 (1.12 g, 5.04 mmol) and HCl (2 M, 4 mL) were added to a solution of intermediate 2 (1.2 g, 5.04 mmol) in ethanol (11 mL) at 25 °C. The resulting mixture was heated to 50 °C and stirred for 1 hour. The mixture was quenched with saturated aqueous K₂CO₃ and extracted with ethyl acetate (50 mL × 3). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to give a crude product, which was purified by combi-flash elution with DCM / MeOH = 20 / 1 to provide 11-A (0.998 g, 53% yield). MS: m / z = 371.0 (M+1).

[0568] Step 2: 11-B

[0569] 11-A (600 mg, 1.62 mmol) and triethylamine (819 mg, 8.1 mmol) were added to a solution of triphosgene (480 mg, 1.62 mmol) in THF (66 mL). The resulting mixture was heated to room temperature and stirred for 1 hour. The reaction was then cooled to 0 °C, and 2,2-dimethoxyethylamine (851 mg, 8.1 mmol) was added. The mixture was then heated to room temperature and stirred at 25 °C for an additional 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give 11-B (1.46 g, crude). MS: m / z = 501.8 (M+1).

[0570] Step 3: 11-C

[0571] HCl (4 M, 7.46 mL) in dioxane was added to a solution of 11-B (1.36 g) in DCM (14 mL). The reaction mixture was stirred at 25 °C for 16 h. The pH of the reaction mixture was then adjusted to approximately 10 with aqueous NaOH. Boc₂O (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 by silica gel column chromatography (DCM / methanol = 20 / 1) to give 11-C (378 mg, 31% yield). MS: m / z = 437.8 (M+1).

[0572] Step 4: 11-D

[0573] K₂CO₃ (332.33 mg, 2.40 mmol) was added 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). The reaction mixture was stirred at 100 °C under argon for 16 h. The resulting mixture was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by combi-flash (eluting with DCM / methanol = 20 / 1) to provide 11-D (309 mg, 52% yield). MS: m / z = 585.7 (M+1).

[0574] Step 5: Intermediate 11

[0575] A mixture of 11-D (309 mg, 0.527 mmol) and HCl (4 M, 10.55 mL) in dioxane 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).

[0576] Example 8: Synthesis of Intermediate 12-Intermediate 16

[0577] Intermediates 12-16 in Table 2 are prepared according to the procedure of intermediate 11.

[0578] Table 2

[0579]

[0580]

[0581] Example 9: Synthesis of Intermediate 17

[0582]

[0583] Step 1: 17-B

[0584] At 25°C, tert-butyl N-aminocarbamate (9.57 g, 72.39 mmol) was added to a solution of 17-A (10 g, 72.39 mmol) in isopropanol (80 mL). The resulting mixture was heated to 90°C for 2 hours. At 25°C, petroleum ether (160 mL) was added to the reaction mixture, and the resulting mixture was stirred for 10 minutes and filtered. The residue was washed with petroleum ether (40 mL × 2) and dried to provide 17-B (12 g, 65% yield). MS: m / z = 197.2 (M+1-56).

[0585] Step 2: 17-C

[0586] Palladium (843 mg, 7.93 mmol) was added to a solution of 17-B (10 g, 39.64 mmol) in methanol (150 mL) at 25 °C under a hydrogen atmosphere. The resulting mixture was stirred at 25 °C for 3 hours. The reaction was filtered and concentrated under reduced pressure to provide 17-C (9 g, 89% yield). MS: m / z = 277.2 (M+23).

[0587] Step 3: 17-D

[0588] At 25°C, HCl / dioxane (4M, 2mL) was added to a solution of 17-C (1g, 3.93mmol) in DCM (15mL), and the mixture was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to provide 17-D (0.72g, 95% yield, HCl salt). MS: m / z = 155 (M+1).

[0589] Step 4: 17-E

[0590] At 25 °C, N-ethyl-N-isopropyl-prop-2-amine (1.38 g, 10.70 mmol) was added to a mixture of 17-D (1.1 g, 7.13 mmol, HCl salt) in ethanol (50 mL) and stirred for 3 minutes. Then, 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 rapid chromatography (30% ethyl acetate in petroleum ether) to provide 17-E (1.5 g, 56% yield). MS: m / z = 375.3 (M+1).

[0591] Step 5: 17-F

[0592] Phenyl chloroformate (376 mg, 2.40 mmol) was added to a solution of 17-E (450 mg, 1.20 mmol) and DIEA (465 mg, 3.61 mmol) in THF (5 mL), and the reaction was stirred at 25 °C for 2 hours. The reaction was concentrated to give 17-F (590 mg, crude). MS: m / z = 495 (M+1).

[0593] Step 6: 17-G

[0594] Crude 17-F (590 mg, 1.2 mmol) was dissolved in 5 mL of pyridine, and 2,2-dimethoxyethylamine (379 mg, 3.61 mmol) was added. The mixture was stirred at 25 °C for 3 hours. The reaction was concentrated to give 17-G (3 g, crude). MS: m / z = 506 (M+1).

[0595] Step 7: 17-H

[0596] A solution of crude 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. Aqueous K₃PO₄ was added to adjust the pH to ~9, and then Boc₂O (388 mg, 1.78 mmol) was added, and the reaction 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 the residue. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 17-H (300 mg, 56.5% yield, in 3 steps). MS: m / z = 442.1 (M+1).

[0597] Step 8: 17-I

[0598] N1,N2-dimethylcyclohexane-1,2-diamine (82 mg, 579.84 μmol), CuI (69 mg, 362.4 μmol), and K2CO3 (300 mg, 2.17 mmol) were added to a solution of 17-H (300 mg, 679.5 μmol) and intermediate 1 in NMP (2 mL). The reaction 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 × 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).

[0599] Step 9: Intermediate 17

[0600] TFA (6.19 g, 54.27 mmol, 4.2 mL) was added to a solution of 17-I (320 mg, 542.71 μmol) in DCM (4 mL), and the reaction was stirred at 25 °C for 16 h. The solvent was removed, the residue was treated with 5 mL of toluene and concentrated, and this was repeated three times to give intermediate 17 (250 mg, 89% yield, TFA salt). MS: m / z = 490.1 (M+1).

[0601] Example 10: Synthesis of Intermediate 18

[0602]

[0603] Step 1: 18-B

[0604] Add 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) to a solution of 18-A (6 g, 28.27 mmol) in toluene (50 mL). Stir the mixture at 90 °C for 20 hours. Dilute the mixture with ethyl acetate (200 mL) and wash with aqueous NaHCO3 (100 mL × 2). Dry the organic phase over sodium sulfate and concentrate under reduced pressure. Purify the crude product by column chromatography (PE / EA = 2 / 1) to give 18-B (5.8 g, 58.18% yield). MS: m / z = 317.8 (M+1).

[0605] Step 2: 18-C

[0606] Sodium borohydride (5.96 g, 157.54 mmol) was added to a solution of 18-B (5 g, 15.75 mmol) in THF (50 mL). The resulting mixture was stirred for 18 hours, quenched with 100 mL HCl (1 M), and extracted with ethyl acetate (200 mL × 3). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give 18-C (5.3 g, crude). MS: m / z = 289.9 (M+1).

[0607] Step 3: 18-D

[0608] MeI (1.1 g, 7.78 mmol) was added dropwise to a mixture of 18-C (1.5 g, 5.19 mmol), silver trifluoromethanesulfonate (2 g, 7.78 mmol), and DCM (22.5 mL) at 0 °C. The reaction mixture was stirred for 3 hours. The resulting mixture was filtered, and the filtrate was concentrated under vacuum to give a crude product, which was purified by combi-flash (PE / EA = 2 / 1) to provide 18-D (323 mg, 20% yield). 1 H NMR (400MHz, DMSO) δ7.51-7.20(m,5H),6.93(s,1H),4.95(s,2H),3.20(s,3H),2.93( s, 2H), 1.73 (dd, J=9.8, 6.2Hz, 6H), 1.42 (dd, J=9.8, 6.2Hz, 6H); MS: m / z=303.9 (M+1).

[0609] Step 4: Intermediate 18

[0610] A mixture of 18-D (323 mg, 1.06 mmol), Pd / C (40 mg), and methanol (10 mL) was stirred under H2 for 18 hours. The reaction was filtered, and the filtrate was concentrated under vacuum to provide intermediate 18 (190 mg, crude). MS: m / z = 170.2 (M+1).

[0611] Example 11: Synthesis of Intermediate 19

[0612]

[0613] Step 1: 19-B

[0614] At 0 °C, a solution of 19-A (5 g, 24.39 mmol), DEAD (5.10 g, 29.27 mmol), and N-(2-aminoethyl)carbamate tert-butyl ester (4.69 g, 29.27 mmol) in THF (50 mL) was added with Ph3P (7.68 g, 29.27 mmol) for 0.5 h. 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), and further stirring for 1 h. The mixture was concentrated, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The aqueous phase was acidified (1 M HCl) to pH ~3 and extracted with ethyl acetate (50 mL × 3), dried over sodium sulfate, filtered, and concentrated to give 19-B (8.1 g, 24.24 mmol, 99.4% yield).

[0615] Step 2: 19-C

[0616] At 30 °C, TEA (7.36 g, 72.72 mmol, 10.14 mL) and HATU (9.22 g, 24.24 mmol) were added to a mixture of 19-B (8.1 g, 24.24 mmol), N-methoxymethylamine (1.48 g, 15.18 mmol, HCl salt) in DCM (100 mL). The reaction solution was stirred at 30 °C for 2 hours. Then, ethyl acetate (100 mL) was added, and the reaction mixture was washed with H2O (100 mL × 3), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (PE / EA = 5 / 1-1 / 1) to obtain 19-C (7.7 g, 20.41 mmol, 84.21% yield).

[0617] Step 3: 19-D

[0618] MeMgBr (1M, 92.78 mL) was added to a solution of 19-C (7 g, 18.56 mmol) in THF (50 mL) at 0 °C. The mixture was then stirred at 25 °C for 2 hours. The mixture was concentrated and purified by column chromatography (EA / PE = 1 / 10-1 / 1) to give 19-D (6 g, 18.06 mmol, 97.34% yield). MS: m / z = 232.0 (M+1-100).

[0619] Step 4: 19-E

[0620] At 0 °C, HCl / dioxane (4 M, 40 mL) was added to a mixture of 19-D (6 g, 18.06 mmol) in methanol (5 mL) and the mixture was stirred for 1 hour. The reaction mixture was then 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 the addition of NaBH3CN (4.54 g, 72.25 mmol) at 0 °C and stirring for 2 hours. The solution was concentrated and purified by silica gel chromatography (DCM / MeOH = 50 / 1-10 / 1, v / v) to obtain 19-E (3.1 g, 14.35 mmol, 79.43% yield).

[0621] Step 5: 19-F

[0622] At 0 °C, KNO3 (7.25 g, 71.73 mmol) was added to a mixture of 19-E (3.1 g, 14.35 mmol) and H2SO4 (40 mL). The reaction solution was stirred at 45 °C for 5 hours. The solution was then poured into ice water (200 mL), and a yellow solid was produced and filtered. The solid was then dissolved in HCl / MeOH (4 M, 50 mL) and refluxed for 2 hours. The mixture was concentrated to obtain 19-F (2 g, 7.66 mmol, 53.40% yield).

[0623] Step 6: 19-G

[0624] Boc₂O (1.81 g, 8.27 mmol) was added 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) at 25 °C, and the mixture was stirred for 2 hours. The solution was then concentrated. The crude product was purified by silica gel chromatography (PE / EA = 10 / 1-4 / 1) to obtain 19-G (2.0 g, 5.54 mmol, 80.31% yield).

[0625] Step 7: 19-H

[0626] Zn (1.36 g, 20.76 mmol) was added 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) at 25 °C. The mixture was stirred for 1 hour, filtered, and concentrated. The crude product was purified by silica gel chromatography (PE / EA = 10 / 1-2 / 1) to obtain 19-H (1.1 g, 3.32 mmol, 79.97% yield).

[0627] Step 8: 19-I

[0628] At -78°C, TEA (977.66 mg, 9.66 mmol, 1.35 mL) was added to a mixture of 19-H (800 mg, 2.42 mmol) and bis(trichloromethyl)carbamate (2.15 g, 7.25 mmol) in DCM (10 mL), and the mixture was stirred for 1 hour. 2,2-Dimethoxyethylamine (1.27 g, 12.08 mmol, 1.32 mL) was added, and the mixture was stirred at 0°C for 30 minutes. 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 hours. Boc₂O (1.05 g, 4.83 mmol, 1.11 mL) was added, and the mixture was stirred at 25°C for 1 hour. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (EA / PE = 1 / 1-1 / 0) to give 19-I (600 mg, 1.51 mmol, 62.37% yield).

[0629] Step 9: 19-J

[0630] At 30 °C, Pd(dppf)Cl2 (12.66 mg, 17.30 μmol) and K2CO3 (71.74 mg, 519.10 μmol) were added to a mixture of 19-I (68.91 mg, 173.03 μmol) and (4-fluoro-3,5-dimethyl-phenyl)boronic acid (37.78 mg, 224.94 μmol) in dioxane (4 mL) and H2O (1 mL). The reaction solution was stirred at 100 °C for 2 hours. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (EA / PE = 1 / 1-1 / 0) to give 19-J (70 mg, 158.55 μmol, 91.63% yield).

[0631] Step 10: 19-K

[0632] A mixture of 19-J (70 mg, 158.55 μmol), intermediate 1 (62.26 mg, 271.80 μmol), K₂CO₃ (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 hours. The solution was then concentrated and purified by silica gel chromatography (PE / EA / TEA = 4 / 1 / 0.01-1 / 1:0.01) to obtain 19-K (68 mg, 115.33 μmol, 72.7% yield). MS: m / z = 590.4 (M+1).

[0633] Step 11: Intermediate 19

[0634] 19-K (50 mg, 84.80 μmol) was dissolved in HCl / dioxane (4 M, 2 mL) and stirred at 25 °C for 16 hours. The reaction was then concentrated to give intermediate 19 (45 mg, 95% yield). MS: m / z = 490.1 (M+1).

[0635] Example 12: Synthesis of intermediates 20 and 24

[0636] Intermediates 20-24 in Table 3 were prepared according to the procedure for intermediate 19.

[0637] Table 3

[0638]

[0639]

[0640] Example 13: Synthesis of Intermediate 25

[0641]

[0642] Step 1: 25-B

[0643] Phenyl chloroformate (153 mg, 975.76 μmol) was added to a solution of 25-A (an intermediate for intermediate 22, 0.26 g, 750.58 μmol) and DIEA (291 mg, 2.25 mmol) in THF (5 mL). The reaction was stirred at 0 °C for 2 h. The reaction was concentrated to give 25-B (0.4 g, crude). MS: m / z = 467.1 (M+1).

[0644] Step 2: 25-C

[0645] Intermediate 18 (290 mg, 1.71 mmol) was added to a solution of 25-B (0.4 g) in pyridine (8 mL), and the reaction was stirred at 20 °C for 15 h. The mixture was concentrated to give a residue, which was purified by silica gel column chromatography (PE / EA = 1 / 1) to give 25-C (0.33 g, 71% yield). MS: m / z = 542.2 (M+1).

[0646] Step 3: 25-D

[0647] 2-bromo-1,1-dimethoxy-ethane (2.8 g, 16.62 mmol, 2 mL), t-BuOK (620 mg, 5.54 mmol), and 18-crown ether-6 (586 mg, 2.22 mmol) were added to a solution of 25-C (0.3 g, 553.86 μmol) in dioxane (10 mL). 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 × 2), dried over sodium sulfate, and concentrated to give the crude product. The crude product was purified by rapid column chromatography (PE / EA = 1 / 1) to give 25-D (0.18 g, 52% yield). MS: m / z = 630.4 (M+1).

[0648] Step 4: Intermediate 25

[0649] HCl (2M, 1.4 mL) was added to a solution of 25-D (0.18 g, 285.82 μmol) in ethyl acetate (2 mL). The reaction was stirred at 25 °C for 6 hours. The reaction was concentrated to give a residue, which was purified by reverse-phase column chromatography (55% MeCN in water) to give intermediate 25 (0.08 g, 56% yield). MS: m / z = 466.2 (M+1).

[0650] Example 14: Synthesis of intermediates 19-P1 and 19-P2

[0651]

[0652] Intermediate 19 (45 mg) was separated by SFC (column: Daicel CHIRALPAK OD-H 250 mm × 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).

[0653] Example 15: Separation 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

[0654] The compounds in Table 4 were obtained by SFC separation as intermediates 19-P1 and 19-P2.

[0655] Table 4

[0656]

[0657]

[0658]

[0659] Example 16: Synthesis of Intermediate 26

[0660]

[0661] LDA (2M, 117.03mL) was added to a solution of 26-A (25g, 195.05mmol) in THF (250mL) at -70°C for 0.5 hours. The mixture was stirred at -70°C for 0.5 hours, and then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (76.65g, 214.56mmol) in THF (250mL) was added to the reaction mixture at -60°C for 1 hour. After the addition, the temperature was slowly increased to 25°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with NH4Cl (200mL) and extracted with ethyl acetate (300mL × 2). The combined organic layers were washed with brine (200mL), dried over sodium sulfate, and concentrated by rotary evaporation to obtain intermediate 26 (95g, crude).

[0662] Example 17: Synthesis of Intermediate 27

[0663]

[0664] Step 1: 27-B

[0665] Ethyl 2-(triphenyl-phosphine)ethyl acetate (46.82 g, 134.40 mmol) was added to a solution of 27-A (25 g, 134.40 mmol) in DCM (100 mL). The reaction 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 a crude product. The crude product was purified by silica gel chromatography (PE / EA = 10 / 1–5 / 1) to give 27-B (26.5 g, 77% yield). MS: m / z = 256.0 (M+1, ESI).

[0666] Step 2: 27-C

[0667] To a solution of 27-B (30 g, 117.14 mmol) in MeOH (300 mL), add NaBH4 (5.32 g, 140.57 mmol) and NiCl2 (1.52 g, 11.71 mmol). Stir the reaction mixture for 1 hour. Dilute the mixture with water (200 mL) and extract with EA (200 mL × 3). Wash the combined organic layers with brine, dry over sodium sulfate, filter, and concentrate to give 27-C (25 g, 82% yield). MS: m / z = 258.0 (M+1).

[0668] Step 3: 27-D

[0669] NH3·H2O (1.13 kg, 30%) was added to a solution of 27-C (25 g, 96.86 mmol) in MeOH (200 mL). The reaction mixture was stirred for 16 hours. The solvent was removed under vacuum to give 27-D (20 g, 90% yield). MS: m / z = 229.0 (M+1).

[0670] Step 4: 27-E

[0671] At 0 °C, TFAA (36.6 g, 174.62 mmol, 24.61 mL) and pyridine (17.2 g, 218.27 mmol, 17.65 mL) were added to a solution of 27-D (20 g, 87.31 mmol) in dry dioxane (200 mL). The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with H₂O (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 a crude product, which was purified by rapid chromatography (PE / EA = 3 / 1) to give 27-E (16 g, 87% yield). MS: m / z = 211.0 (M+1).

[0672] Step 5: 27-F

[0673] Ethyl 3-bromo-2-oxopropionate (27.7 g, 142.14 mmol, 17.77 mL) and NaHCO3 (11.9 g, 142.14 mmol) were added to a solution of 27-E (15 g, 71.07 mmol) in MeCN (200 mL). The mixture was stirred at 90 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (PE / EA = 4 / 1) to give 27-F (1.0 g, 5% yield).

[0674] Step 6: 27-G

[0675] A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (298 mg, 1.17 mmol), 27-F (300 mg, 976.75 μmol), Pd(dppf)Cl2 (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 hours. The mixture was concentrated under vacuum, 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).

[0676] Step 7: 27-H

[0677] 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)Cl2 (66 mg, 90.34 μmol) in dioxane (3 mL) and water (1 mL) was stirred at 110 °C for 2 hours. 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 column chromatography on silica gel (PE / EA = 8 / 1) to give 27-H (200 mg, 59% yield). MS: m / z = 339.1 (M+1).

[0678] Step 8: 27-I

[0679] Pd / C (47 mg, 10%) was added to a solution of 27-H (150 mg, 443.26 μmol) in MeOH (3 mL), and the mixture was stirred at 25 °C in H2 for 1 hour. The mixture was filtered, and the filtrate was concentrated to give 27-I (145 mg). MS: m / z = 341.1 (M+1).

[0680] Step 9: Intermediate 27

[0681] A solution of sodium hydroxide (5 M, 1.06 mL) was added to a solution of 27-I (180 mg, 528.77 μmol) in methanol (5 mL), and the mixture was stirred at 50 °C for 3 hours. 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 chromatography (35% MeCN in H₂O) to give intermediate 27 (98 mg, 59% yield). MS: m / z = 313.2 (M+1).

[0682] Example 18: Synthesis of Intermediate 28

[0683]

[0684] Step 1: 28-A

[0685] At 0 °C, KHMDS (1 M, 7.76 mL) was added dropwise to a solution of 27-I (330 mg, 969.40 μmol) and 1,3,2-dioxane-2,2-dioxide (361 mg, 2.91 mmol) in DMPU (10 mL). The reaction mixture was stirred at 0 °C for 1 hour. A 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 × 3). The organic phase was washed with aqueous LiCl (10 mL × 3), followed by washing with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by rapid column chromatography (PE / EA = 1 / 1) to give 28-A (200 mg, 56% yield). MS: m / z = 367.2 (M+1).

[0686] Step 2: Intermediate 28

[0687] Aqueous NaOH (2M, 6mL) was added to a solution of 28-A (81mg, 221.04μmol) in MeOH (3mL), and the mixture was stirred at 50°C for 2 hours. The reaction mixture was extracted with ethyl acetate (10mL × 2). The aqueous solution was then adjusted to pH ~3 with HCl (1M). The solution was extracted with ethyl acetate (10mL × 3), and the combined organic phases were dried over sodium sulfate and concentrated to give intermediate 28 (80mg, crude). MS: m / z = 339.1 (M+1).

[0688] Example 19: Synthesis of Intermediate 29

[0689] Intermediate 29 in Table 5 is prepared according to the procedure of intermediate 28.

[0690] Table 5

[0691]

[0692] Example 20: Synthesis of Intermediate 30

[0693]

[0694] At 0 °C, 30-A (300 mg, 881.28 μmol) and (4R)-4-methyl-1,3,2-dioxane-2,2-dioxide (122 mg, 881.28 μmol) in THF (5 mL) were added to a solution of KHMDS (1 M, 7.05 mL). The mixture was stirred at 0 °C for 2 hours. The mixture was poured into NH4Cl (20 mL) containing water 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 vacuum to give intermediate 30 (300 mg, 96% yield). MS: m / z = 353.1 (M+1).

[0695] Example 21a: Synthesis of intermediate 31

[0696]

[0697] Step 1: 31-B

[0698] Sodium bicarbonate (14.65 g, 174.40 mmol) and ethyl 3-bromo-2-oxopropionate (25.51 g, 130.80 mmol, 16.35 mL) were added to a solution of 31-A (15 g, 87.20 mmol, 10.34 mL) in MeCN (100 mL). The mixture was stirred at 90 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was diluted with H₂O (50 mL), extracted with ethyl acetate (50 mL × 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).

[0699] Step 2: 31-C

[0700] 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-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (2.99 g, 11.78 mmol), KOAc (1.78 g, 18.13 mmol), and Pd(dppf)Cl2 (663 mg, 906.36 μmol) in dioxane (30 mL) was stirred at 90 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under vacuum to give 31-C (2.5 g, crude). MS: m / z = 316.2 (M+1).

[0701] Step 3: 31-D

[0702] 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 to a solution of 31-C (2.5 g, 7.93 mmol) in dioxane (20 mL) and water (5 mL). The mixture was stirred at 90 °C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography on silica gel (PE / EA = 3 / 1) to give 31-D (2.1 g, 88% yield). MS: m / z = 300.1 (M+1).

[0703] Step 4: 31-E

[0704] Under hydrogen atmosphere, Pd / C (10%, 50% wetting, 400 mg) was added to a solution of 31-D (1.3 g, 4.34 mmol) in methanol (30 mL). The reaction was stirred at 15 psi at 25 °C for 2 hours. 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).

[0705] Step 5: 31-F

[0706] Hydrogen peroxide (1.88 mL, 30%) was added dropwise 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). 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 × 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1) to give 31-F (530 mg, 43% yield). MS: m / z = 341.3 (M+1).

[0707] Step 6: 31-G

[0708] To a solution of 31-F (220 mg, 646.27 μmol) in DMPU (3 mL), 1,3,2-dioxane-2,2-dioxide (241 mg, 1.94 mmol) was added, followed by slow addition of LiHMDS (1 M, 5.82 mL) to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL × 10), dried over sodium sulfate, and concentrated to give a residue, which was purified by column chromatography on silica gel (EA / PE = 1 / 5) to give 31-G (135 mg, 57% yield). MS: m / z = 367.1 (M+1).

[0709] Step 7: Intermediate 31

[0710] Add NaOH (5M, 1.47mL) to a solution of 31-G (135mg, 368.40μmol) in MeOH (2mL). Stir the mixture at 50°C for 3 hours. Concentrate the mixture under vacuum, and extract the residue with HCl (1M, 10mL) using ethyl acetate (10mL × 2). Wash the combined organic layers with brine (10mL × 2), dry over sodium sulfate, and concentrate under vacuum to give intermediate 31 (65mg, 50% yield). MS: m / z = 339.1 (M+1).

[0711] Example 21b: Synthesis of intermediate 32

[0712]

[0713] Step 1: 32-A

[0714] To a solution of 27-F (10 mg, 32.56 μmol) in dioxane (2 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2-(trifluoromethyl)pyridine (9 mg, 32.56 μmol), Pd(dppf)Cl2 (3 mg, 3.2 μmol), and K2CO3 (9 mg, 65.12 μmol) were added. The mixture was stirred at 90 °C for 16 hours. The mixture was concentrated under vacuum to give a residue, which was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid chromatography (PE / EA = 2 / 1) to give 32-A (10 mg, 82% yield). MS: m / z = 374.1 (M+1).

[0715] Step 2: Intermediate 32

[0716] To a solution of 32-A (10 mg, 26.79 μmol) in MeOH (1 mL), NaOH (5 M, 535.72 μL) was added, and 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 mixture was filtered, and the filter cake was washed with H₂O (0.5 mL) and dried under vacuum to give intermediate 32 (8 mg, 87% yield). MS: m / z = 346.2 (M+1).

[0717] Example 22: Synthesis of Intermediate 33

[0718]

[0719] Step 1: 33-A

[0720] LiHMDS (1 M, 1.63 mL) was added to a three-necked flask and cooled to -40 °C. Then, 27-F (100 mg, 325.58 μmol) and 1,3,2-dioxane-2,2-dioxide (60 mg, 488.37 μmol) were added to THF (2 mL). The mixture was stirred at -40 °C for 2 hours. The reaction mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over sodium sulfate, and concentrated under vacuum to give a 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).

[0721] Step 2: 33-B

[0722] To a solution of 33-A (15 mg, 45.02 μmol) in dioxane (5 mL) and water (0.5 mL), K₂CO₃ (18 mg, 135.06 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2-(trifluoromethyl)pyridine (12 mg, 45.02 μmol), and Pd(dppf)Cl₂ (32 mg, 45.02 μmol) were added. The mixture was stirred at 90 °C for 2 hours. Dioxane was removed under vacuum, and the crude product was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. 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).

[0723] Step 3: Intermediate 33

[0724] Add 2.0 mL of 6 M NaOH to a solution of 33-B (15 mg, 37.56 μmol) in THF (1 mL) and MeOH (1 mL). Stir the reaction mixture at 25 °C for 2 hours. Concentrate the mixture and adjust the pH to approximately 5 with 1 N HCl. Extract the reaction mixture with ethyl acetate (20 mL × 3), wash the combined organic layers with brine (10 mL), dry over sodium sulfate, and concentrate under vacuum to give intermediate 33 (13 mg, 93% yield). MS: m / z = 372.0 (M+1).

[0725] Example 23: Separation of intermediates 27-P1 and 27-P2

[0726]

[0727] Intermediate 27 (100 mg) was separated by SFC (column: Daicel CHIRALPAK AD-H 0.46 cm ID×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).

[0728] Example 24: Synthesis and isolation of intermediates 28-P1, 28-P2, 30-P1, 30-P2, 30-P3, 30-P4, 31-P1, and 31-P2

[0729] The compounds in Table 6 were obtained by SFC isolation, as described in intermediates 27-P1 and 27-P2.

[0730] Table 6

[0731]

[0732]

[0733]

[0734] Example 25: Synthesis of Intermediate 34

[0735]

[0736] Step 1: 34-B

[0737] K₂CO₃ (10.29 g, 74.60 mmol) and Pd(dppf)Cl₂ (2.73 g, 3.73 mmol) were added 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-dioxaborhexacyclopentane (7.84 g, 37.30 mmol) in dioxane (100 mL) and water (10 mL). 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 the residue, which was combined with the solid to give 34-B (6 g, 59% yield). MS: m / z = 272.2 (M+1).

[0738] Step 2: Intermediate 34

[0739] Pd / C (10%, 50% wetting, 1 g) was added to a solution of 34-B (5 g, 18.43 mmol) in DMF (25 mL) and MeOH (25 mL). The mixture was stirred at 15 psi under H2 for 4 hours. 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).

[0740] Example 26: Synthesis of intermediates 35 and 36

[0741] Intermediates 35-36 in Table 7 were prepared according to the procedure for intermediate 34.

[0742] Table 7

[0743]

[0744] Example 27: Synthesis of Intermediate 37

[0745]

[0746] Step 1: 37-A

[0747] Add 2-fluorobenzonitrile (6.78 g, 55.95 mmol, 6.05 mL) and potassium tert-butoxide (6.28 g, 55.95 mmol) to a solution of 34-A (5.0 g, 18.65 mmol) in DMSO (50 mL). Stir the mixture at 140 °C for 16 hours. Cool the mixture to 25 °C, pour it into water, and extract with ethyl acetate (30 mL × 2). Wash the combined organic layers with water (30 mL × 2) and brine (30 mL), concentrate under vacuum, and purify by column chromatography on silica gel (PE / EA = 20 / 1 to 10 / 1) to give 37-A (2.5 g, 36% yield). MS: m / z = 369 (M+1).

[0748] Step 2: 37-B

[0749] To a solution of 37-A (1.3 g, 3.52 mmol) in dioxane (10 mL), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (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) were added. The mixture was stirred at 90 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated under vacuum and purified by column chromatography on silica gel (PE / EA = 10 / 1) to give 37-B (1.22 g, 88% yield). MS: m / z = 373 (M+1).

[0750] Step 3: 37-C

[0751] Pd / C (60 mg, 10%, 55% wetting) was added to a solution of 37-B (600 mg, 1.52 mmol) in EtOH (10 mL). The mixture was stirred at 25 °C under hydrogen for 30 min. The mixture was filtered, and the filtrate was concentrated under vacuum to give 37-C (560 mg, crude). MS: m / z = 375 (M+1).

[0752] Step 4: 37-D

[0753] Hydroxylamine hydrochloride (185.59 mg, 2.67 mmol) and sodium bicarbonate (224.37 mg, 2.67 mmol) were added to a solution of 37-C (200 mg, 534.14 μmol) in DMSO (5 mL). 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 vacuum to give 37-D (200 mg, crude). MS: m / z = 408 (M+1).

[0754] Step 5: 37-E

[0755] Di(imidazol-1-yl) ketone (111 mg, 687 μmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]acoxane (104 mg, 687 μmol) were added to a solution of 37-D (200 mg, 343.59 μmol) in DMSO (5 mL). The mixture was stirred at 25 °C for 3 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 to give 37-E (120 mg, crude). MS: m / z = 434 (M+1).

[0756] Step 6: Intermediate 37

[0757] Add 1.15 mL of 2 M NaOH to a solution of 37-E (120 mg, 229 μmol) in 5 mL MeOH. Stir the mixture at 60 °C for 1 hour. Concentrate the mixture and add 10 mL of water to the residue. Extract the mixture with ethyl acetate (10 mL × 2), and neutralize the aqueous phase with aqueous HCl, then extract with ethyl acetate (10 mL × 2). Wash the combined organic layers with brine (10 mL), dry over sodium sulfate, and concentrate under vacuum to give intermediate 37 (90 mg, 67% yield). MS: m / z = 406 (M+1).

[0758] Example 28: Synthesis of Intermediate 38

[0759] Intermediate 38 in Table 8 is prepared according to the procedure of intermediate 37.

[0760] Table 8

[0761]

[0762] Example 29: Synthesis of Intermediate 39

[0763]

[0764] Step 1: 39-A

[0765] Add to a solution of intermediate 34 (300 mg, 1.10 mmol) in DCM (6 mL) Molecular sieve (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 at 35 °C under oxygen for 16 h. Water (50 mL) was added to quench the reaction. The resulting solution was extracted with ethyl acetate (50 mL × 2), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the 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).

[0766] Step 2: Intermediate 39

[0767] At 0 °C, 2 M NaOH (2 mL) was added dropwise to a solution of 39-A (290 mg, 768.35 μmol) in MeOH (6 mL). The reaction solution was stirred at 25 °C for 16 hours. 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 layers were dried over anhydrous sodium sulfate and concentrated to give intermediate 39 (245 mg, 91% yield). MS: m / z = 350.2 (M+1).

[0768] Example 30: Synthesis of Intermediate 40

[0769]

[0770] Step 1: 40-A

[0771] In an ice-water bath, bis(trimethylsilyl)amino potassium (0.5 M, 15.70 mL) was added to a solution of intermediate 36 (1.1 g, 3.92 mmol) in DMF (10 mL), and the mixture was 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. The mixture was then added to saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to give 40-A (1.1 g, 87.78% yield). MS: m / z = 319.9 (M+1).

[0772] Step 2: 40-B

[0773] Hydroxylamine hydrochloride (718.07 mg, 10.33 mmol) and DIPEA (1.34 g, 10.33 mmol) were added to a solution of 40-A (1.1 g, 3.44 mmol) in ethanol (15 mL). The mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated under vacuum to give a 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).

[0774] Step 3: 40-C

[0775] Di(imidazol-1-yl) ketone (1.01 g, 6.24 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]acoxane (950.44 mg, 6.24 mmol, 931.80 μL) were added to a solution of 40-B (1.1 g, 3.12 mmol) in DMSO (10 mL). 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 × 3). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give 40-C (1 g, 84.66% yield). MS: m / z = 378.8 (M+1).

[0776] Step 4: Intermediate 40

[0777] Lithium hydroxide hydrate (277.26 mg, 6.61 mmol) was added to a solution of 40-C (500 mg, 1.32 mmol) in water (5 mL), THF (5 mL), and methanol (5 mL). The resulting solution was stirred at 25 °C for 16 hours. Approximately half the volume of methanol was removed under vacuum, and HCl (1 M) was added to the residue until pH ~5. The resulting mixture was extracted with ethyl acetate (20 mL × 2), and 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).

[0778] Example 31: Synthesis of Intermediate 41

[0779] Intermediate 41 in Table 9 is prepared according to the procedure of intermediate 40.

[0780] Table 9

[0781]

[0782] Example 32: Synthesis of Intermediate 42

[0783]

[0784] Step 1: 42-B

[0785] To a mixture of 42-A (7.0 g, 26.71 mmol) in EtOH / H₂O (60 mL, 5 / 1), NaOH (2.14 g, 53.43 mmol) was added. After stirring at 25 °C for 2 hours, the volatile fraction was removed under reduced pressure. The residue was diluted with water (100 mL) and the pH was adjusted to ~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) and brine (100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to provide 42-B (7.1 g, crude). MS: m / z = 249.0 (M+1).

[0786] Step 2: 42-C

[0787] HOBT (4.58 g, 33.87 mmol), EDCI (6.50 g, 33.87 mmol), and DIPEA (10.94 g, 84.67 mmol) were added to a mixture of 42-B (7.00 g, 28.22 mmol) and 2-(trimethylsilyl)ethyl-1-ol (4.00 g, 33.87 mmol) in DMF (70 mL). After stirring at 25 °C for 4 hours, 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) and brine (100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 50 / 1) to provide 42-C (7.3 g, 74.27% yield). 1 H NMR (400MHz, CDCl3) δ7.99-7.97(m,1H),7.79-7.76(m,1H),7.41-7.37(m,1H ),7.16-7.13(m,1H),4.45-4.41(m,2H),1.18-1.14(m,2H),0.02(s,9H)ppm.

[0788] Step 3: 42-D

[0789] CuI (151.66 mg, 0.80 mmol) and K3PO4 (4.22 g, 19.91 mmol) were added 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). 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) and brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to provide 42-D (400 mg, 9.63% yield). MS: m / z = 522.3(M+1).

[0790] Step 4: Intermediate 42

[0791] NaOH (61.60 mg, 1.54 mmol) was added to a mixture of 42-D (400 mg, 0.77 mmol) in EtOH / H₂O (12 mL, 5 / 1). After stirring at 25 °C for 2 hours, the resulting 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) and brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to provide intermediate 42 (190 mg, crude). MS: m / z = 494.5 (M+1).

[0792] Example 33: Synthesis of intermediate 43

[0793]

[0794] Step 1: 43-A

[0795] DIEA (188 mg, 1.46 mmol) and 2-(chloromethoxy)ethyl-trimethylsilane (107 mg, 640.78 μmol) were added to a solution of intermediate 41 (0.1 g, 291.26 μmol) in THF (10 mL). The reaction was stirred at 0 °C for 1 h. 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). MS: m / z = 626.3 (M+23).

[0796] Step 2: Intermediate 43

[0797] MgBr2 (518 mg, 2.82 mmol) was added to a solution of 43-A (0.17 g, 281.53 μmol) in DMSO (5 mL). The reaction was stirred at 40 °C for 8 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were 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).

[0798] Example 34: Synthesis of Intermediate 44

[0799]

[0800] Step 1: 44-B

[0801] Potassium carbonate (7.73 g, 55.91 mmol, 3.37 mL) was added to a solution of 44-A (4 g, 27.95 mmol) in DMF (5 mL) and acetonitrile (35 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 × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the 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).

[0802] Step 2: 44-C

[0803] Sodium borohydride (973.31 mg, 25.73 mmol) was slowly added to a solution of 44-B (3 g, 12.86 mmol) in MeOH (30 mL). The reaction mixture was stirred at 25 °C for 5 hours. The reaction mixture was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phases were 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).

[0804] Step 3: 44-D

[0805] A solution of 44-C (856 mg, 4.17 mmol) in thionyl chloride (10 mL) was heated at 80 °C for 16 hours. The reaction mixture was concentrated to dryness and extracted from water (10 mL) 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 the 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).

[0806] Step 4: 44-E

[0807] Cesium carbonate (437 mg, 1.34 mmol) was added to a solution of intermediate 35 (270 mg, 894.23 μmol) in DMF (5 mL), and the mixture was stirred at 25 °C for 10 min. Then 44-D (200 mg, 894.23 μmol) was added, and the reaction mixture was stirred at 60 °C for 5 h. 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 the 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).

[0808] Step 5: 44-F

[0809] A solution of 44-E (414 mg, 847.36 μmol) in TFA (5 mL) was heated at 60 °C for 24 hours. 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).

[0810] Step 6: Intermediate 44

[0811] A solution of sodium hydroxide (25%, 30 μL) was added to a solution of 44-F (125 mg, 313.71 μmol) in THF (3 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated, and then 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 × 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).

[0812] Example 35: Synthesis of Intermediate 45

[0813]

[0814] Step 1: 45-B

[0815] Sodium methanethiol (730 mg, 10.42 mmol) was added to a solution of 45-A (1 g, 5.19 mmol) in THF (10 mL), and the mixture was stirred overnight. The mixture was diluted with H₂O (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 by silica gel column chromatography (PE / EA = 10 / 1) to give 45-B (200 mg, yield 18.87%). MS: m / z = 204.9 (M+1).

[0816] Step 2: 45-C

[0817] At 0 °C, LiAlH4 (44.6 mg, 1.17 mmol) was added to a solution of 45-B (200 mg, 0.98 mmol) in THF (5 mL). The mixture was stirred at 0 °C for 3 hours. The reaction was quenched with H2O (10 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL) and dried over MgSO4, filtered, and concentrated to give 45-C (60 mg, crude). MS: m / z = 163.0 (M+1).

[0818] Step 3: 45-D

[0819] To a solution of 45-C (60 mg, 0.37 mmol) in DCM (3 mL), methanesulfonyl chloride (32 mg, 0.28 mmol) and DMAP (67.78 mg, 0.56 mmol) were added, and the mixture was stirred overnight. The reaction mixture was poured into H₂O (10 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to give 45-D (50 mg, yield 74.87%). MS: m / z = 180.8 (M+1).

[0820] Step 4: 45-E

[0821] Cesium carbonate (180.34 mg, 0.55 mmol) was added to a solution of 45-D (50 mg, 0.28 mmol) and intermediate 35 (100 mg, 0.33 mmol) in MeCN (2 mL), and the mixture was stirred for 16 hours. The mixture was filtered, and the filtrate was diluted with H2O (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give 45-E (80 mg, yield 65.05%). MS: m / z = 445.7 (M+1).

[0822] Step 5: 45-F

[0823] m-CPBA (91.12 mg, 448.84 μmol, 85% purity) was added to a solution of 45-E (80 mg, 179.53 μmol) in DCM (2 mL), and the mixture was stirred for 16 hours. The reaction was quenched with hydrated Na₂S₂O₃ (3 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over MgSO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to give 45-F (40 mg, 46.65% yield). MS: m / z = 477.6 (M+1).

[0824] Step 6: Intermediate 45

[0825] At 0°C, aqueous lithium hydroxide (3M, 0.1mL) was added dropwise to a solution of 45-F (40mg, 83.75μmol) in THF (1mL). The mixture was stirred at 60°C for 2 hours. The mixture was filtered and the filtrate was concentrated to give intermediate 45 (20mg, crude). MS: m / z = 387.7 (M+1).

[0826] Example 36: Synthesis of Intermediate 46

[0827]

[0828] Step 1: 46-A

[0829] Sodium hydride (60% dispersion in mineral oil, 857.49 mg, 37.30 mmol) was added to a mixture of 34-A (10 g, 37.30 mmol) in DMF (50 mL) under a nitrogen atmosphere, and the reaction mixture was stirred at 25 °C for 1 hour, followed by the slow addition of 2-chloroacetonitrile (2.82 g, 37.30 mmol). The resulting mixture was stirred for an additional 18 hours. 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). 1 H NMR (400MHz, CDCl3) δ7.88 (d, J = 1.7Hz, 1H), 7.65-7.50 (m, 1H), 7.42-7.29 (m, 2H), 5.62 (s, 2H), 4.45 (q, J = 7.1Hz, 2H), 1.46 (t, J = 7.1Hz, 3H).

[0830] Step 2: 46-B

[0831] A mixture of 46-A (7.2 g, 23.44 mmol) and 1,3,2-dioxane-2,2-dioxide (7.27 g, 58.60 mmol) in THF (50 mL) under a nitrogen atmosphere was cooled to 5 °C, and then lithium bis(trimethylsilyl)amino (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 × 3). The combined organic layers were dried over sodium sulfate and concentrated under vacuum 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).

[0832] Step 3: 46-C

[0833] 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 hours. 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 vacuum 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).

[0834] Step 4: 46-D

[0835] Add 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) to a mixture of 46-C (2.66 g, 7.26 mmol) in DMSO (30 mL). Stir the mixture at 25 °C for 3 hours. Cool the reaction mixture to 0 °C, quench it with saturated aqueous NH4Cl (50 mL), and extract with ethyl acetate (50 mL × 3). Dry the combined organic layers with sodium sulfate and concentrate under vacuum to give 46-D (2.2 g, 77.23% yield). MS: m / z = 391.6 (M+1).

[0836] Step 5: 46-E

[0837] 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-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (2.54 g, 9.99 mmol), and potassium acetate (1.96 g, 19.98 mmol) in dioxane (25 mL) was degassed for 15 min, and then cyclopentyl(diphenyl)phosphine, dichloromethane, palladium dichloride, and iron (244.77 mg, 299.73 μmol) were added. The reaction mixture was degassed again for 15 min, and then heated at 80 °C for 16 h. The mixture was cooled, filtered, and washed with MTBE (10 mL × 4). The organic extracts were combined, concentrated, and then added to a 2 M NaOH aqueous solution (26 mL) in an ice bath. The alkaline aqueous solution was extracted with MTBE (10 mL × 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 × 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 hexane) to give 2-(6,6-dimethyl-2,5-dihydropyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (1.5 g, 6.3 mmol).

[0838] A mixture of 2-(6,6-dimethyl-2,5-dihydropyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (1.5 g, 6.3 mmol), intermediate 46-D (2 g, 5.10 mmol), Na₂CO₃ (1.08 g, 10.20 mmol), and Pd(dppf)Cl₂ (416.43 mg, 509.94 μmol) in dioxane (15 mL) and water (5 mL) under a nitrogen atmosphere was heated at 90 °C for 16 hours. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 50 / 1) to give 46-E (2.5 g, crude). MS: m / z = 423.8 (M+1).

[0839] Step 6: 46-F

[0840] 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 for 16 hours under a H2 atmosphere (1 atm). The mixture was filtered, and the filtrate was concentrated under reduced pressure. Pd / C (1.5 g) was added to the residue in methanol, and the mixture was stirred at 25 °C for 16 hours under a H2 atmosphere (1 atm). The mixture was filtered and concentrated to the 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).

[0841] Step 7: 46-G

[0842] 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 hours. The reaction mixture was concentrated under vacuum, 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).

[0843] Step 8: 46-H

[0844] Add 2,3,4,6,7,8,9,10-octahydropyrimidino[1,2-a]acoxane (342.98 mg, 2.25 mmol) and di(imidazol-1-yl)methyl ketone (365.31 mg, 2.25 mmol) to a mixture of 46-G (450 mg, 1.13 mmol) in DMSO (5 mL). Stir the reaction mixture at 25 °C for 3 hours. Cool the reaction mixture to 0 °C, quench it with saturated aqueous NH4Cl (15 mL), and extract with ethyl acetate (15 mL × 3). Dry the combined organic layers with sodium sulfate and concentrate under vacuum to give 46-H (440 mg, 91.80% yield). MS: m / z = 425.7 (M+1).

[0845] Step 9: Intermediate 46

[0846] Lithium hydroxide hydrate (216.98 mg, 5.17 mmol) was added to a solution of 46-H (440 mg, 1.03 mmol) in methanol (2 mL), water (2 mL), and THF (2 mL). The resulting solution was stirred at 50 °C for 16 h. The solvent was removed under vacuum, 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 × 2), and 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).

[0847] Example 37: Separation of intermediates 35-P1 and 35-P2

[0848]

[0849] Intermediate 35 (5.3g) was processed via SFC (column: IE 4.6×250mm 5μm; mobile phase: hexane / EtOH=30 / 70; column temperature: 25℃; flow rate: 1mL / min) separation to give intermediate 35-P1 (Rt=10.94min) and intermediate 35-P2 (2.5g,Rt=21.33min).

[0850] Example 38: Separation of intermediates 46-P1 and 46-P2

[0851] The compounds in Table 10 were obtained by SFC separation as intermediates 35-P1 and 35-P2.

[0852] Table 10

[0853]

[0854] Example 39: Synthesis of Intermediate 47

[0855]

[0856] Step 1: 47-A

[0857] Sodium hydroxide (597.21 mg, 14.93 mmol) was added to a solution of intermediate 35-P2 (1.5 g, 4.98 mmol) in methanol (20 mL) and water (10 mL). The mixture was stirred at 60 °C for 3 hours. Approximately half the volume of methanol was removed under vacuum, and 1 M HCl was added to the residue until pH ~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).

[0858] Step 2: 47-B

[0859] In an ice-water bath, thionyl chloride (679.19 mg, 5.71 mmol) was added to a solution of 47-A (1.30 g, 4.76 mmol) in DMA (30 mL). After the addition, the resulting mixture was heated to 25 °C and stirred for 3 hours. In an ice-water bath, TEA (1.44 g, 14.27 mmol) and N-methylaniline (611.57 mg, 5.71 mmol) were added to the resulting mixture. The mixture was heated to 25 °C and stirred for 16 hours. 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).

[0860] Step 3: 47-C

[0861] 47-B (1.52 g, 4.19 mmol) was added to a suspension of sodium hydride (503.17 mg, 12.58 mmol, 60% dispersion in mineral oil) in 1,3-dimethylimidazolium-2-one (40 mL) in an ice-water bath. Following the addition, the resulting mixture was heated to 25 °C and stirred for 1 hour. 2-Chloroacetonitrile (474.90 mg, 6.29 mmol) was added, and the resulting solution was stirred at 25 °C for 16 hours. Saturated aqueous NH4Cl (80 mL) was added to the resulting mixture, and the aqueous layer was extracted with ethyl acetate (40 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 47-C (1.68 g, crude). MS: m / z = 402 (M+1).

[0862] Step 4: 47-D

[0863] LiHMDS (1M, 33.47mL) was added to a solution of 47-C (1.68g, 4.18mmol) and (4R)-4-methyl-1,3,2-dioxane-2,2-dioxide (1.73g, 12.55mmol) in DMPU (20mL) under ice-water cooling (<15°C). The resulting solution was stirred at 15°C for 4 hours. The reaction was quenched by saturated aqueous NH4Cl (30mL), and the aqueous layer was extracted with ethyl acetate (30mL × 3). The combined organic layers were washed with water (20mL) and brine (15mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to give 47-D (380mg, 20.57% yield). MS: m / z = 442 (M+1).

[0864] Step 5: 47-E

[0865] Sodium bicarbonate (722.89 mg, 8.61 mmol) was added to a solution of 47-D (380 mg, 860.58 μmol) and hydroxylamine hydrochloride (598.02 mg, 8.61 mmol) in DMSO (10 mL). The resulting mixture was heated at 60 °C for 5 hours, followed by the addition of ethyl acetate (70 mL). The organic layer was separated and washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMSO (10 mL), to which 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 hours. Subsequently, saturated aqueous NH4Cl (20 mL) was 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 chromatography (PE / EA = 1 / 1) to give 47-E (220 mg, 51.07% yield). 1 HNMR(400MHz, CDCl3)δ11.14(s,1H),7.60-7.23(m,5H),7.06(t,J=28.0Hz,4H),4.13-3.97(m,3H),3.82-3.63(m,2H ), 3.48 (s, 3H), 2.86 (s, 1H), 1.98 (s, 3H), 1.88-1.66 (m, 2H), 1.49-1.33 (m, 2H), 1.18 (M, 6H) ppm; MS: m / z=501 (M+1).

[0866] Step 6: Intermediate 47

[0867] Potassium hydroxide (246.57 mg, 4.39 mmol) was added to a solution of 47-E (220.00 mg, 439.48 μmol) in methoxyethanol (3 mL). The reaction mixture was heated at 100 °C for 3 hours. After cooling, HCl (6 M) was added to the resulting mixture in an ice-water bath until pH ~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) and brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give intermediate 47 (270 mg, crude). MS: m / z = 412 (M+1).

[0868] Example 40: Synthesis of intermediates 48 and 49

[0869] The compounds in Table 11 were prepared according to the procedure for intermediate 47.

[0870] Table 11

[0871]

[0872] Example 41: Synthesis of Intermediate 50

[0873]

[0874] Step 1: 50-A

[0875] NaOH (13.35 mmol, 10% aqueous solution) was added to a solution of 37-C (1 g, 2.67 mmol) in THF (30 mL), and the reaction was stirred at 20 °C for 16 hours. Most of the solvent was evaporated, and the residue was diluted with 5 mL of water and loaded with concentrated HCl until pH ~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).

[0876] Step 2: Intermediate 50

[0877] Dibal-H (1M, 4.39 mL) was added to a solution of 50-A (380 mg, 1.10 mmol) in THF (5 mL), and the mixture was stirred at 20 °C for 48 hours. The reaction mixture was poured into 5 mL of 1M HCl and extracted with ethyl acetate (5 mL × 3). The organic layer was dried over sodium sulfate and concentrated to give the residue. The residue was purified by reverse-phase chromatography (ACN: 0.1% HCOOH in H₂O = 50:50) to give intermediate 50 (190 mg, 50% yield). MS: m / z = 350.2 (M+1).

[0878] Example 42: Synthesis of intermediates 51-P1 and 51-P2

[0879]

[0880] Step 1: 51-B

[0881] At -78 °C, n-BuLi (2.4 M, 6.35 mL) was added dropwise to a solution of 51-A (1 g, 7.62 mmol) in THF (10 mL). The reaction mixture was heated to -60 °C and stirred for 1 h. Then, DMF (5.57 g, 76.21 mmol) was 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 vacuum. 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).

[0882] Step 2: 51-C

[0883] At 25 °C, a solution of 51-B (1 g, 6.28 mmol) in THF (10 mL) was added dropwise to a mixture of LiBH4 (276.33 mg, 12.56 mmol) in THF (10 mL). The resulting mixture was stirred for 18 hours, then diluted with HCl (1 M, 1 mL). The mixture was adjusted to pH ~8 with saturated aqueous NaHCO3 and extracted with DCM (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (EA / DCM = 1 / 3) to give 51-C (0.9 g, 5.58 mmol, 88.87% yield). MS: m / z = 161.9 (M+1).

[0884] Step 3: 51-D

[0885] In an ice bath, MsCl (78.45 mg, 6.82 mmol) was added dropwise to a mixture of 51-C (1 g, 6.20 mmol) and DMAP (1.14 g, 9.30 mmol) in DCM (2 mL). After stirring for 18 hours, the resulting mixture was concentrated. The residue was purified by silica gel column chromatography (EA / DCM = 1 / 5) to give 51-D (390 mg, 2.17 mmol, 35.0% yield). 1 H NMR (400MHz, CDCl3) δ7.47 (s, 1H), 4.80 (d, J = 0.5Hz, 2H), 2.70 (s, 3H).

[0886] Step 4: 51-E

[0887] Intermediate 35 (50 mg, 165.90 mol) was added to a suspension of Cs₂CO₃ (108.17 mg, 331.81 μmol) in MeCN (5 mL) in an ice bath. After stirring for 1 hour, 51-D (29.81 mg, 165.90 μmol) was added and the resulting mixture was stirred for 16 hours. The mixture was diluted with ice water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give 51-E (50 mg, 112.46 μmol, 67.79% yield). MS: m / z = 444.9 (M+1).

[0888] Step 5: 51-F

[0889] 51-E (800 mg, 1.8 mmol) was mixed fractionally with mCPBA (776.28 mg, 85% purity) in DCM (20 mL) under an argon atmosphere and with stirring at 0 °C. The reaction was stirred at 0 °C for 30 min, then at 25 °C for 18 h. The mixture was washed with NaHCO3 (2 M), water, and brine. The organic phase was dried over sodium sulfate and concentrated to give a residue, which was purified by column chromatography (PE / EA = 1 / 1) to give 51-F (600 mg, 70% yield). MS: m / z = 476.9 (M+1).

[0890] Step 6: Intermediate 51-P1 and Intermediate 51-P2

[0891] A mixture of 51-F (600 mg, 1.26 mmol), NaOH (503.56 mg, 12.59 mmol), and THF (3 mL) in a sealed tube was heated at 60 °C for 18 hours. The solvent was removed under vacuum, and the residue was diluted with water (3 mL) and adjusted to pH 3-5 with HCl (1 M). The solids were collected by filtration and dried, and then separated by chiral preparative HPLC (column: OJ-H, 20×250 mm; flow rate: 40 g / min; solvent: MeOH (NH4OH 0.2%): CO2 = 30:70; time: 7.94 min, 12.42 min) to provide intermediates 51-P1 (150 mg, 388.13 μmol, 30.83% yield, RT = 5.13 min) and 51-P2 (150 mg, 388.13 μmol, 30.83% yield, RT = 7.27 min).

[0892] Intermediate 51-P1: ¹H NMR (400MHz, DMSO) δ 13.08 (bs, ¹H), 11.03 (d, J = 2.2Hz, ¹H), 7.68 (d, J = 8.7Hz, ¹H), 7.52 (s, ¹H), 7.27 (dd, J = 8.7, 1.5Hz, ¹H), 7.21 (s, ¹H), 7.02 (d, J = 2.6Hz, ¹H), 5.64 (s, 2H), 3.71 (d, J = 7.3Hz, 2H), 3.02 (t, J = 12.4Hz, 1H), 1.69 (d, J = 12.8Hz, 2H), 1.64–1.46 (m, 2H), 1.32–1.24 (m, 3H), 1.19 (s, 3H). MS: m / z = 387 (M+1).

[0893] Intermediate 51-P2: 1H NMR (400MHz, DMSO) δ13.03(bs,1H),11.03(s,1H),7.68(d,J=8.8Hz,1H),7.52(s,1H),7.27(d,J=8.6Hz,1H),7.21(s,1H),7.02(s,1H),5. 64 (s, 2H), 3.72 (d, J = 7.7Hz, 2H), 3.01 (d, J = 12.8Hz, 2H), 1.68 (s, 2H), 1.56 (dt, J = 26.0, 10.9Hz, 2H), 1.26 (d, J = 12.3Hz, 3H), 1.19 (s, 3H).

[0894] Example 43: Synthesis of Intermediate 52

[0895]

[0896] Step 1: 52-A

[0897] A mixture of 46-B (2 g, 6.0 mmol), sodium bicarbonate (2.52 g, 30.01 mmol, 1.17 mL), and hydroxylamine hydrochloride (2.09 g, 30.01 mmol, 1.25 mL) in DMSO (50 mL) was heated at 50 °C for 3 hours. 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 vacuum to give the residue. The residue (together with crude product from another batch) was purified by column chromatography (PE / EA = 3 / 1) to give 52-A (1.32 g, byproduct).

[0898] Step 2: 52-B

[0899] A mixture of 52-A (1.1 g, 3.13 mmol), 2-(6,6-dimethyl-2,5-dihydropyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (447.52 mg, 1.88 mmol), sodium carbonate (663.95 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (458.36 mg, 626.43 μmol) in dioxane (10 mL) and water (3 mL) was heated at 90 °C for 18 hours. The solvent was removed under vacuum to give the crude product. The crude product was purified by column chromatography (PE / EA = 1 / 10) to give 52-B (1 g, 83.48% yield).

[0900] Step 3: 52-C

[0901] Pd / C (10%, 556.51 mg) was added to a mixture of 52-B (1 g, 2.62 mmol) in methanol (15 mL), and the mixture was stirred for 18 hours under a hydrogen atmosphere using a balloon. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under vacuum to give a residue, which was purified by column chromatography (PE / EA = 1 / 10) to give 52-C (1 g, 2.60 mmol, 99.48% yield).

[0902] Step 4: 52-D

[0903] A mixture of 52-C (160 mg, 416.16 μmol) and phosphorus pentasulfide (370.0 mg, 832.32 μmol) in THF (3 mL) was heated at 50 °C for 18 hours. The solvent was removed under vacuum to give a crude product, which was purified by column chromatography (PE / EA = 3 / 1) to obtain 52-D (130 mg, 78% yield). MS: m / z = 400.8 (M+1).

[0904] Step 5: 52-E

[0905] At 25 °C, s-chlorochloromethanethioate (163.51 mg, 1.25 mmol) was slowly added to a mixture of 52-D (100 mg, 249.67 μmol) in THF (3 mL), and the mixture was stirred for 2 hours. The mixture was quenched with water and extracted with DCM (20 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give a residue, which was purified by combi-flash (PE / EA = 5 / 1) to provide 52-E (75 mg, 65.5% yield). MS: m / z = 458.9 (M+1).

[0906] Step 6: 52-F

[0907] At 10 °C, a solution of triphenylphosphine (146.99 mg, 0.56 mmol) in dioxane (5 mL) was added to a mixture of 52-E (257 mg, 0.56 mmol) and dioxane (10 mL), and the reaction mixture was stirred for 10 min. Azide-trimethylsilane (129 mg, 1.12 mmol) was added, and the reaction mixture was stirred at 120 °C for 3 h. The solvent was removed under reduced pressure, and the residue was purified by combi-flash (DCM / methanol = 15 / 1) to provide 52-F (60 mg, 24%). MS: m / z = 441.8 (M+1).

[0908] Step 7: Intermediate 52

[0909] A mixture of 52-F (60 mg, 0.136 mmol) in KOH (2 M, 2 mL) and THF (5 mL) was stirred at 70 °C for 18 hours. Most of the solvent was removed under reduced pressure, and the mixture was adjusted to pH 5–6 and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over sodium sulfate and then filtered. The filtrate was concentrated under vacuum to provide intermediate 52 (60 mg, crude). MS: m / z = 413.8 (M+1).

[0910] Example 44: Synthesis of Intermediate 53

[0911]

[0912] Step 1: 53-B

[0913] The mixture of 53-A (11 g, 52.31 mmol) in thionyl chloride (180.40 g, 1.52 mol, 110.0 mL) was stirred at 70 °C for 16 h. The mixture was concentrated to dryness and dissolved in DCM (100 mL). NH3H2O ​​(100 mL) was added in an ice-water bath, and the reaction was heated to 25 °C and stirred for 0.5 h. The mixture was concentrated under reduced pressure to provide 53-B (16.26 g, crude). MS: m / z = 208.9 (M+1).

[0914] Step 2: 53-C

[0915] At 0 °C, sulfonyl chloride (15.81 g, 117 mmol) was added very slowly to a solution of 53-B (16.26 g) in DCE (160 mL). The reaction mixture was then stirred at 25 °C for 3 hours. The resulting mixture was concentrated under vacuum, and the residue was treated with ethyl acetate (100 mL) and H₂O (100 mL). The aqueous layer was then extracted with ethyl acetate (200 mL × 2). The combined organics were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give 53-C (7.3 g, 92% yield). MS: m / z = 102.0 (M+1).

[0916] Step 3: 53-D

[0917] K₂CO₃ (19.95 g, 144.37 mmol) was added to a solution of 53-C (7.3 g, 72.19 mmol) in DMF (50 mL) at 0 °C, followed by the addition of benzyl bromide (14.2 mL, 83.01 mmol). The reaction mixture was allowed to be stirred at 25 °C for 24 hours. The reaction mixture was diluted with H₂O (200 mL) and extracted with Et₂O. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to give a crude product, which was purified by rapid column chromatography (heptane / EA = 4 / 1) to give 53-D (3.78 g, 27% yield). 1H NMR (400MHz, CDCl3) δ8.48 (d, J=4.7Hz, 1H), 7.49 (dd, J=7.7, 1.0Hz, 2H), 7.45-7.32 (m, 3H), 6.67 (d, J=4.7Hz, 1H), 5.45 (s, 2H); MS: m / z=191.9 (M+1).

[0918] Step 4: 53-E

[0919] 53-D (500 mg, 2.61 mol) was added to freshly prepared LDA (0.58 mmol) in Et2O (4.5 mL) under N2 at -78 °C to Et2O (0.3 mL). After 15 min, DMF (213 mg, 2.92 mmol) was added to Et2O (0.2 mL), and stirring was continued at -78 °C for 15 min. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to give a residue, which was purified by combi-flash (PE / EA = 4 / 1) to provide 53-E (100 mg, 17% yield). 1 H NMR (400MHz, CDCl3) δ10.05 (s, 1H), 7.53-7.33 (m, 5H), 7.17 (s, 1H), 5.46 (s, 2H); MS: m / z=220.1 (M+1).

[0920] Step 5: 53-F

[0921] Sodium borohydride (67 mg, 1.77 mmol) was added to a solution of 53-E (259 mg, 1.18 mmol) in methanol (10 mL). The mixture was stirred at 25 °C for 0.5 h. The solvent was removed, and the residue was purified by combi-flash (DCM / methanol = 20 / 1) to provide 53-F (159 mg, 60% yield). MS: m / z = 221.9 (M+1).

[0922] Step 6: 53-G

[0923] At 25°C, thionyl chloride (177 mg, 1.49 mmol) was added to a solution of 53-F (110 mg, 0.497 mmol) in DCM (2 mL). The reaction was stirred for 2 hours. The reaction mixture was concentrated under vacuum to provide 53-G (110 mg, crude). MS: m / z = 239.9 (M+1).

[0924] Step 7: 53-H

[0925] A mixture of intermediates 35, 53-G (109 mg, 0.456 mmol), Cs₂CO₃ (297 mg, 0.912 mmol), and DMF (5 mL) was stirred at 60 °C for 3 hours. Water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under vacuum and purified by combi-flash (DCM / methanol = 20 / 1) to provide 53-H (112 mg, 48% yield). MS: m / z = 504.7 (M+1).

[0926] Step 8: 53-I

[0927] The mixture of 53-H (107 mg, 0.212 mmol) and TFA (5 mL) was stirred at 50 °C for 2 hours. The reaction mixture was concentrated under vacuum to give 53-I (80 mg, 91% yield). MS: m / z = 414.8 (M+1).

[0928] Step 9: Intermediate 53

[0929] A mixture of 53-H (84 mg, 0.202 mmol) in NaOH (2 M, 5 mL) and THF (5 mL) was stirred at 25 °C for 2 hours. Most of the solvent was removed, and the mixture was adjusted to pH 5–6 and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under vacuum to give intermediate 53 (60 mg, 76% yield). MS: m / z = 386.7 (M+1).

[0930] Example 45: Synthesis of Intermediate 54

[0931]

[0932] Step 1: 54-A

[0933] A 20 mL microwave reaction tube was loaded with 46-B (600 mg, 1.80 mmol), (2-methyl-4-pyridyl)boronic acid (295.94 mg, 2.16 mmol), K₂CO₃ (746.65 mg, 5.40 mmol), and cyclopentyl(diphenyl)phosphine in water (3 mL) and dioxane (12 mL); dichloromethane; palladium dichloride; and iron (147.06 mg, 180.08 μmol). After removing O₂ by bubbling N₂ into the reaction solution, the tube was sealed and heated in a Biotage microwave reactor at 120 °C for 50 min. The reaction was cooled to 25 °C, diluted with ethyl acetate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by rapid chromatography (EA in PE, 0%–50%) to provide 54-A (590 mg, 1.71 mmol, 87.59% yield). MS: m / z = 346.2(M+1).

[0934] Step 2: Intermediate 54

[0935] A mixture of 54-A (550 mg, 1.59 mmol) and lithium hydroxide hydrate (267.29 mg, 6.37 mmol) in THF (6 mL) and water (1 mL) was stirred at 25 °C for 24 h. The reaction mixture was acidified with 1 M HCl and concentrated. The crude product was purified by FCC (methanol in DCM, 0%–10%) to give intermediate 54 (300 mg, 945.36 μmol, 59.37% yield). MS: m / z = 318.1 (M+1).

[0936] Example 46: Synthesis of Compound 1

[0937]

[0938] Step 1: 1-1

[0939] Add 2 mL of 6 M NaOH to a solution of 33-A (30 mg, 90.04 μmol) in 5 mL of MeOH. Stir the reaction mixture at 25 °C for 2 hours. Remove the MeOH, adjust the pH of the mixture to approximately 5 with 1 M HCl, and extract the mixture with 20 mL × 3 ethyl acetate. Wash the combined organic layers with 10 mL of brine, dry over sodium sulfate, and concentrate under vacuum to give 1-1 (25 mg, 91% yield). MS: m / z = 305.0 (M+1).

[0940] Step 2: 1-2

[0941] DIEA (52 mg, 409.67 μmol) was added to a solution of 1-1 (25 mg, 81.93 μmol), intermediate 3 (40 mg, 81.93 μmol), and HATU (46 mg, 122.9 μmol) in DMF (2 mL). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (30 mL) and filtered. The filtrate was concentrated and purified by preparative TLC (DCM / MeOH = 10 / 1) to give 1-2 (30 mg, 47% yield). MS: m / z = 776.1 (M+1).

[0942] Step 3: 1-3

[0943] To a solution of 1-2 (30 mg, 38.63 μmol) in toluene (5 mL), 2,2-dimethylmorpholine (22 mg, 193.14 μmol), t-BuONa (11 mg, 115.89 μmol), Jonephos (3 mg, 7.73 μmol), and Pd2(dba)3 (4 mg, 3.86 μmol) were added. The mixture was stirred at 100 °C for 16 h. The reaction mixture was extracted with ethyl acetate (50 mL × 2), the combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 1-3 (10 mg, 32% yield). MS: m / z = 811.3 (M+1).

[0944] Step 4: 1-4

[0945] Add NH₂OH·HCl (25 mg, 369.96 μmol) and NaHCO₃ (31 mg, 369.96 μmol) to a solution of 1-3 (10 mg, 12.33 μmol) in DMSO (2 mL). Stir the mixture at 60 °C for 16 hours. Dilute the reaction mixture with ethyl acetate (20 mL), wash with brine (10 mL × 2), dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate to give 1-4 (10 mg, 96% yield). MS: m / z = 844.3 (M+1).

[0946] Step 5: Compound 1

[0947] DBU (15 mg, 59.25 μmol) and CDI (8 mg, 59.25 μmol) were added to a solution of 1-4 (10 mg, 11.85 μmol) in DMSO (3 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction was concentrated and purified by preparative HPLC (column: Xbridge 5 μm C18 150 × 19 mm, mobile phase: MeCN-H2O (0.1% FA)) to give compound 1 (1.0 mg, 9.70% yield). 1 H NMR (400MHz, CD3OD) δ8.15(d,J=21.6Hz,1H),7.66-7.40(m,5H),7.16(d,J=6.0Hz,2H),6.88-6.64(m,4H),5.34-5.20(m,1H),4.11(s, 3H), 3.87-3.77(m,2H), 3.62-3.47(m,2H), 2.97-2.65(m,6H), 2.27(s,6H), 1.47-1.43(m,4H), 1.33-1.29(m,9H); MS: m / z=870.2(M+1).

[0948] Example 47: Synthesis of Compound 2

[0949]

[0950] Step 1: 2-1

[0951] DIEA (90 mg, 700.22 μmol) was added to a solution of intermediate 33 (13 mg, 35.01 μmol), intermediate 3 (17 mg, 35.01 μmol), and HATU (19 mg, 52.52 μmol) in DMF (2 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (30 mL) and filtered. The filtrate was concentrated and purified by preparative TLC (DCM / MeOH = 10 / 1) to give 2-1 (12 mg, 41% yield). MS: m / z = 843.2 (M+1).

[0952] Step 2: 2-2

[0953] To a solution of 2-1 (12 mg, 14.24 μmol) in DMSO (1 mL), add NaHCO3 (23 mg, 284.76 μmol) and NH2OH·HCl (19 mg, 284.76 μmol). Stir the mixture at 60 °C for 16 hours. Dilute the reaction mixture with ethyl acetate (20 mL), wash with brine (10 mL × 2), dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate to dryness to give 2-2 (10 mg, 80% yield). MS: m / z = 876.2 (M+1).

[0954] Step 3: Compound 2

[0955] CDI (2 mg, 11.42 μmol) and DBU (3 mg, 11.42 μmol) were added to a solution of 2-2 (10 mg, 11.42 μmol) in DMSO (1 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL × 3) and brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by preparative HPLC (column: Xbridge 5 μm C18 150 × 19 mm, mobile phase: MeCN-H2O (0.1% NH4OH)) to give compound 2 (1.1 mg, 11% yield). 1 H NMR (400MHz, CD3OD)δ

[0956] 8.81-8.65(m,2H),8.16-7.84(m,3H),7.69-7.64(m,2H),7.48-7.43( m,1H),7.33-7.13(m,4H),6.86-6.62(m,2H),5.33-5.17(m,1H),4.10 -4.00(m,3H),3.61-3.46(m,2H),2.86-2.63(m,2H),2.25(s,6H),1.75-1.71(m,2H),1.45-1.39(m,2H),1.27(s,3H); MS: m / z=902.2(M+1).

[0957] Example 48: Synthesis of Compounds 3-23

[0958] The compounds in Table 12 were prepared according to the procedure for compound 2.

[0959] Table 12

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970] Example 49: Synthesis of Compound 24

[0971]

[0972] DIEA (15 mg, 112.36 μmol) was added to a solution of intermediates 19-P1 (11 mg, 22.47 μmol), 46-P2 (10 mg, 25.16 μmol), and HATU (13 mg, 33.71 μmol) in NMP (2 mL). The reaction mixture was stirred at 25 °C for 16 h. The mixture was concentrated and purified by reverse-phase column chromatography (MeCN: 0.5% FA in H2O = 60:40) to give compound 24 (3.2 mg, 16% yield). 1 H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.31(s,1H),7.63-7.50(m,4H),7.25-7. 24(m,3H),7.06(s,1H),6.91-6.82(m,2H),5.65(s,1H),4.33(s,2H),4.11(s,3 H),3.90(s,2H),3.72(d,J=7.6Hz,2H),3.04(s,1H),2.23(s,6H),1.67-1.63(m ,6H),1.62-1.37(m,5H),1.28-1.23(m,3H),1.18(s,3H); MS: m / z=869.3(M+1).

[0973] Example 50: Synthesis of Compounds 25-52

[0974] The compounds in Table 13 were prepared according to the procedure for compound 24.

[0975] Table 13

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988] Example 51: Synthesis of Compound 53

[0989] Step 1: 53-1

[0990] DIEA (21 mg, 161.10 μmol) was added to a solution of intermediate 43 (17 mg, 35.44 μmol), intermediate 25-P2 (15 mg, 32.22 μmol), and HATU (18 mg, 48.33 μmol) in DMF (2 mL). The reaction was stirred at 20 °C for 3 hours. The mixture was concentrated and purified by reverse-phase column chromatography (70% MeCN in water) to give 53-1 (0.02 g, 67% yield). MS: m / z = 921.3 (M+1).

[0991] Step 2: Compound 53

[0992] CH3COOH (52 mg, 868.49 μmol) and TBAF (1 M, 868 μL) were added to a solution of 53-1 (0.02 g, 21.71 μmol) in THF (2 mL). The reaction was stirred at 80 °C for 72 h. The mixture was concentrated and purified by reverse-phase column chromatography (65% MeCN in water) to give compound 53 (7 mg, 41% yield). 1H NMR (400MHz, CD3OD) δ7.46 (s, 1H), 7.41-7.38 (m, 2H), 7.19 (d, J = 8.4Hz, 1H), 6.98 (t, J = 8.4Hz, 2H ),6.84(s,1H),6.51(s,2H),6.22(s,1H),5.63(s,1H),5.35(s,2H),4.51(s,2H),4.21(s,1H),3.9 7(d,J=10.8Hz,2H),3.73(s,1H),3.50(td,J=10.8,3.6Hz,2H),3.19(s,3H),2.92(s,2H),2.87-2 .75(m,1H),1.94(s,6H),1.78-1.67(m,3H),1.42(s,6H),1.38-1.19(m,4H); MS: m / z=791.3(M+1).

[0993] Example 52: Synthesis of Compound 54

[0994] The compounds in Table 14 were prepared according to the procedure for compound 53.

[0995] Table 14

[0996]

[0997]

[0998] Example 53: Synthesis of Compound 55

[0999]

[1000] Step 1: 55-1

[1001] Intermediate 50 (18 mg, 53.64 μmol), HATU (34 mg, 89.40 μmol), and DIEA (29 mg, 223.49 μmol) were added to a solution of intermediate 8 (20 mg, 44.70 μmol) in DMF (2 mL). The reaction was stirred at 15 °C for 4 hours. The reaction mixture was diluted with ethyl acetate (10 mL), and the ethyl acetate layer was washed with brine (5 mL × 5), dried over sodium sulfate, and concentrated to give a residue, which was purified by reverse-phase chromatography (0.1% FA:MeCN = 44:56 in water) to give 55-1 (12 mg, 34% yield). MS: m / z = 801.2 (M+23).

[1002] Step 2: Compound 55

[1003] 2-Methylbut-2-ene (5.40 mg, 77.04 μmol), KH₂PO₄ (6 mg, 46.22 μmol), and NaClO₂ (4 mg, 46.22 μmol) were added to a solution of 55-1 (12 mg, 15.41 μmol) in dioxane / H₂O (3:1, 3 mL). The reaction was stirred at 20 °C for 4 hours. The mixture was concentrated and purified by reverse-phase reaction (0.1% FA:MeCN = 43:57 in water) to give compound 55 (3.7 mg, 30% yield). 1 H NMR(400MHz,MeOD)δ8.28(s,1H),8.15(s,1H),7.93(d,J=8.0Hz,1H),7.6 7-7.47(m,7H),7.16-7.12(m,3H),7.01-6.99(m,2H),6.84(s,1H),6.67(s ,1H),4.62-4.44(m,2H),4.21-4.20(m,2H),4.10-4.03(m,4H),3.58(t,J =11.2Hz,2H),2.88-2.86(m,1H),1.86-1.79(m,4H); MS: m / z=795.2(M+1).

[1004] Example 54: Synthesis of Compounds 56 and 57

[1005] The compounds in Table 15 were prepared according to the procedure for compound 55.

[1006] Table 15

[1007]

[1008] Example 55: Synthesis of Compound 58

[1009]

[1010] At 25°C, TEA (27.14 mg, 268.19 μmol) was added to a mixture of intermediate 8 (40 mg, 89.40 μmol), intermediate 40 (46.98 mg, 134.10 μmol), EDCI (34.28 mg, 178.80 μmol), HOBT (18.12 mg, 134.10 μmol), and DCM (1.5 mL). The mixture was stirred overnight. The resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over sodium sulfate and then filtered. The crude product was further purified by preparative HPLC (Waters 2545, column: Gemini-C18 150 × 21.2 mm, 5 μm; mobile phase: MeCN-H2O (0.1% FA), from 25% to 40% MeCN) to provide compound 58 (15.5 mg, 22%). 1 H NMR (400MHz, DMSO) δ8.47(d,J=5.2Hz,1H),8.26(s,1H),8.13(d,J=13.2Hz,2H),7.75(s,2H),7.70-7.45(m,5H),7.31-7.22(m,2H),7.1 0(s,1H),7.00(s,1H),6.79(s,1H),5.48(s,2H),4.90(s,2H),4.39(s,2H),4.25(s,2H),4.09(s,3H),2.54(s,3H); MS: m / z=779.5(M+1).

[1011] Example 56: Synthesis of Compound 59

[1012]

[1013] Step 1: 59-1

[1014] Intermediate 34 (3.7 g, 0.014 mol) was added to a suspension of sodium hydride (840 mg, 21 mmol, 60% in mineral oil) in dry DMF (30 mL). The solution was stirred at 20 °C for 10 min. Then, 1,3-difluoro-2-nitrobenzene (2.16 g, 0.014 mol) was added to the reaction mixture, and the reaction was heated at 100 °C for 2 h. The reaction was quenched with 50 mL of saturated NH4Cl solution and extracted with ethyl acetate (80 mL × 3). The organic phase was washed with water (30 mL × 3) and brine (30 mL), dried over sodium sulfate, and concentrated to give 59-1 (5.56 g, crude). MS: m / z = 413 (M+1).

[1015] Step 2: 59-2

[1016] (4-Methoxyphenyl)methylamine (1.85 g, 0.013 mol) and K₂CO₃ (9.88 g, 0.072 mol) were added to a solution of 59-1 (5.56 g, 0.013 mol) in DMF (30 mL). The reaction was heated at 80 °C for 1 hour. The reaction mixture was diluted with 50 mL of ethyl acetate, washed with brine (30 mL × 3), dried over sodium sulfate, and concentrated under low pressure to give 59-2 (3.2 g, 47% yield). MS: m / z = 530.1 (M+1).

[1017] Step 3: 59-3

[1018] TFA (10 mL) was added to a solution of 59-2 (3.2 g, 0.006 mol) in DCM (20 mL). The reaction was stirred at 40 °C for 2 hours. The reaction mixture was diluted with 20 mL of water and extracted with DCM (30 mL × 3). The organic phase was dried over sodium sulfate and concentrated to give a residue, which was purified by silica gel chromatography (PE / EA = 10 / 1 to 2 / 1) to give 59-3 (2.16 g, 88% yield). MS: m / z = 410 (M+1).

[1019] Step 4: 59-4

[1020] Reducing Fe (2.96 g, 0.052 mol) and NH4Cl (5.34 g, 0...

Claims

1. A compound selected from the group consisting of: Or its pharmaceutically acceptable salts or tautomers.

2. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, a carrier or excipient, and the compound of claim 1 or a pharmaceutically acceptable salt or tautomer thereof.

3. A compound is: Or its pharmaceutically acceptable salts or tautomers.

4. The compound according to claim 3, wherein:

5. The compound according to claim 3, which is Pharmaceutically acceptable salts.

6. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, a carrier or excipient, and the compound of claim 3 or a pharmaceutically acceptable salt or tautomer thereof.

7. A compound is: Or its pharmaceutically acceptable salts or tautomers.

8. The compound according to claim 7, wherein:

9. The compound according to claim 7, which is Pharmaceutically acceptable salts.

10. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, a carrier or excipient, and the compound of claim 7 or a pharmaceutically acceptable salt or tautomer thereof.

11. A compound is: Or its pharmaceutically acceptable salts or tautomers.

12. The compound according to claim 11, wherein:

13. The compound according to claim 11, which is Pharmaceutically acceptable salts.

14. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, a carrier or excipient, and the compound of claim 11 or a pharmaceutically acceptable salt or tautomer thereof.

15. A compound is: Or its pharmaceutically acceptable salts or tautomers.

16. The compound according to claim 15, wherein:

17. The compound according to claim 15, which is Pharmaceutically acceptable salts.

18. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, a carrier or excipient, and the compound of claim 15 or a pharmaceutically acceptable salt or tautomer thereof.

19. A compound is: Or its pharmaceutically acceptable salts or tautomers.

20. The compound according to claim 19, wherein:

21. The compound according to claim 19, which is Pharmaceutically acceptable salts.

22. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, a carrier or excipient, and the compound of claim 19 or a pharmaceutically acceptable salt or tautomer thereof.

23. A compound is: Or its pharmaceutically acceptable salts or tautomers.

24. The compound according to claim 23, which is 25. The compound according to claim 23, which is Pharmaceutically acceptable salts.

26. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, a carrier or excipient, and the compound of claim 23 or a pharmaceutically acceptable salt or tautomer thereof.

27. A compound is: Or its pharmaceutically acceptable salts or tautomers.

28. The compound according to claim 27, wherein:

29. The compound according to claim 27, which is Pharmaceutically acceptable salts.

30. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, a carrier or excipient, and the compound of claim 27 or a pharmaceutically acceptable salt or tautomer thereof.

31. A compound is: Or its pharmaceutically acceptable salts or tautomers.

32. The compound according to claim 31, which is 33. The compound according to claim 31, which is Pharmaceutically acceptable salts.

34. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, a carrier or excipient, and the compound of claim 31 or a pharmaceutically acceptable salt or tautomer thereof.

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