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

Abstract

The present application relates to tetrahydropyrazolo-pyrazinyl-dihydroimidazolone or tetrahydropyrazolo-pyridinyl-dihydroimidazolone compounds, and methods of use thereof. The present application relates to a process for the preparation of tetrahydropyrazolo-pyrazinyl-dihydroimidazolone or tetrahydropyrazolo-pyridinyl-dihydroimidazolone. The present application relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, that modulates the activity of the GLP-1 receptor; pharmaceutical compositions comprising a compound of formula (I); and a method of treating or preventing a disease in which the GLP-1 receptor functions.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202610482644.1 (22) Application Date 2021.07.20 (66) Domestic Priority Data PCT / CN2020 / 102955 2020.07.20 CN PCT / CN2021 / 070120 2021.01.04 CN (62) Divisional Application Data 202180063652.8 2021.07.20 (71) Applicant Chengyi Biotechnology (USA) Company Address Massachusetts, USA (72) Inventors Ren Zaifang, Sun Xuefeng, Zhou Jingye (74) Patent Agency Beijing Anxin Fangda Intellectual Property Agency Co., Ltd. 11262 Patent Attorneys Ling Cui, Zheng Xia (51) Int.Cl. A61K 31 / 437 (2006.01) A61K 31 / 5025(2006.01) C07D 519 / 00(2006.01) A61P 3 / 10(2006.01) (54) Invention Title Tetrahydropyrazolo-pyrazinyl-dihydroimidazolide or tetrahydropyrazolo-pyridinyl-dihydroimidazolide compounds and methods of using thereof (57) Abstract This application relates to tetrahydropyrazolo-pyrazinyl-dihydroimidazolide or tetrahydropyrazolo-pyridinyl-dihydroimidazolide compounds and methods of using thereof. 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 of treating or preventing diseases in which GLP-1 receptors function. Claims 4 pages, Description 247 pages, CN 122461300 A 2026.07.28 CN 1 22 46 13 00 A 1. Use of a compound of formula (I) in the preparation of a pharmaceutical composition for the treatment or prevention of non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus) in a subject with corresponding need, wherein the compound of formula (I) is: (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: is or; R1 is (CRCRC)O-2-C3-C6 cyclic hydrocarbon group, (CRCRC)O-2-phenyl group or comprising a 5- or 6-membered ring and 1-3 ions selected from N, O The heteroatom of S is (CRCRC)0-2-heteroaryl, wherein the cyclic hydrocarbon, phenyl, 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, NO2, and C3-C6 cyclic hydrocarbon group, wherein the cyclic hydrocarbon group is a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group; each RC is independently H, a C1-C3 alkyl, or a C1-C3 haloalkyl; R2 is a C3-C10 cyclic hydrocarbon group, a phenyl group, a heterocyclic group comprising one or two 5- or 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 cyclic hydrocarbon group, phenyl group, heterocyclic group, or heteroaryl group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, OH, halogens, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2, wherein the cyclic hydrocarbon group is a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group; is a bicyclic heteroaryl ring selected from the following: , , , , , , , , , , , , and; Each R3 is independently a halogen, a C3-C10 cycloalkyl group, a phenyl group, 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 cycloalkyl group, phenyl group, heterocyclic group, 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 group, a bridged cycloalkyl group, or a monocyclic cycloalkyl group, provided that at least one R3 is a cycloalkyl group, a phenyl group, a heterocyclic group, or a heteroaryl group; 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; L is or is a 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 are capable of forming a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing 1 to 3 heteroatoms selected from N, O, and S;R5 and R6 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen, or R5 and R6 together with the carbon atoms to which they are attached form a C3-C6 cyclic hydrocarbon group, wherein the C3-C6 cyclic hydrocarbon 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, and halogen; and 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 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted by a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyl ... The alkyl group is substituted with a halogenated alkoxy group, OH group, halogenated group, or oxosubstituted group, and when L is present, T is not C(O)OH, or when L is a phenylene ring substituted with two substituents attached to adjacent carbon atoms, and the two substituents together with the carbon atoms to which they are attached form a 5- or 6-membered ring, T is H, provided that when L is present, 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 the heteroaryl group is optionally substituted, L is present, and when R5 and R6 together with the carbon atoms to which they are attached form a C3-C6 cyclic hydrocarbon group, then the C3-C6 cyclic hydrocarbon group is not substituted; provided that when L is present, T is H. Yes, T is an oxadiazolone group, L is, R5 and R6 together with the carbon atoms to which they are attached form an unsubstituted C3-C6 cyclic hydrocarbon group, and R3 is a heterocyclic group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O and S, then R3 is substituted; The condition is that when T is an oxadiazolone group, L is, and R5 and R6 are each methyl, then R3 is not a heteroaryl group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O and S; and the condition is that when T is an oxadiazolone group, L is, and R5 and R6 are each H, and R3 is a heterocyclic group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O and S, then R3 is substituted. 2. The use according to claim 1, wherein the compound is selected from Table A or its pharmaceutically acceptable salts or tautomers. 3. The use according to claim 1, wherein the compound is selected from: , , , , , , , , , CN 122461300 A and, or pharmaceutically acceptable salts or tautomers thereof. (Claims 3 / 4, page 4, CN 122461300 A)Page 4 / 4 5 CN 122461300 A Tetrahydropyrazolo-pyrazinyl-dihydroimidazolide or tetrahydropyrazolo-pyridinyl-dihydroimidazolide compounds and methods of use thereof

[0001] This application is a divisional application of application filed on July 20, 2021, application number 202180063652.8, entitled “Tetrahydropyrazolo-pyrazinyl-dihydroimidazolide or tetrahydropyrazolo-pyridinyl-dihydroimidazolide compounds and methods of use thereof”.

[0002] Related Applications 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 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 food intake. 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, thereby providing therapeutic opportunities for a variety of metabolic disorders and related comorbidities. Recently, liraglutide and semaglutide treatments have shown reductions in liver fat and promoted NASH regression in clinical trials, indicating potential utility against NASH. However, most of these GLP-1 analogs require invasive subcutaneous administration. Smegglutide 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.

[0004] Currently, there are no approved small molecule GLP-1 receptor agonists for treating diabetes or other metabolic disorders in which GLP-1 receptors act. Therefore, there is a need for small molecule GLP-1 receptor agonists as a therapeutic option for treating these disorders. This application addresses this need.

[0005] Summary This application provides novel GLP-1 receptor ligands that can be used to treat diseases or disorders in which GLP-1 receptors act, such as those described herein, including but not limited to diabetes, obesity, overweight, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, hypertension, stroke, coronary heart disease.Diseases, congestive heart failure, arrhythmias, 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).

[0006] A first aspect of this application relates to compounds of formula (I): (See specification 1 / 247 page 6 CN 122461300 A) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, wherein A, X, Y, T, L, R2, and R4 are described in detail below.

[0007] 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.

[0008] Another aspect of this application relates to a method of 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 the 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.

[0009] Another aspect of this application relates to a method of modulating (e.g., activating or stimulating) a GLP-1 receptor. The method includes 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.

[0010] Another aspect of this application relates to compounds of formula (I) or compounds described herein, or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, or compounds comprising formula (I) or compounds described herein.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 thereof, for use in a method of treating or preventing GLP-1 receptor-mediated diseases or disorders or modulating (e.g., activating or stimulating) GLP-1 receptors.

[0011] 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 thereof, 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.

[0012] 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 associated with the regulation of the GLP-1 receptor.

[0013] This application also provides compounds and compositions that have an improved therapeutic profile (e.g., efficacy, pharmacodynamics, safety) relative to known GLP-1 receptor agonists and alternative routes of administration, for treating a variety of diseases including diabetes, obesity, metabolic diseases, cardiovascular diseases, liver diseases, NASH, kidney diseases, neurodegenerative diseases, and other diseases associated with the regulation of the GLP-1 receptor.

[0014] Detailed Description of Compounds of this Application This application relates to compounds and compositions thereof capable of modulating the activity of the GLP-1 receptor. The present application is characterized by: Specification 2 / 247 pages 7 CN 122461300 A 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 the present application or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof to a subject with appropriate need. The compound of the present 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 related to the regulation of GLP-1 receptors.

[0015] In a first aspect of the present application, a compound of formula (I) is described: or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:R1 is (CRCRC)0-2-C3-C6 cyclic hydrocarbon, (CRCRC)0-2-phenyl, or (CRCRC)0-2-heteroaryl comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the cyclic hydrocarbon, phenyl, 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, NO2, and C3-C6 cyclic hydrocarbon, wherein the cyclic hydrocarbon is a spirocyclic hydrocarbon, a bridged cyclic hydrocarbon, or a monocyclic hydrocarbon; each RC is independently H, a C1-C3 alkyl, or a C1-C3 haloalkyl. R2 is a C3-C10 cyclic hydrocarbon group, a phenyl group, a heterocyclic group comprising one or two 5- or 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 cyclic hydrocarbon group, phenyl group, heterocyclic group, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, OH, halogens, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2, wherein the cyclic hydrocarbon group is a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group; Specification 3 / 247 pages 8 CN 122461300 A Each R3 is independently a halogen, a C3-C10 cycloalkyl group, a phenyl group, 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 cycloalkyl group, phenyl group, heterocyclic group, 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 group, a bridged cycloalkyl group, or a monocyclic cycloalkyl group, provided that at least one R3 is a cycloalkyl group, a phenyl group, a heterocyclic group, or a heteroaryl group; 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; L is or is a phenylene, wherein the phenylene is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and halogen, or wherein when the...When the phenylene ring is substituted by two substituents attached to adjacent carbon atoms, the two substituents together with the carbon atoms to which they are attached can form a 5- or 6-membered ring, wherein the 5- or 6-membered ring optionally contains 1 to 3 heteroatoms selected from N, O, and S; R5 and R6 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen, or R5 and R6 together with the carbon atoms to which they are attached, form a C3-C6 cyclic hydrocarbon group, which is optionally 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 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 to 3 heteroatoms selected from N, O and S, wherein the heteroaryl group is optionally substituted by a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, OH, OH and halogen; C1-C6 haloalkoxy, OH, halogen, or oxosubstituted, and when L is present, 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. Specification 4 / 247 page 9 CN 122461300 A 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): Specification 5 / 247 page 10 CN 122461300 A Specification 6 / 247 page 11 CN 122461300 A The structure of a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: each R7 is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; and each R11 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 cycloalkyl group.

[0016] 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): Specification 7 / 247 pages 12 CN122461300 A Instructions for Use, 8 / 247 pages, 13 CN 122461300 A or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer of thereof, wherein: each R7 is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; and each R11 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 cycloalkyl group.

[0017] For each of the formulas described herein, where applicable: In some embodiments, in some embodiments, in some embodiments, R1 is (CRCRC)O-2-phenyl substituted with 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, 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... (Specification 9 / 247, page 14, CN 122461300 A) The compounds include alkyl, 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), 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).

[0018] In some embodiments, R1 is (CRCRC)O-2-phenyl 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, 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 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)), OH, halogens (e.g., F, Cl, Br, or I), NH2, NH- (C1- C4 alkyl groups (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).

[0019] In some embodiments, R1 is (CRCRC)O-2-phenyl 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, wherein each 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, ... The halogens are: 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).

[0020] In some embodiments, R1 is (CRCRC)O-2-phenyl substituted with one, two, or three substituents as described herein.

[0021] In some embodiments, R1 is (CRCRC)O-2-phenyl substituted with one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl.

[0022] In some embodiments, R1 is (CRCRC)O-1-phenyl substituted with one or more substituents as described herein.

[0023] In some embodiments, R...R1 is a (CRCRC)O-1-phenyl substituted with one, two, or three substituents as described herein.

[0024] In some embodiments, R1 is a (CRCRC)O-1-phenyl substituted with one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl.

[0025] In some embodiments, R1 is a phenyl substituted with one or more substituents as described herein.

[0026] In some embodiments, R1 is a phenyl substituted with one, two, or three substituents as described herein.

[0027] In some embodiments, R1 is a phenyl substituted with one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl.

[0028] In some embodiments, R1 is a CRCRC-phenyl substituted with one or more substituents as described herein. Specification 10 / 247 pages 15 CN 122461300 A

[0029] In some embodiments, R1 is a CRCRC-phenyl substituted with one, two or three substituents as described herein.

[0030] In some embodiments, R1 is a CRCRC-phenyl substituted with one, two or three substituents selected from methyl, CF3, F and Cl.

[0031] In some embodiments, R1 is optionally substituted with one or more substituents independently selected from the following (CRCRC) O-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 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, 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, and C3-C6 cyclic hydrocarbons (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0032] In some embodiments, R1 is an (CRCRC) O-2-C3-C6 cyclic hydrocarbon (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl) 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 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), 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).

[0033] In some embodiments, R1 is a (CRCRC) O-2-C3-C6 cyclic hydrocarbon group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl) optionally substituted with one, two, or three substituents as described herein.

[0034] In some embodiments, R1 is a (CRCRC) O-2-C3-C6 cyclic hydrocarbon group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl) optionally substituted with one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl.

[0035] In some embodiments, R1 is a (CRCRC) O-1-C3-C6 cyclic hydrocarbon group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl) optionally substituted with one or more substituents as described herein.

[0036] In some embodiments, R1 is optionally substituted with one, two, or three substituents as described herein (see specification 11 / 247).Page 16 CN 122461300 A (CRCRC)O-1-C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl).

[0037] In some embodiments, R1 is a (CRCRC)O-1-C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutyl, bicyclopentyl, or bicyclohexyl) optionally substituted with one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl.

[0038] In some embodiments, R1 is cyclohexyl or bicyclopentyl, wherein each is optionally substituted with one or more substituents as described herein.

[0039] In some embodiments, R1 is cyclohexyl or bicyclopentyl, wherein each is optionally substituted with one, two, or three substituents as described herein.

[0040] 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.

[0041] In some embodiments, R1 is a (CRCRC)O-2-heteroaryl group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the (CRCRC)O-2-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, ... The following compounds are used to substituted for halogens: 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; 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, and C3-C6 cyclic hydrocarbon groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0042] In some embodiments, R1 is a (CRCRC)O-2-heteroaryl group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the (CRCRC)O-2-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)), straight-chain C1-C4 alkoxy or branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, ... The following are substituted for halogens: 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); 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 hydrocarbons (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0043] In some embodiments, R1 is a (CRCRC)O-2-heteroaryl group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the (CRCRC)O-2-heteroaryl group is optionally substituted as described herein.

[0044] In some embodiments, R1 is a (CRCRC)O-1-heteroaryl group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, as described in the specification 12 / 247 pages 17 CN 122461300 A, wherein the (CRCRC)O-1-heteroaryl group is optionally substituted as described herein.

[0045] In some embodiments, 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.

[0046] In some embodiments, R1 is a (CRCRC)O-2-heteroaryl group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the (CRCRC)O-2-heteroaryl group is optionally substituted as described herein.

[0047] In some embodiments, R1 is a (CRCRC)O-2-heteroaryl group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O, and S.(CRCRC)O-1-heteroaryl, wherein the (CRCRC)O-1-heteroaryl is optionally substituted as described herein.

[0048] In some embodiments, R1 is a heteroaryl comprising a 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted as described herein.

[0049] In some embodiments, each RC is H.

[0050] In some embodiments, at least one RC 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).

[0051] In some embodiments, each RC is independently 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)).

[0052] In some embodiments, R2 is a heterocyclic group comprising one or two 5- or 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 with one or more substituents independently selected from: optionally a straight-chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy). C1-C6 alkyl groups substituted with 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 substituted with one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy groups or branched C3-C6 alkoxy groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl, wherein each is ... and straight-chain C1-C6 alkoxy groups or branched C3-C6 alkoxy groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert 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, 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.)Examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl), CN and NO2.

[0053] 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, isopropyl, 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), and 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 these 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...). (See specification 13 / 247, page 18, CN 122461300 A) R2 is a heterocyclic group comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein each is optionally substituted with 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.

[0054] 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.

[0055] In some embodiments, R2 is a heterocyclic group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted with one or more substituents as described herein.

[0056] In some embodiments, R2 is a heterocyclic group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted with one or more substituents as described herein.

[0057] In some embodiments, R2 is a heterocyclic group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S.A heteroaryl atom, wherein the heteroaryl atom is optionally 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, 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 these 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, 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, and NO2.

[0058] In some embodiments, R2 is a heteroaryl group comprising 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 as described herein.

[0059] In some embodiments, R2 is a heteroaryl group comprising two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N and O, wherein the heteroaryl group is optionally substituted with one or more substituents as described herein.

[0060] In some embodiments, R2 is a heteroaryl group comprising two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, wherein the heteroaryl group is optionally substituted with one or more substituents as described herein.

[0061] 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.

[0062] 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.

[0063] In some embodiments, R2 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 with one or more substituents as described herein.

[0064] In some embodiments, R2 is an indazole or imidazopyridyl group, wherein each is optionally substituted with one or more substituents independently selected from: optionally linear C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., specification 14 / 247 pages 19 CN 122461300 A). C1-C6 alkyl groups substituted with methoxy, ethoxy, propoxy, 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, 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.

[0065] In some embodiments, R2 is an indazole or imidazopyridyl group, wherein each is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isopropyl, 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 by one or more halogens (e.g., F, Cl).Alkoxy groups can be substituted with one or more halogens (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), 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, each of which is substituted with one or more halogens (e.g., F, Cl)), OH, and halogens (e.g., F, Cl, Br, or I).

[0066] 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, 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).

[0067] In some embodiments, R2 is an indazole or imidazopyridyl, wherein each is optionally substituted with one, two, or three substituents as described herein.

[0068] In some embodiments, R2 is a spiroC3-C10 cyclic hydrocarbon, a bridged C3-C10 cyclic hydrocarbon, or a mono-C3-C10 cyclic hydrocarbon (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, wherein each may be a spirocyclic hydrocarbon, a bridged cyclic hydrocarbon, or a mono-cyclic hydrocarbon): optionally substituted with a straight-chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, secondary...). C1-C6 alkyl groups substituted with 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)), straight-chain C1-C6 alkoxy groups or branched C3-C6 alkoxy groups (e.g., butoxy, tert-butoxy, pentoxy, 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., butoxy, tert-butoxy, pentoxy, or hexyl, wherein each is substituted with one or more halogens (e.g., F, Cl)), and specification 15 / 247 pages 20 CN 122461300 AMethoxy, 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.

[0069] In some embodiments, R2 is a bicyclooctyl group 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, 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 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.

[0070] In some embodiments, R2 is a phenyl group substituted with one or more substituents independently selected from the following: optionally substituted with a straight-chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-hydroxyl, ...C1-C6 alkyl groups substituted with 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)), straight-chain C1-C6 alkoxy groups or branched C3-C6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy). The following substances may be substituted for halogens: , 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.

[0071] In some embodiments, R2 is indazole, imidazopyridyl, phenyl, or bicyclooctyl, wherein each is optionally independently substituted by one or more substituents independently selected from: optionally linear C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, ... C1-C6 alkyl groups substituted with 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)), straight-chain C1-C6 alkoxy groups or branched C3-C6 alkoxy groups (e.g., methoxy, ethoxy, propionyl, acetyl, 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, propionyl, acet ... Oxygen, 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 surrounded by one or more halogens (e.g., F, Cl).Substitution), 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 and NO2.

[0072] In some embodiments, R2 is indazole, imidazopyridyl, phenyl or bicyclooctyl, wherein each is optionally independently substituted by one or more substituents independently selected from: optionally linear C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, ... C1-C6 alkyl groups substituted with 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)), straight-chain C1-C6 alkyl groups Oxygen 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 or branched C3-C6 haloalkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, wherein each is substituted by one or more halogens (e.g., F, Cl)), OH, and halogens (e.g., F, Cl, Br, or I).

[0073] 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.

[0074] In some embodiments, the is selected from the following bicyclic heteroaryl rings: In some embodiments, (See page 17 / 247, CN 122461300 A); In some embodiments, (See page 18 / 247, CN 122461300 A); (See page 19 / 247, CN 122461300 A); (See page 20 / 247, CN 122461300 A); (See page 21 / 247, CN 122461300 A); (See page 22 / 247, CN 122461300 A); (See page 23 / 247, CN 122461300 A);In some embodiments, at least one R3 is a spiroC3-C10 cyclic hydrocarbon group, a bridged C3-C10 cyclic hydrocarbon group, or a mono-C3-C10 cyclic 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 mono-cyclic hydrocarbon group) optionally substituted by one or more substituents selected independently 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, each substituted by one or more halogens (e.g., (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), 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, 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, ... ... 122461300 A (isobutyl, sec-butyl, tert-butyl, pentyl or hexyl), CN and NO2.

[0075] In some embodiments, at least one R3 is a spiroC3-C10 cyclic hydrocarbon group, a bridged C3-C10 cyclic hydrocarbon group, or a mono-C3-C10 cyclic hydrocarbon group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, wherein each may be a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a mono-cyclic hydrocarbon group) optionally substituted by one or more substituents selected independently 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) substitution), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy)Halogens (e.g., methyl, 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).

[0076] In some embodiments, at least one R3 is a spiroC3-C10 cyclic hydrocarbon group, a bridged C3-C10 cyclic hydrocarbon group, or a mono-C3-C10 cyclic hydrocarbon group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, wherein each may be a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a mono-cyclic hydrocarbon group) optionally substituted by one or more substituents selected independently 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)); 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).

[0077] In some embodiments, at least one R3 is a spiroC3-C10 cyclic hydrocarbon group, a bridged C3-C10 cyclic hydrocarbon group, or a mono-C3-C10 cyclic 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 mono-cyclic hydrocarbon group) optionally substituted by one or more substituents selected independently 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)) and halogens (e.g., F, Cl, Br, or I).

[0078] In some embodiments, at least one R3 is a spiroC3-C10 cyclic hydrocarbon group, a bridged C3-C10 cyclic hydrocarbon group, or a mono-C3-C10 cyclic hydrocarbon group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclo...) optionally substituted with one or two substituents as described herein.Hexyl, cycloheptyl, cyclooctyl, each of which can be a spirocyclic hydrocarbon group, a bridged cyclocyclic hydrocarbon group, or a monocyclic hydrocarbon group.

[0079] 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-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 Halogenated alkoxy or branched C3-C6 halogenated alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, butoxy, 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, and NO2.

[0080] 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-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 Halogenated alkoxy or branched C3-C6 halogenated alkoxy (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).

[0081] 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, wherein each 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 haloalkoxy (e.g., Methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, wherein each is substituted with one or more halogens (e.g., F, Cl) and halogens (e.g., F, Cl, Br, or I).

[0082] 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)) and halogens (e.g., F, Cl, Br, or I).

[0083] In some embodiments, at least one R3 is a phenyl group optionally substituted with one or two substituents as described herein.

[0084] In some embodiments, at least one R3 is a phenyl group substituted with one or two substituents as described herein.

[0085] 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, said heterocyclic 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, 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, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkyl orBranched 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, wherein the heterocyclic group containing two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S can be spirocyclic or fused-ring heterocyclic groups.

[0086] 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, 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 hexyloxy 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. The heterocyclic group may contain a straight-chain C1-C6 haloalkoxy or a 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 a halogen (e.g., F, Cl, Br, or I).

[0087] 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...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.

[0088] 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.

[0089] 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 may be a spirocyclic heterocyclic group or a fused-ring heterocyclic group.

[0090] 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 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 may be a spirocyclic heterocyclic group or a fused-ring heterocyclic group. Specification 27 / 247 pages 32 CN 122461300 A

[0091] 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 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, 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, 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.

[0092] 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 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, 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)), and halogens (e.g., F, Cl, Br, or I).

[0093] 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, 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 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).

[0094] 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).

[0095] 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 substituted with one or two substituents as described herein. Specification 28 / 247 pages 33 CN 122461300 A

[0096] 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 substituted with one or two substituents as described herein.

[0097] In some embodiments, at least one R3 is a heterocyclic group comprising one 5- or 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.

[0098] 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 substituted with one or two substituents as described herein.

[0099] 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.A heterocyclic group containing a heteroatom, wherein the heterocyclic group is substituted with one or two substituents as described herein.

[0100] In some embodiments, at least one R3 is a heterocyclic group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted with one or more substituents as described herein.

[0101] In some embodiments, at least one R3 is a heterocyclic group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted with one or two substituents as described herein.

[0102] In some embodiments, at least one R3 is a heterocyclic group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is substituted with one or two substituents as described herein.

[0103] In some embodiments, at least one R3 is a heterocyclic group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic group is optionally substituted with one or more substituents as described herein.

[0104] In some embodiments, at least one R3 is a heterocyclic group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, said heterocyclic group optionally substituted with one or two substituents as described herein.

[0105] In some embodiments, at least one R3 is a heterocyclic group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, said heterocyclic group substituted with one or two substituents as described herein.

[0106] In some embodiments, at least one R3 is a tetrahydropyranyl group optionally substituted with one or more substituents as described herein.

[0107] In some embodiments, at least one R3 is a tetrahydropyranyl group optionally substituted with one or two substituents as described herein.

[0108] In some embodiments, at least one R3 is a tetrahydropyranyl group substituted with one or two substituents as described herein.

[0109] 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, 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, sec-butoxy, tert-butoxy, pentoxy, or hexoxy), straight-chain C1-C6 haloalkyl orBranched 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.

[0110] 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, 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)), and halogens (e.g., F, Cl, Br, or I).

[0111] 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: linear C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), linear 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)), linear C1-C4 alkoxy or branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy).alkyl, 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).

[0112] 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).

[0113] 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 with one or two substituents as described herein.

[0114] 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 with one or more substituents as described herein.

[0115] In some embodiments, at least one R3 is a heteroaryl group comprising one 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.

[0116] In some embodiments, at least one R3 is a heteroaryl group comprising one 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.

[0117] 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.

[0118] 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 optionally substituted with one or more substituents as described herein.

[0119] 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 optionally substituted with one or two substituents as described herein.

[0120] 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.The heteroaryl group of CN 122461300 A, page 35 of book 30 / 247, is substituted with one or two substituents as described herein.

[0121] In some embodiments, at least one R3 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 with one or more substituents as described herein.

[0122] In some embodiments, at least one R3 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 with one or two substituents as described herein.

[0123] In some embodiments, at least one R3 is a heteroaryl group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is substituted with one or two substituents as described herein.

[0124] In some embodiments, at least one R3 is a pyridyl group optionally substituted with one or more substituents as described herein.

[0125] In some embodiments, at least one R3 is a pyridyl group optionally substituted with one or two substituents as described herein.

[0126] In some embodiments, at least one R3 is a pyridyl group substituted with one or two substituents as described herein.

[0127] 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, isopropyl ... Propoxy, 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).

[0128] 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).

[0129] 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).

[0130] 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). In some embodiments, L is a phenylene 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 replaced by one or more halogens (e.g., F, Cl), OH, and halogens (e.g., F, Cl, Br, or I).

[0131] In some embodiments, L is a phenylene ring substituted with two substituents attached to adjacent carbon atoms in the phenylene ring, and the two substituents together with the carbon atoms to which they are attached may 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.

[0132] In some embodiments, R5 and R6 are each H.

[0133] 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 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 haloalkoxy (e.g., methoxy, ethoxy)R5, R6, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy, wherein each is substituted with one or more halogens (e.g., F, Cl), OH, or halogens (e.g., F, Cl, Br, or I).

[0134] In some embodiments, R5 and R6 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), wherein the C3-C6 cycloalkyl group is 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, ... The following compounds may be used: 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 (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).

[0135] 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), said C3-C6 cyclic hydrocarbon group optionally being 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, ... 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 and halogens (e.g., F, Cl, Br, or I).

[0136] 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).

[0137] 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).

[0138] In some embodiments, R5 and R6 together with the carbon atoms to which they are attached form a cyclopropyl group, said cyclopropyl group optionally being substituted with one or two 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).

[0139] In some embodiments, R5 and R6 together with the carbon atoms to which they are attached form a cyclopropyl group.

[0140] In some embodiments, T is C(O)OH.

[0141] In some embodiments, T is (CH2)NHS(O)2-(C1-C6 alkyl).

[0142] 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 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, wherein each is substituted with one or more halogens (e.g., F, Cl)), OH, halogen (e.g., F, Cl, Br or I) and oxo (i.e. = O).

[0143] In some embodiments, T is a heteroatom comprising a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O and S.The aryl group, wherein 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, 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)), OH, halogens (e.g., F, Cl, Br, or I), and oxo (i.e., =O).

[0144] 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 by one or more substituents as described herein.

[0145] 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 by one or more substituents as described herein.

[0146] 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.

[0147] 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 by one or more halogens (e.g., F, Cl)), a straight-chain C1-C6 alkoxy, or a branched C 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, or halogens (e.g., F, Cl, Br, or I). Specification 33 / 247 pages 38 CN122461300 A

[0148] 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 by one or more halogens (e.g., F, Cl)), or a straight-chain C1-C4 alkyl. 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)), OH, or a halogen (e.g., F, Cl, Br, or I).

[0149] 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).

[0150] In some embodiments, at least one R11 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, 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).

[0151] In some embodiments, at least one R11 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)), or a straight-chain C1-C4 alkyl. 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, 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).

[0152] In some embodiments, at least one R11 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 by one or more halogens (e.g., F, Cl)), or a straight-chain C1-C4 alkyl. Alkoxy or branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), straight 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). Specification 34 / 247 pages 39 CN 122461300 A

[0153] In some embodiments, at least one R11 is F.

[0154] In some embodiments, at least one R11 is F, and at least one R11 is methyl. Instruction manual 35 / 247 pages 40 CN 122461300 A Instruction manual 36 / 247 pages 41 CN 122461300 A Instruction manual 37 / 247 pages 42 CN122461300 A Instruction Manual 38 / 247 pages 43 CN 122461300 A Instruction Manual 39 / 247 pages 44 CN 122461300 A Instruction Manual 40 / 247 pages 45 CN 122461300 A Instruction Manual 41 / 247 pages 46 CN 122461300 A Instruction Manual 42 / 247 pages 47 CN 122461300 A Instruction Manual 43 / 247 pages 48 CN 122461300 A Instruction Manual 44 / 247 pages 49 CN 122461300 A Instruction Manual 45 / 247 pages 50 CN 122461300 A Instruction Manual 46 / 247 pages 51 CN 122461300 A Instruction Manual 47 / 247 pages 52 CN 122461300 A Specification 48 / 247 pages 53 CN 122461300 A Specification 49 / 247 pages 54 CN 122461300 A Specification 50 / 247 pages 55 CN 122461300 A Specification 51 / 247 pages 56 CN 122461300 A Specification 52 / 247 pages 57 CN 122461300 A Specification 53 / 247 pages 58 CN 122461300 A Specification 54 / 247 pages 59 CN 122461300 A Specification 55 / 247 pages 60 CN 122461300 A 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.

[0155] Table A, Specification Page 56 / 247, 61 CN 122461300 A; Specification Page 57 / 247, 62 CN 122461300 A; Specification Page 58 / 247, 63 CN 122461300 A; Specification Page 59 / 247, 64 CN 122461300 A; Specification Page 60 / 247, 65 CN 122461300 A; Specification Page 61 / 247, 66 CN 122461300 A; Specification Page 62 / 247, 67 CN 122461300 AInstruction manual pages 63 / 247, page 68, CN 122461300 A; Instruction manual pages 64 / 247, page 69, CN 122461300 A; Instruction manual pages 65 / 247, page 70, CN 122461300 A; Instruction manual pages 66 / 247, page 71, CN 122461300 A; Instruction manual pages 67 / 247, page 72, CN 122461300 A; Instruction manual pages 68 / 247, page 73, CN 122461300 A; Instruction manual pages 69 / 247, page 74, CN 122461300 A; Instruction manual pages 70 / 247, page 75, CN 122461300 A; Instruction manual pages 71 / 247, page 76, CN 122461300 A; Instruction manual pages 72 / 247, page 77, CN 122461300 A; Instruction manual pages 73 / 247, page 78, CN. 122461300 A Instruction Manual 74 / 247 Page 79 CN 122461300 A Instruction Manual 75 / 247 Page 80 CN 122461300 A Instruction Manual 76 / 247 Page 81 CN 122461300 A Instruction Manual 77 / 247 Page 82 CN 122461300 A Instruction Manual 78 / 247 Page 83 CN 122461300 A Instruction Manual 79 / 247 Page 84 CN 122461300 A Instruction Manual 80 / 247 Page 85 CN 122461300 A Instruction Manual 81 / 247 Page 86 CN 122461300 A Instruction Manual 82 / 247 Page 87 CN 122461300 A Instruction Manual 83 / 247 Page 88 CN 122461300 A Specification page 84 / 247, page 89, CN 122461300 A; Specification page 85 / 247, page 90, CN 122461300 A; Specification page 86 / 247, page 91, CN 122461300 A; Specification page 87 / 247, page 92, CN 122461300 A; Specification page 88 / 247, page 93, CN 122461300 A; Specification page 89 / 247, page 94, CN 122461300 A. Compared with known compounds such as known GLP-1 agonists, the compounds of this application have advantageous properties. For example, the compounds of this application exhibit more effective GLP-1 agonist activity and more favorable pharmacokinetic properties (e.g., such as Cmax, Tmax).And / or AUC measurement), and / or less interaction 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 of this application can be measured according to methods generally available in the art, such as those exemplified herein.

[0156] Due to the presence of double bonds, the compounds of this application may 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.

[0157] In one embodiment, the compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) are pharmaceutically acceptable salts. In another embodiment, the compound of this application (e.g., a compound of any formula disclosed herein or any single compound) is a solvate. In another embodiment, the compound of this application (e.g., a compound of any formula disclosed herein or any single compound) is a hydrate.

[0158] Details of this application are set forth in the description which follows. Although similar or equivalent methods and materials 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.

[0159] The articles “a” and “an” are defined in this application to refer to one or more (i.e., at least one) grammatical objects of the article. By way of example, “an element” means one element or more elements.

[0160] Unless otherwise indicated, the term “and / or” is used in this application to mean “and” or “or”.

[0161] 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.

[0162] As used herein, the term “alkyl” refers to a saturated, straight-chain or branched hydrocarbon group comprising between one and six carbon atoms in some embodiments. Examples of C1-C8 alkyl groups include, but are not limited to, methyl.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.

[0163] 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.

[0164] The term "alkoxy" refers to an -O-alkyl group.

[0165] As used herein, the terms "hal," "halogen," and "halogen" refer to an atom selected from fluorine, chlorine, bromine, and iodine.

[0166] 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.

[0167] 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.

[0168] As used herein, the term "cycloalkyl" represents 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 cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; and examples of C3-C12 cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclic [2.2.1]heptyl, and bicyclic [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. Specification 91 / 247 pages 96 CN 122461300 A

[0169] 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 monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more rings). Heteroaryl includes, but is not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrroleyl, pyrazolyl, and others.Imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, and similar groups.

[0170] 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.

[0171] 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]octane-8-amine, 8-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide and similar groups.

[0172] The term “alkylamino” refers to a group having a structure such as NH (C1-C6 alkyl), wherein C1-C6 alkyl is as previously defined.

[0173] The term “dialkylamino” refers to a group having a structure such as N (C1-C6 alkyl)2, wherein C1-C6 alkyl is as previously defined.

[0174] According to this application, any 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.

[0175] As described herein, the compounds of this application may optionally be substituted with one or more substituents, such as those generally described above, or as exemplified by the specific categories, subclasses, and types 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 preceded by the term “optionally,” refers to the substitution of a hydrogen group in a given structure with the group of the specified substituent. Unless otherwise indicated, optionally substituted groups may have substituents at each substituted position of the 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 substituents may be the same or different at each position. As used herein, the terms “optionally substituted,” “optionally substituted alkyl,” “optionally substituted alkenyl,” “optionally substituted cycloalkyl,” “optionally substituted cycloalkenyl,” “optionally substituted aryl,” “optionally substituted heteroaryl,” “optionally substituted aralkyl,” “optionally substituted heteroaryl,” “optionally substituted heterocyclic,” 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-C1-C12-alkyl, -NH-C2-C12-alkenyl, -NH-C2-C12-alkynyl, -NH-C3-C12-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocyclic alkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C1-C12-alkyl, -O-C2-C12-alkenyl, -O-C2-C12-alkynyl, -O-C3-C12-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclic alkyl, -C(O)-C1-C12-alkyl, -C(O)-C2-C12-alkenyl, -C(O)-C2-C12-alkynyl, -C(O)-C3-C12-cycloalkyl-C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclic hydrocarbon, -CONH2, -CONH-C1-C12-alkyl, -CONH-C2-C12-alkenyl, -CONH-C2-C12-ynyl, -CONH-C3-C12-cyclic hydrocarbon, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclic hydrocarbon, -OCO2-C1-C12-alkyl, -OCO2-C2-C12-alkenyl, -OCO2-C2-C12-ynyl, -OCO2-C3-C12-cyclic hydrocarbon, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocyclic hydrocarbon, -OCONH2, -OCONH-C1-C12-alkyl, -OCONH-C2-C12- Alkenyl, -OCONH-C2-C12-alkynyl, -OCONH-C3-C12-cyclic hydrocarbon, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclic hydrocarbon, -NHC(O)-C1-C12-alkyl, -NHC(O)-C2-C12-alkenyl, -NHC(O)-C2-C12-alkynyl, -NHC(O)-C3-C12-cyclic hydrocarbon, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclic hydrocarbon, -NHCO2-C1-C12-alkyl, - NHCO2-C2-C12-alkenyl, -NHCO2-C2-C12-alkynyl, -NHCO2-C3-C12-cyclic hydrocarbon, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocyclic hydrocarbon, -NHC(O)NH2, -NHC(O)NH-C1-C12-alkyl, -NHC(O)NH-C2-C12-alkenyl, -NHC(O)NH-C2-C12-alkynyl, -NHC(O)NH-C3-C12-cyclic hydrocarbon, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocyclic hydrocarbon, -NHC(S)NH2, -NHC(S)NH-C1-C12-alkyl, -NHC(S)NH-C2-C12-alkenyl, -NHC(S) NH-C2-C12-alkynyl, -NHC(S)NH-C3-C12-cyclic hydrocarbon, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocyclic hydrocarbon, -NHC(NH)NH2, -NHC(NH)NH-C1-C12-alkyl, -NHC(NH)NH-C2-C12-alkenyl, -NHC(NH)NH-C2-C12-alkynyl, -NHC(NH)NH-C3-C12-cyclic hydrocarbon, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocyclic hydrocarbon group, -NHC(NH)-C1-C12-alkyl group, -NHC(NH)-C2-C12-alkenyl group, -NHC(NH)-C2-C12-alkynyl group, -NHC(NH)-C3-C12-cyclic hydrocarbon group, -NHC(NH)-aryl group, -NHC(NH)-heteroaryl group, -NHC(NH)-heterocyclic hydrocarbon group, -C(NH)NH-C1-C12-alkyl group, -C(NH)NH-C2-C12-alkenyl group, -C(NH)NH-C2-C12-alkynyl group, C(NH)NH-C3-C12-cyclic hydrocarbon group, -C (NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocyclic hydrocarbon, -S(O)-C1-C12-alkyl, -S(O)-C2-C12-alkenyl, -S(O)-C2-C12-alkynyl, -S(O)-C3-C12-cyclic hydrocarbon, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocyclic hydrocarbon-SO2NH2, -SO2NH-C1-C12-alkyl, -SO2NH-C2-C12-alkenyl, -SO2NH-C2-C12-alkynyl, -SO2NH-C3-C12-cyclic hydrocarbon, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocyclic hydrocarbon, -NHSO2-C1-C12-alkyl, -NHSO2-C2-C12- Alkenyl, -NHSO2-C2-C12-alkynyl, -NHSO2-C3-C12-cyclic hydrocarbon, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocyclic hydrocarbon, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocyclic hydrocarbon, -C3-C12-cyclic hydrocarbon, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C12-alkyl, -S-C2-C12-alkenyl, -S-C2-C12-alkynyl, -S-C3-C12-cyclic hydrocarbon, -S-aryl, -S-heteroaryl, -S-heterocyclic hydrocarbon or methylthiomethyl.

[0176] As used herein, 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 a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.

[0177] The compounds of this application may form salts, which are also within the scope of this application. Unless otherwise indicated, a compound referring to a formula herein should be understood to include references to its salts. Specification 93 / 247 pages 98 CN 122461300 A

[0178] Representative “pharmaceutically acceptable salts” include, for example, water-soluble salts and water-insoluble salts, such as acetates,Amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium salt, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, ethanedisulfonate, etopoate, ethanesulfonate, fumarate, fumarate, gluconate, gluconate, glutamate, glycolyllarsanilate, hexafluorophosphate, hexylresorcinate, heparin, hydrobromide, hydrochloride, hydroxynaphthylcarboxylate, iodide, hydroxyethylsulfonate Lactates, lacturonates, laurates, magnesium salts, malates, maleates, mandelates, methanesulfonates, methyl bromide, methyl nitrates, methyl sulfates, mucilages, naphthalene sulfonates, nitrates, N-methylglucosamine ammonium salts, 3-hydroxy-2-naphthoate, oleates, oxalates, palmitates, papoate (1,1-methylene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenates, phosphates / bisphosphonates, picrates, polygalacturonates, propionates, p-toluenesulfonates, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicylates, suramates, tannates, tartrates, teoclates, toluenesulfonates, triethyliodide, and valerates.

[0179] The compounds of this application, for example, including pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers of compounds, may exist in a solvated or non-solventized form with other solvent molecules.

[0180] “Solvate” means a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds or salts have a tendency to capture a fixed molar ratio of solvent molecules in a crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, and if the solvent is an alcohol, the solvate formed is an alcohol. Hydrates are formed by the combination of one or more water molecules with one molecule of a substance, wherein the water retains its molecular state as H2O.

[0181] 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 those salts, solvates, and esters of prodrugs), such as those that may exist due to asymmetric carbons on multiple substituents, including enantiomeric forms (which even in the absence of asymmetry)In the case of carbon, rotational isomers, rotational 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.

[0182] The term “isomer” refers to compounds having the same composition and molecular weight but different in physical and / or chemical properties. Structural differences may lie in the configuration (geometric isomers) or the 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 single enantiomers or diastereomers.

[0183] In this specification, the structural formula of a compound is used in some cases to represent a certain isomer for convenience, but this application includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, and similar isomers.

[0184] “Isomeric” means compounds having the same molecular formula but different 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 enantiomeric forms with opposite chirality is called a "racemic mixture".

[0185] The compounds of this application may contain asymmetric centers 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 geometric isomers and positional isomers. For example, if this applicationIf a compound incorporates a double bond or a fused ring, then 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. The compound may be in a racemic form or an enantiomerically pure form, or in any other stereochemical form. The determination results may reflect data collected for the racemic form, the enantiomerically pure form, or any other stereochemical form.

[0186] A carbon atom bonded to four different substituents is referred to as a “chiral center.”

[0187] A “chiral isomer” means 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 a “diastereomer mixture”). 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. Substituents under consideration attached to the chiral center 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).

[0188] "Geometric isomer" means that its existence is attributed to a diastereomer whose rotation around the double bond is hindered. 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.

[0189] In another embodiment of this application, the compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) are enantiomers. In some embodiments, the compound is (S)-enantiomer. In other embodiments, the compound is (R)-enantiomer. In yet another embodiment, the compounds of this application (e.g., compounds of any formula disclosed herein or any single compound) may be (+) or (-) enantiomers. The compound may contain more than one stereocenter.

[0190] In another embodiment of this application, the compounds of this application (e.g., compounds of any formula disclosed herein) are enantiomers.The compound (or any single compound) is a diastereomer. In some embodiments, the compound is a cis diastereomer. In other embodiments, the compound is an anti diastereomer.

[0191] A mixture of diastereomers can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as, for example, by 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), separating the diastereomers, and converting (e.g., hydrolyzing) the diastereomers of the individual specification 95 / 247 pages 100 CN 122461300 A into their corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

[0192] 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.

[0193] A “tautomer” is one of two or more structural isomers that exist in equilibrium and readily transform from one isomer form to another. This transformation results in the formal 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 be interconverted through tautomerization is called tautomerism.

[0194] Of the many possible types of tautomerism, two are typically observed. In keto-enol tautomerism, the 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 its cyclic (ring) form, as is presented by glucose.

[0195] 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-imine.

[0196] This application relates to compounds of this application capable of modulating (e.g., activating or stimulating) GLP-1 receptors (e.g., the compounds of this application).This application relates to compounds of any kind disclosed herein (or any single compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, which may be used to treat diseases and disorders associated with the regulation of GLP-1 receptors. This application also relates to compounds of this application (e.g., compounds of any kind disclosed herein or any single compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, which may be used to regulate (e.g., activate or stimulate) GLP-1 receptors. 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.

[0197] In some embodiments, this application provides compounds of this application (e.g., compounds of any kind 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 compound has advantageous properties, such as increased potency, improved oral bioavailability, or a desirable pharmacodynamic / pharmacokinetic profile.

[0198] The efficacy of an agonist / activator / stimulant can be determined by its EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more effective agonist / activator / stimulant relative to a compound with a higher EC50 value.

[0199] The compounds of this application can be converted to 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, when valence and structure permit, are considered to include both the compounds shown and their N-oxide derivatives (which may be designated as NO or N+-O-). 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 a parent amine via an oxidizing agent such as m-CPBA. All nitrogen-containing compounds shown and claimed are also considered to cover, where valence and structure permit, 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.

[0200] The term “prodrug” as used herein means a compound that can be converted into the disclosed compound in vivo by metabolic means (e.g., by hydrolysis).

[0201] Since prodrugs are known to enhance many desirable qualities of a drug (e.g., solubility, bioavailability, manufacturing, etc.),Therefore, 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 thereof. "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 that, when administered to a mammalian subject, 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 containing alcohol and amine functional groups, such as acetate, formate, and benzoate derivatives.

[0202] The terms “crystalline polymorph,” “polymorph,” or “crystalline form” mean a crystalline structure in which the compound (or its salt or solvate) can crystallize in different crystalline stacking arrangements, all having the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to be dominant.

[0203] 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., one atom is replaced by an atom of a different element or a particular functional group is present, or one functional group is replaced by another functional group). Thus, an analogue is a compound that is functionally similar to or equivalent to the reference compound but structurally dissimilar to or not equivalent to the reference compound in terms of origin.

[0204] 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 may be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, and fluorine, such as 3H, 11C, 14C, 2H, and 18F.

[0205] 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 those incorporating radioisotopes like 3H and 14C, can be used for drug and / or substrate tissue distribution determination. Tritium, i.e., 3H isotopes, and carbon-14, i.e., 14C isotopes, are useful due to their ease of preparation and detectability. 11C and 18F isotopes are useful in PET (positron emission tomography). PET is useful in brain imaging. Furthermore, substitution with a heavier isotope, such as deuterium (2H), 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 in the specification of examples, page 97 / 247, 102 CN 122461300 A. 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.

[0206] As used herein, 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.

[0207] “Patient” or “subject” is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cattle, pig, or a non-human primate such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0208] 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 of the subject as described herein.

[0209] The term “treatment” with respect to a subject means improvement of at least one symptom of a disorder in the subject. Treatment includes cure, improvement, or at least partial relief of the disorder.

[0210] The compounds of this application or their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers or tautomers are described in this application.The body can also be used to prevent diseases, conditions, or disorders. As used herein, “preventing” or “prevention” describes reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.

[0211] 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.

[0212] 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 mutant is 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 mutant is known to play a role, or to reducing the severity of said one or more diseases. Specifically, this application relates to methods for treating or alleviating the severity of diseases or conditions as described herein, wherein the methods include administering to a subject with a corresponding 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.

[0213] Methods for preparing the compounds The compounds of this application can be prepared by a variety of methods including standard chemistry. Suitable synthetic routes are depicted in the schemes given below.

[0214] The compounds of this application (e.g., a compound of any form 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 is well understood that protecting groups of sensitive or reactive groups are employed as necessary according to general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd ed., Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. The selection of processes, reaction conditions, and their execution order should be consistent with the preparation of the compounds of this application.

[0215] Those skilled in the art will recognize the presence of stereocenters 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 synthesized by stereodirectional synthesis. (Specification 98 / 247, page 103)CN 122461300 A or obtained by the separation of the final product or any convenient intermediate. The separation 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" (Wiley-Interscience, 1994) by EL Eliel, SH Wilen and LN Mander.

[0216] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic processes, inorganic processes and / or enzymatic processes.

[0217] 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., any compound of any formula disclosed herein or any single compound) can be synthesized by following the steps outlined in the examples, schemes, procedures and / or synthesis (e.g., examples) described herein. Starting materials are commercially available or prepared by known procedures as reported in the literature or as described.

[0218] Mixtures 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.

[0219] Analytical methods, materials, and instruments, unless otherwise noted, reagents and solvents are 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 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 for collection. 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, and 254 nm and by ESI. Column: Poroshell 120 EC-C18 2.7 μm 4.6 × 100 mm; flow rate: 0.8 mL / min; solvent ASolvent A (100 / 0.1 water / formic acid), Solvent B (100 acetonitrile); Gradient: Hold 5% B for 0.3 min, 5%-95% B from 0.3 min to 2 min, Hold 95% B for 4.8 min, 95%-5% B from 4.8 min to 5.4 min, then Hold 5% B for 6.5 min. Alternatively, column: Acquity UPLC BEH C18 1.7 µm 2.1 × 50 mm; flow rate 0.5 mL / min; Solvent A (water containing 0.1% formic acid), Solvent B (acetonitrile); Gradient: Hold 5% B for 0.2 min, 5%-95% B from 0.2 min to 2.0 min, Hold 95% B for 3.1 min, then Hold 5% B for 3.5 min.

[0220] Abbreviations used in the following examples and elsewhere herein are: Specification 99 / 247 pages 104 CN 122461300 A Biological Assays 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 assays and human GLP-1 activity assays, are described in the examples.

[0221] Compared to known small molecule GLP-1 receptor agonists, the compounds of this application also have 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 exemplified herein.

[0222] Methods of Using the Compounds Specification 100 / 247 pages 105 CN 122461300 A The compounds of this application can be used to modulate (e.g., activate or stimulate) GLP-1 receptors. Therefore, the compounds of this application can be used to treat diseases or disorders related to 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 related to the regulation of GLP-1 receptors. For example, diseases or disorders related to 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.

[0223] "Diabetes" is a metabolic disorder of the production and use of glucose due to the inability to maintain adequate blood glucose levels in the body.The term "deficiency" refers to a state or disease that is deficient in blood sugar and encompasses both insulin-dependent diabetes mellitus (type 1 diabetes) and non-insulin-dependent diabetes mellitus (type 2 diabetes).

[0224] "Dementia" includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia.

[0225] "Diabetic complications" are complications arising 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. Major diabetic complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0226] Liver diseases (e.g., liver diseases associated with GLP-1 receptors) include, but are not limited to, NASH, NAFLD, hepatitis, liver fibrosis, cirrhosis, autoimmune liver diseases, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, and alcoholic liver disease.

[0227] 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.

[0228] 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 kind 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 kind disclosed herein or any single compound). In one embodiment, modulating a GLP-1 receptor is activating a GLP-1 receptor. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0229] Another aspect of this application relates to a compound of this application (e.g., a compound of any kind disclosed herein or...Any single compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of treating a GLP-1 receptor-mediated disease or disorder. 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. Specification 101 / 247 pages 106 CN 122461300 A

[0230] 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 a method of treating a GLP-1 receptor-mediated disease or disorder. 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.

[0231] 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 a 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.

[0232] 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 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.

[0233] 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 medicaments 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.

[0234] In another aspect, this application relates to the use of a pharmaceutical composition of a compound of this application (e.g., a compound of any formula disclosed herein or any single compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for treating a GLP-1 receptor-mediated disease or disorder. In one embodiment, the GLP-1 receptor-mediated disorder is 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.

[0235] Another aspect of this application relates to the use of a compound of this application (e.g., a compound of any formula disclosed herein or any single compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for modulating a GLP-1 receptor. In one embodiment, modulating a GLP-1 receptor is activating or stimulating a GLP-1 receptor. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0236] In another aspect, this application relates to the use of the compounds of this application (e.g., compounds of any form disclosed herein or any single compound) or pharmaceutical compositions thereof, or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers or tautomers thereof, 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.

[0237] The compounds disclosed in this application may be administered in an effective amount for treating or preventing disorders and / or preventing the development of disorders in a subject.

[0238] The compounds of this application may be administered in a therapeutically effective amount in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or treatment modalities such as non-pharmacological therapies. For example, synergistic effects may occur with other antiproliferative substances, anticancer substances, immunomodulatory substances (see page 102 / 247 of CN 122461300 A), or anti-inflammatory substances. In some embodiments, the compounds of this application (e.g., compounds of any formula 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. The compounds of this application may also be administered in combination with other therapies.In such cases, the dosage of the co-administered compound will naturally vary depending on the type of co-drug used, the specific drug used, the condition being treated, etc.

[0239] Combination therapy includes the administration of the subject compound 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 drug therapies or treatment modalities. Generally, combination therapy envisions the administration of two or more drugs during a single cycle or course of therapy.

[0240] Pharmaceutical Compositions This application also provides pharmaceutical compositions comprising a combination of a compound of the present 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, and at least one pharmaceutically acceptable excipient or carrier.

[0241] A “pharmaceutical composition” is a formulation comprising a compound of the present application in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in 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 is sometimes necessary to routinely vary the dosage according to the patient’s age and condition. The dosage will also depend on the route of administration. Multiple routes are anticipated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, sublingual, sublingual, intrapleural, intrathecal, intranasal, and similar routes. Dosage forms for topical or transdermal application of the compounds of 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 preservative, buffer, or propellant.

[0242] As used herein, the phrase “pharmaceuticalally acceptable” means suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the limits of reasonable medical judgment.Those compounds, materials, compositions, carriers, and / or dosage forms whose benefits / risks are proportionate.

[0243] "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 as well as for human pharmaceutical use. As used in this specification and claims, "pharmaceutical-acceptable excipient" includes one or more such excipients.

[0244] 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, such as intravenous administration, intradermal administration, subcutaneous administration, oral (e.g., inhalation) administration, transdermal (topical) administration, and transmucosal administration. Solutions or suspensions intended for parenteral, intradermal, or subcutaneous application may include the following components: no instructions 103 / 247 pages 108 CN 122461300 A; bacterial diluents, such as water for injection, saline solution, non-volatile oil, polyethylene glycol, glycerin, 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 an acid or base, 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.

[0245] 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 of time after treatment.

[0246] The term “therapeutic effective amount” as used herein refers to the amount of a drug agent used to treat, alleviate or prevent an identified disease or condition, or to exhibit 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 therapeutic agent or combination of therapeutic agents for administration. The therapeutic effective amount for a given situation can be determined by routine experiments within the skill and judgment of a clinician. In one embodiment, the disease or disorder is the disease or disorder described herein.

[0247] For any compound, the therapeutic effective amount can be initially estimated in a cell culture assay (e.g., a cell culture assay of proliferative cells) or in an animal model (typically a rat, mouse, rabbit, dog or pig). Animal models can also be used.Determine the appropriate concentration range and route of administration. Such information can then be used to determine the dosage and route of administration useful for human use. Therapeutic / prophylactic efficacy and toxicity can be determined in cell cultures or laboratory animals using standard pharmaceutical procedures, such as ED50 (the dose that is therapeutically effective in 50% of the population) and LD50 (the dose that is lethal to 50% of the population). The dose ratio between toxic effects and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD50 / ED50. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dosage can vary within this range, depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0248] Adjust the dosage and administration to provide sufficient levels of the active agent or maintain the desired effect. Factors that can be considered include the severity of the disease state, the general health of the subject, the subject's age, weight and sex, diet, the time and frequency of administration, the combination of drugs, response sensitivity, and tolerance / response to the therapy. Long-acting pharmaceutical compositions can be administered every 3 to 4 days, weekly, or bi-weekly, depending on the half-life and clearance of the particular formulation.

[0249] Pharmaceutical compositions comprising an active compound (i.e., compounds of any form disclosed herein or any single compound) can be manufactured in a manner generally known, such as by means of conventional mixing processes, dissolving processes, granulation processes, dragee-making processes, levigating processes, emulsifying processes, encapsulation processes, embedding processes, or lyophilization processes. 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 that can be used pharmaceutically. Of course, the appropriate formulation depends on the chosen route of administration.

[0250] Suitable pharmaceutical compositions for injectable use include sterile aqueous solutions (in the case of water solubility) 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, or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be a fluid sufficient to be injectable. 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 containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol and the like) and suitable mixtures. 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. Various antibacterial agents and antimicrobial agents can be used.Fungicides such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like achieve their antimicrobial effects. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, polyols such as mannitol, sorbitol, and sodium chloride. Prolonged absorption of the injectable composition can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0251] Sterile injectable solutions can be prepared by incorporating the active compound in a desired amount into a suitable solvent (which may have one or a combination of the ingredients listed above, as needed), 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 ingredients 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 of the active ingredient plus any other desired ingredients from its previously sterile filtered solution.

[0252] 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 used 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.

[0253] For administration by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant such as a gas such as carbon dioxide, or a nebulizer.

[0254] Systemic administration may also be by mucosal or transdermal means. For mucosal or transdermal administration, 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 administration. Transmucosal application can be achieved by using a nasal spray.This is achieved via aerosol or suppository. For transdermal administration, as is generally known in the art, the active compound is formulated as an ointment, cream, gel, or lotion.

[0255] The active compound can be prepared with a pharmaceutically acceptable carrier that will protect the compound from rapid elimination from the body, such as controlled-release formulations, including implants and microcapsule 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. 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.

[0256] It is particularly advantageous to formulate oral or parenteral compositions in dosage units that are easy to administer and have uniform dosage. As used herein, the dosage unit form 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, as per specification 105 / 247 pages 110 CN 122461300 A, and the desired drug carrier. The specifications of the dosage unit form used in this application are determined by and directly depend on the unique characteristics of the active compound and the specific therapeutic effect to be achieved.

[0257] 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, as well as the experience and judgment of the clinician or practitioner administering the therapy, and other factors influencing the chosen dosage. The dosage may range from about 0.01 mg / kg per day to about 5000 mg / kg per day. 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 cell.

[0258] The pharmaceutical composition may be included in a container, package, or dispenser along with instructions for use.

[0259] 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.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 selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edemacid, 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, napsylic acid, nitric acid, oxalic acid, dihydroxynaphthoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, etc. 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, arginine, etc.

[0260] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and salts of 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.

[0261] 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.

[0262] The compounds of this application may also be prepared as esters, such as pharmaceutically acceptable esters. For example, the carboxylic acid functional group in the compound may be converted to its corresponding ester, such as a methyl ester, ethyl ester, or other ester. Furthermore, the alcohol group in the compound may be converted to its corresponding ester, such as an acetate, propionate, or other ester.

[0263] The compounds of this application may 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 in vivo. Because prodrugs are known to enhance many desirable qualities of drugs (e.g., solubility, bioavailability, ...(Manufacturing, etc.), therefore, the compounds of this application can be delivered in the form of prodrugs. 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 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. Prodrugs include compounds of this application wherein a hydroxyl group, amino group, mercapto group, carboxyl group, or carbonyl group is bonded to any group that can be cleaved in vivo to form a free hydroxyl group, free amino group, free mercapto group, free carboxyl group, or free carbonyl group, respectively.

[0264] 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 the like, see Bundegaard, H., Design of Prodrugs, pp. 1-92, Elsevier, New York-Oxford (1985).

[0265] The compound or a pharmaceutically acceptable salt, tautomer, prodrug, solvation, metabolite, polymorph, analog, or derivative thereof is administered orally, nasally, percutaneously, pulmonaryly, by inhalation, sublingually, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectically, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound or a pharmaceutically acceptable salt, solvation, prodrug, stereoisomer, or tautomer thereof is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0266] Dosing regimens using the compound are selected based on a variety 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 or a pharmaceutically acceptable salt, solvation, prodrug, stereoisomer, or tautomer thereof used. A general practitioner or veterinarian can readily determine and prescribe an effective amount of medicine required to prevent, counteract, or halt the progression of the condition.

[0267] 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.

[0268] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of this application are apparent from the various examples provided. 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.

[0269] Examples This application is further illustrated by the following examples and synthesis schemes. The following examples and synthesis schemes 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 examples 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 thereof 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.

[0270] Example 1: Synthesis of Intermediate 1 Specification 107 / 247 pages 112 CN 122461300 A Step 1: 1-B 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).

[0271] Step 2: 1-C At 10°C, 1-B (19.2 g, 89.3 g) was added to the reaction mixture.NaNO2 (7.39 g, 107 mmol) was added to a solution of 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).

[0272] Step 3: Intermediate 1 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 hours, 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 (400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.45 (dd, J = 8.8, 6.2 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 4.07 (s, 3H) ppm; MS: m / z = 229 (M + 1).

[0273] Example 2: Synthesis of Intermediate 2 Step 1: 2-B 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, the mixture was added dropwise at 0°C. (See page 113 CN of the instruction manual, page 108 / 247)122461300 A MsCl (30.6 mL, 0.395 mol) was continuously stirred 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. ¹H NMR (400 MHz, 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 = 6.9 Hz, 3H) ppm; MS: m / z = 254 (M + 1).

[0274] Step 2: 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 stirred at 35°C for 2 hours. Then 2-B (79.6 g, 0.313 mol) was added and stirred for another 48 hours. 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). ¹H NMR (400 MHz, CDCl₃) δ 4.68 (m, ¹H), 3.95 (m, ¹H), 2.80 - 2.63 (m, ¹H), 1.45 (s, 9H), 1.31 (dd, J = 11.8, 6.0 Hz, 3H) ppm; MS: m / z = 185 (M + 1).

[0275] Step 3: 2-D At 0 °C, methanesulfonic acid (37.6 mL, 0.580 mol) was added to a mixture of 2-C (43 g, 0.232 mol) and THF (500 mL) and stirred for 20 min. The reaction mixture was heated to 65 °C and stirred for 3 hours. 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). ¹H NMR (400 MHz, CDCl₃) δ 3.39 - 3.26 (m, 1H), 2.40 (m, 2H), 1.24 (dJ = 6.4 Hz, 3H) ppm; MS: m / z = 85 (M + 1).

[0276] Step 4: 2-E 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 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).

[0277] Step 5: Intermediate 2 At 25°C, t-BuOK (13.5 g, 120.2 mmol) was added to a mixture of 2-E (34.1 g) in THF (500 mL) and stirred for 2 hours. 2 N HCl (90 mL) was added and stirred for 30 min. 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 (400 MHz, CDCl3) δ 5.17 - 4.97 (m, 1H), 4.36 (m, 1H), 3.80 (d, J = 5.6 Hz, 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).

[0278] Example 3: Synthesis of Intermediate 3, Specification 109 / 247 pages, 114 CN 122461300 A Step 1: 3-B At -78°C, n-BuLi (2.5 M, 3.94 mL, 9.85 mmol) was added to a solution of 3-A (2 g, 9.85 mmol) in THF (20 mL). The reaction mixture was stirred at -70°C for 1 hour. Di-tert-butyl-diazepine-1,2-dicarboxylate (2.27 g, 9.85 mmol) was added, and the reaction mixture was stirred at -40°C for 30 min and then heated to 25°C.Continue for another 2 hours. Add aqueous NH4Cl (50 mL) and extract the aqueous layer with ethyl acetate (50 mL × 2). Dry the combined organic layers with sodium sulfate, concentrate and purify by silica gel column (PE / EA = 10 / 1) to give 3-B (2.58 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ 7.17 - 6.92 (m, 2H), 2.22 (s, 6H), 1.53 - 1.46 (m, 18H) ppm; MS: m / z = 439 (M-1).

[0279] Step 2: 3-C Add methanesulfonic acid (1.40 g, 14.58 mmol) to the 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).

[0280] Step 3: 3-D 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).

[0281] Step 4: Add methanesulfonic acid (196 mg / mL) to a solution of 3-E (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 (page 115, CN 122461300 A, page 110 / 247) 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).

[0282] Step 5: 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 hours. 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).

[0283] Step 6: Intermediate 3 At 25°C, HCl / dioxane (4 M, 3 mL) was added to a solution of 3-F (400 mg, 678.39 μmol) in DCM (3 mL). The reaction mixture was stirred at 25°C for 2 hours. Excess solvent was removed under reduced pressure to give crude product intermediate 3 (396 mg, HCl salt). MS: m / z = 490 (M + 1).

[0284] Example 4: Synthesis of Intermediates 4-7 Intermediates 4-7 in Table 1 were prepared according to the procedure for intermediate 3. Instructions for Use, pages 111 / 247, 116 CN 122461300 A, Example 5: Synthesis of Intermediate 8, Instructions for Use, pages 112 / 247, 117 CN 122461300 A, Step 1: 8-B to 8-A (10 g, 104.07 mmol) in methanol (60...2-Aminoethanol (7.63 g, 124.89 mmol) was added to a solution in mL and 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 (300 MHz, CDCl3): δ 7.49 (d, J = 7.5 Hz, 1H), 7.39 - 7.14 (m, 5H), 6.20 (d, J = 52.6 Hz, 1H), 5.12 (d, J = 7.1 Hz, 2H), 4.52 (s, 2H), 3.89 - 3.70 (m, 2H), 3.58 (d, J = 4.9 Hz, 2H).

[0285] Step 2: 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). ¹H NMR (300 MHz, CDCl₃): δ 7.51 (bs, 1H), 7.41–7.33 (m, 5H), 6.09 (d, J = 10.7 Hz, 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).

[0286] Step 3: 8-D at 0°C, NIS (7.87 g, 34.98 mmol) in 150 mL of MeCN (6 g, 23.32 mmol) solution in MeCN (150 mL) was added dropwise to the solution of 8-C (6 g, 23.32 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), brine (100 mL), and concentrated to give 8-D (8.2 g, 91.76% yield). MS: m / z = 383.6 (M + 1).

[0287] Step 4: 8-E A mixture of 8-D (8 g, 20.88 mmol), diphenylmethanimine (7.57 g, 41.76 mmol), potassium tert-butoxide (7.03 g, 62.63 mmol), 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). ¹H NMR (400 MHz, 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). Stirring continued for 1 hourThe mixture was then 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).

[0288] Step 5: 8-F A mixture of 8-E (2.16 g, 4.95 mmol), 1-bromo-4-fluorobenzene (1.73 g, 9.90 mmol), Pd(OAc)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).

[0289] Step 6: 8-G HCl / dioxane (4 M, 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).

[0290] Step 7: 8-H 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 1 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).

[0291] Step 8: 8-I to 8-HA solution of 140 mg (281.40 μmol) in DCM (2 mL) was added to HCl / dioxane (4 M, 1 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 + 114 / 247 pages, 119 CN 122461300 A 1).

[0292] Step 9: 8-J 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).

[0293] Step 10: Intermediate 8 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).

[0294] Example 6a: Synthesis of intermediate 9 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 to 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 stopped. 6 M HCl (58.35 mL) was added.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). ¹H NMR (400 MHz, DMSO) δ 7.15 (bs, 5H), 3.09 (t, J = 9.4 Hz, 1H), 2.16–1.94 (m, 4H), 1.94–1.72 (m, 2H), 1.57 (m, 2H); MS: m / z = 151.0 (M+1).

[0295] Example 6b: Synthesis of Intermediate 10 Step 1: 10-B A solution of methyllithium bromide complex (1 M, 161.72 mL) of ether 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). 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 200 mL of RBF in a -78°C bath. A vacuum was slowly applied to the system and the distillate was collected. A solution of 10-B (130 mL, about 0.3 M) in diethyl ether was obtained, which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 1.93 (s, 6H).

[0296] Step 2: 10-C Under a nitrogen atmosphere, Mn(dpm)3 (435.41 mg, 720.0 μmol) was dissolved in isopropanol (200 mL) and cooled to 0°C. A solution of phenylsilane (3.90 g, 36.0 mmol) and (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 hours. 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). ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (s, ¹H).2.37 (s, 1H), 1.92 (s, 6H), 1.40 (s, 18H).

[0297] Step 3: Intermediate 10 At 25°C, HCl / dioxane (4 M, 69.54 mL) was added to a solution of 10-C (8.3 g, 27.82 mmol) in DCM (20 mL). The reaction was stirred at 25°C for 16 hours. After filtration, the solid was collected and dried to give intermediate 10 (3.3 g, 69.35% yield, HCl salt).

[0298] Example 7: Synthesis of intermediate 11 Step 1: 11-A At 25°C, 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). 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).

[0299] Step 2: 11-B 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).

[0300] Step 3: 11-C 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 hours. The reaction mixture was then adjusted to pH ~ 10 with aqueous NaOH. (Instructions for Use 116 / 247, page 121, CN 122461300 A) Boc2O (710 mg, 3.25 mmol) was added, and the reaction mixture was stirred at 25°C for 4 hours. Pour the reaction mixture into water (15)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).

[0301] Step 4: 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 hours. 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).

[0302] Step 5: Intermediate 11 The mixture of 11-D (309 mg, 0.527 mmol) and HCl (4 M, 10.55 mL) in dioxane was stirred for 0.5 hours. The solvent was removed under reduced pressure to give intermediate 11 (250 mg, 97% yield). MS: m / z = 485.8 (M + 1).

[0303] Example 8: Synthesis of Intermediates 12-16 Intermediates 12-16 in Table 2 were prepared according to the procedure for intermediate 11.

[0304] Table 2 Specification 117 / 247 pages 122 CN 122461300 A Example 9: Synthesis of Intermediate 17 Specification 118 / 247 pages 123 CN 122461300 A Step 1: 17-B 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).

[0305] Step 2: 17-C At 25°C under a hydrogen atmosphere, palladium (843 mg, 7.93 mmol) was added to a solution of 17-B (10 g, 39.64 mmol) in methanol (150 mL). 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).

[0306] Step 3: 17-D At 25°C, HCl / dioxane (4 M, 2 mL) was added to a solution of 17-C (1 g, 3.93 mmol) in DCM (15 mL), and the mixture was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to provide 17-D (0.72 g, 95% yield, HCl salt). MS: m / z = 155 (M + 1).

[0307] Step 4: 17-E 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).

[0308] Step 5: 17-F 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).

[0309] Step 6: 17-G 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).

[0310] Step 7: 17-H The crude 17-G (3 g) was reacted with THFThe solution in (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).

[0311] Step 8: 17-I 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 hours. The reaction 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).

[0312] Step 9: 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 hours. 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).

[0313] Example 10: Synthesis of Intermediate 18 Step 1: 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) were added to a solution of 18-A (6 g, 28.27 mmol) in toluene (50 mL). The mixture was stirred at 90 °C for 20 hours. The mixture was diluted with ethyl acetate (200 mL) and then diluted with aqueous NaHCO3 (100 mL × 100 mL).2) Washing. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (PE / EA = 2 / 1) to give 18-B (5.8 g, 58.18% yield). MS: m / z = 317.8 (M + 1). Specification 120 / 247 pages 125 CN 122461300 A

[0314] Step 2: 18-C 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 and quenched with 100 mL HCl (1M) 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 product). MS: m / z = 289.9 (M + 1).

[0315] Step 3: 18-D At 0 °C, 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). 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). 1H NMR (400 MHz, DMSO) δ 7.51 - 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, 6.2 Hz, 6H), 1.42 (dd, J = 9.8, 6.2 Hz, 6H); MS: m / z = 303.9 (M + 1).

[0316] Step 4: Intermediate 18 A mixture of 18-D (323 mg, 1.06 mmol), Pd / C (40 mg) and methanol (10 mL) was stirred under 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).

[0317] Example 11: Synthesis of intermediate 19 Step 1: 19-B was added to 19-A (5 g, 24.39 mmol) and DEAD (5.10 g, crude) at 0 °C.A solution of N-(2-aminoethyl)carbamate (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).

[0318] Step 2: 19-C 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).

[0319] Step 3: 19-D At 0 °C, MeMgBr (1 M, 92.78 mL) was added to a solution of 19-C (7 g, 18.56 mmol) in THF (50 mL). 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).

[0320] Step 4: 19-E was added to a mixture of 19-D (6 g, 18.06 mmol) in methanol (5 mL) at 0 °C with HCl / dioxane (4 M, 40 mL) and stirred for 1 hour. The reaction mixture was concentrated to give a white solid. Then, DCM was added.(40 mL) and TEA (18.28 g, 180.62 mmol, 25.17 mL), NaBH3CN (4.54 g, 72.25 mmol) was added at 0 °C and stirred 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).

[0321] Step 5: 19-F 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).

[0322] Step 6: 19-G At 25 °C, 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), 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).

[0323] Step 7: 19-H At 25°C, 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). 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).

[0324] Step 8: 19-I 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 stirred.Continue stirring for 1 hour. Add 2,2-dimethoxyethylamine (1.27 g, 12.08 mmol, 1.32 mL) and stir at 0°C for 30 min. Concentrate the mixture to give a residue, dissolve the residue in THF (20 mL), and add trifluoromethanesulfonic acid (724.99 mg, 4.83 mmol, 423.97 μL) at 30°C. Stir the reaction solution at 70°C for 2 hours. Add Boc2O (1.05 g, 4.83 mmol, 1.11 mL) according to the instructions (page 127, CN 122461300 A) and stir at 25°C for 1 hour. Filter and concentrate the mixture. 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).

[0325] Step 9: 19-J 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).

[0326] Step 10: 19-K 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).

[0327] Step 11: Intermediate 19 19-K (50 mg, 84.80 μmol) was dissolved in HCl / dioxane (4 M, 2 mL) and stirred at 25°C.Stirring continued for 16 hours. The reaction was then concentrated to give intermediate 19 (45 mg, 95% yield). MS: m / z = 490.1 (M + 1).

[0328] Example 12: Synthesis of intermediates 20-24 Intermediates 20-24 in Table 3 were prepared according to the procedure for intermediate 19.

[0329] Table 3 Specification 123 / 247 pages 128 CN 122461300 A Example 13: Synthesis of Intermediate 25 Specification 124 / 247 pages 129 CN 122461300 A Step 1: 25-B Phenyl chloroformate (153 mg, 975.76 μmol) was added to a solution of 25-A (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 hours. The reaction was concentrated to give 25-B (0.4 g, crude). MS: m / z = 467.1 (M + 1).

[0330] Step 2: 25-C 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 hours. 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).

[0331] Step 3: 25-D was added to a solution of 25-C (0.3 g, 553.86 μmol) in dioxane (10 mL) with 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). The reaction was sealed in a tube and heated at 120 °C for 36 hours. 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 a 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).

[0332] Step 4: Intermediate 25 HCl (2 M, 1.4 μmol) 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).

[0333] Example 14: The synthesis intermediate 19 (45 mg) of intermediate 19-P1 and intermediate 19-P2 was separated by SFC (column: Daicel CHIRALPAK OD-H 250 mm 20 mm, specification 125 / 247 pages 130 CN 122461300 A 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).

[0334] 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. The compounds in Table 4 were obtained by SFC separation as intermediates 19-P1 and 19-P2. Instructions for Use, Pages 126 / 247, 131, CN 122461300 A; Instructions for Use, Pages 127 / 247, 132, CN 122461300 A; Example 16: Synthesis of Intermediate 26. At -70°C, LDA (2 M, 117.03 mL) was added to a solution of 26-A (25 g, 195.05 mmol) in THF (250 mL) for 0.5 hours. The mixture was stirred at -70°C for 0.5 hours, and then at -60°C, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (76.65 g, 214.56 mmol) in THF (250 mL) was added to the reaction mixture 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 aqueous NH4Cl (200 mL) and extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated by rotary evaporation to obtain intermediate 26 (95 g, crude product).

[0335] Example 17: Synthesis of intermediate 27 128 / 247 pages 133 CN 122461300 AStep 1: 27-B 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).

[0336] Step 2: 27-C NaBH4 (5.32 g, 140.57 mmol) and NiCl2 (1.52 g, 11.71 mmol) were added to a solution of 27-B (30 g, 117.14 mmol) in MeOH (300 mL). The reaction mixture was stirred for 1 hour. The mixture was diluted with water (200 mL) and extracted with EA (200 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give 27-C (25 g, 82% yield). MS: m / z = 258.0 (M + 1).

[0337] Step 3: 27-D 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).

[0338] Step 4: 27-E 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).

[0339] Step 5: 27-F to 27-E (15 g, 71.07%)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 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).

[0340] Step 6: 27-G A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane-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, 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).

[0341] Step 7: 27-H A mixture of 27-G (320 mg, 903.43 μmol), intermediate 26 (470 mg, 1.81 mmol), potassium carbonate (375 mg, 2.71 mmol), and Pd(dppf)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).

[0342] Step 8: 27-I Pd / C (47 mg, 443.26 μmol) was added to a solution of 27-H (150 mg, 443.26 μmol) in MeOH (3 mL).10%), 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).

[0343] Step 9: Intermediate 27 A sodium hydroxide solution (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).

[0344] Example 18: Synthesis of Intermediate 28 Step 1: 28-A 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).

[0345] Step 2: Intermediate 28 Aqueous NaOH (2 M, 6 mL) was added to a solution of 28-A (81 mg, 221.04 μmol) in MeOH (3 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was extracted with ethyl acetate (10 mL × 2). The aqueous solution was then adjusted to pH ~ 3 with HCl (1 M). The solution was extracted with ethyl acetate (10 mL × 3), and the combined organic phases were dried over sodium sulfate and concentrated to give intermediate 28 (80 mg, crude). MS: m / z = 339.1 (M + 1).

[0346] Example 19: Synthesis of Intermediate 29Intermediate 29 in Table 5 was prepared according to the procedure for intermediate 28.

[0347] Table 5 Example 20: Synthesis of intermediate 30 At 0°C, 30-A (300 mg, 881.28 μmol) and (4R)-4-methyl-1,3,2-dioxathiacyclopentane 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 aqueous NH4Cl (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over sodium sulfate, and concentrated under vacuum to give intermediate 30 (300 mg, 96% yield). MS: m / z = 353.1 (M + 1).

[0348] Example 21a: Synthesis of Intermediate 31 Step 1: 31-B Sodium bicarbonate (14.65 g, 174.40 mmol) and ethyl 3-bromo-2-oxo-propionate (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).

[0349] Step 2: 31-C Specification 131 / 247 pages 136 CN 122461300 A 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-dioxaborhexacyclopentanane (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).

[0350] Step 3: 31-D to 31-C (2.5 g)A solution of K₂CO₃ (2.19 g, 15.86 mmol), Pd(dppf)Cl₂ (580 mg, 793.22 μmol), and intermediate 26 (4.13 g, 15.86 mmol) in dioxane (20 mL) and water (5 mL) was added, and 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).

[0351] Step 4: 31-E 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).

[0352] Step 5: 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).

[0353] Step 6: 31-G was added to a solution of 31-F (220 mg, 646.27 μmol) in DMPU (3 mL) with 1,3,2-dioxane-2,2-dioxide (241 mg, 1.94 mmol), and then LiHMDS (1 M, 5.82 mL) was slowly added to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were then extracted with brine (10 mL × 2 mL).Washed with 10 mL of 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).

[0354] Step 7: Intermediate 31 NaOH (5 M, 1.47 mL) was added to a solution of 31-G (135 mg, 368.40 μmol) in MeOH (2 mL). The mixture was stirred at 50 °C for 3 hours. The mixture was concentrated under vacuum and the residue was added to HCl (1 M, 10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried with sodium sulfate, and concentrated under vacuum to give intermediate 31 (65 mg, 50% yield). MS: m / z = 339.1 (M + 1).

[0355] Example 21b: Synthesis of intermediate 32, 132 / 247 pages, CN 122461300 A. Step 1: 32-A. 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 to a solution of 27-F (10 mg, 32.56 μmol) in dioxane (2 mL). 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).

[0356] Step 2: Intermediate 32 NaOH (5 M, 535.72 μL) was added to a solution of 32-A (10 mg, 26.79 μmol) in MeOH (1 mL), 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).

[0357] Example 22: Synthesis of Intermediate 33 Step 1: 33-ALiHMDS (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) in THF (2 mL) were added. 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).

[0358] Step 2: 33-B 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 to a solution of 33-A (15 mg, 45.02 μmol) in dioxane (5 mL) and water (0.5 mL). 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).

[0359] Step 3: Intermediate 33 NaOH (6 M, 2.0 mL) was added to a solution of 33-B (15 mg, 37.56 μmol) in THF (1 mL) and MeOH (1 mL). The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated and adjusted to pH ~ 5 with 1 N HCl. The reaction mixture was extracted with ethyl acetate (20 mL × 3), the combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under vacuum to give intermediate 33 (13 mg, 93% yield). MS: m / z = 372.0 (M + 1).

[0360] Example 23: Separation of intermediates 27-P1 and 27-P2 Intermediate 27 (100 mg) via 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℃) separation to give intermediate 27-P1 (40 mg) and intermediate 27-P2 (40 mg).

[0361] Example 24: Synthesis and separation of intermediates 28-P1, 28-P2, 30-P1, 30-P2, 30-P3, 30-P4, 31-P1 and 31-P2 The compounds in Table 6 were obtained by SFC separation as described in intermediates 27-P1 and 27-P2.

[0362] Table 6 Specification 134 / 247 pages 139 CN 122461300 A Example 25: Synthesis of Intermediate 34 Specification 135 / 247 pages 140 CN 122461300 A Step 1: 34-B 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 hours. The reaction was cooled and diluted with 200 mL ethyl acetate and 100 mL water. The solid was filtered, and the organic layer was dried over anhydrous sodium sulfate and concentrated to give a residue, which was combined with the solid to give 34-B (6 g, 59% yield). MS: m / z = 272.2 (M + 1).

[0363] Step 2: Intermediate 34 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).

[0364] Example 26: Synthesis of Intermediates 35 and 36 Intermediates 35-36 in Table 7 were prepared according to the procedure for intermediate 34.

[0365] Table 7Example 27: Synthesis of Intermediate 37 Step 1: 37-A 2-fluorobenzonitrile (6.78 g, 55.95 mmol, 6.05 mL) and potassium tert-butoxide (6.28 g, 55.95 mmol) were added to a solution of 34-A (5.0 g, 18.65 mmol) in DMSO (50 mL). The mixture was stirred at 140 °C for 16 hours. The mixture was cooled to 25 °C, poured into water, and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with water (30 mL × 2) and brine (30 mL), concentrated under vacuum, and purified by column chromatography on silica gel (PE / EA = 136 / 247 pages 141 CN 122461300 A 20 / 1 to 10 / 1) to give 37-A (2.5 g, 36% yield). MS: m / z = 369 (M + 1).

[0366] Step 2: 37-B 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 to a solution of 37-A (1.3 g, 3.52 mmol) in dioxane (10 mL). 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).

[0367] Step 3: 37-C Add Pd / C (60 mg, 10%, 55% wetting) to a solution of 37-B (600 mg, 1.52 mmol) in EtOH (10 mL). Stir the mixture at 25°C under hydrogen for 30 min. Filter the mixture and concentrate the filtrate under vacuum to give 37-C (560 mg, crude). MS: m / z = 375 (M + 1).

[0368] Step 4: 37-D Add hydroxylamine hydrochloride (185.59 mg, 2.67 mmol) and sodium bicarbonate (224.37 mg, 2.67 mmol) to a solution of 37-C (200 mg, 534.14 μmol) in DMSO (5 mL). Stir the mixture at 60°C for 4 hours. Pour the mixture into water and dilute with ethyl acetate (10 mL ×2) Extraction. 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).

[0369] Step 5: 37-E 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).

[0370] Step 6: Intermediate 37 NaOH (2 M, 1.15 mL) was added to a solution of 37-E (120 mg, 229 μmol) in MeOH (5 mL). The mixture was stirred at 60 °C for 1 hour. The mixture was concentrated, and water (10 mL) was added to the residue. The mixture was extracted with ethyl acetate (10 mL × 2), and the aqueous phase was neutralized with aqueous HCl and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under vacuum to give intermediate 37 (90 mg, 67% yield). MS: m / z = 406 (M + 1).

[0371] Example 28: Synthesis of Intermediate 38 Intermediate 38 in Table 8 was prepared according to the procedure for intermediate 37. Specification 137 / 247 pages 142 CN 122461300 A Example 29: Synthesis of Intermediate 39 Step 1: 39-A Add 4 Å 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) to a solution of intermediate 34 (300 mg, 1.10 mmol) in DCM (6 mL). The mixture was stirred at 35 °C under oxygen for 16 hours. 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 extracted with...The sample was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by silica gel chromatography (PE / EA = 20 / 1) to give 39-A (290 mg, 70% yield). MS: m / z = 400.1 (M + 23).

[0372] Step 2: Intermediate 39 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).

[0373] Example 30: Synthesis of intermediate 40, 138 / 247 pages, 143 CN 122461300 A Step 1: 40-A 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 hour. 2-chloroacetonitrile (888.77 mg, 11.77 mmol, 740.64 μL) was added, and the resulting solution was stirred at 25 °C for 16 hours. Saturated aqueous NH4Cl (50 mL) was added to the mixture, and the mixture was 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).

[0374] Step 2: 40-B 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).

[0375] Step 3: 40-C to 40-B (1.1 g, 3.12 g)A solution of 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) in DMSO (10 mL) was added. The reaction mixture was stirred at 25 °C for 3 hours. 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).

[0376] Step 4: Intermediate 40 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. About 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).

[0377] Example 31: Synthesis of Intermediate 41 Intermediate 41 in Table 9 was prepared according to the procedure for intermediate 40. Instructions for Use, Pages 139 / 247, 144, CN 122461300 A, Example 32: Synthesis of Intermediate 42, Step 1: 42-B. NaOH (2.14 g, 53.43 mmol) was added to a mixture of 42-A (7.0 g, 26.71 mmol) in EtOH / H2O (60 mL, 5 / 1). 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).

[0378] Step 2: 42-C to 42-B (7.00 g, 28.22 mmol) and 2-(trimethylsilyl)ethanol-1-ol (4.00 g, 33.87 mmol)A mixture of HOBT (4.58 g, 33.87 mmol), EDCI (6.50 g, 33.87 mmol), and DIPEA (10.94 g, 84.67 mmol) was added to 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). 1H NMR (400 MHz, CDCl3) δ 7.99 - 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.

[0379] Step 3: 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 hours. 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).

[0380] Step 4: Intermediate 42 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).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).

[0381] Example 33: Synthesis of intermediate 43 Step 1: 43-A DIEA (188 mg, 1.46 mmol) and 2-(chloromethoxy)ethyl-trimethyl-silane (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 hour. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases 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).

[0382] Step 2: Intermediate 43 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 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).

[0383] Example 34: Synthesis of Intermediate 44 Step 1: 44-B 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, methylbenzene (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).

[0384] Step 2: 44-C 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).

[0385] Step 3: 44-D A solution of 44-C (856 mg, 4.17 mmol) in thionyl chloride (10 mL) was heated at 80 °C for 16 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).

[0386] Step 4: 44-E 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 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).

[0387] Step 5: 44-F The 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).

[0388] Step 6: Intermediate 44 The 44-F (125 mg, 313.71 μmol) was heated in THF (3 mL) to give 44-F (125 mg, 313.71 μmol).Sodium hydroxide solution (25%, 30 μL) was added to the solution in 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).

[0389] Example 35: Synthesis of Intermediate 45, Specification 142 / 247 pages, CN 122461300 A. Step 1: 45-B. 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).

[0390] Step 2: 45-C 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).

[0391] Step 3: 45-D Methanesulfonyl chloride (32 mg, 0.28 mmol) and DMAP (67.78 mg, 0.56 mmol) were added to a solution of 45-C (60 mg, 0.37 mmol) in DCM (3 mL), 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)(74.87% yield). MS: m / z = 180.8 (M + 1).

[0392] Step 4: 45-E 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, 65.05% yield). MS: m / z = 445.7 (M + 1).

[0393] Step 5: 45-F 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).

[0394] Step 6: Intermediate 45 At 0°C, aqueous lithium hydroxide (3 M, 0.1 mL) was added dropwise to a solution of 45-F (40 mg, 83.75 μmol) in THF (1 mL). The mixture was stirred at 60°C for 2 hours. The mixture was filtered and the filtrate was concentrated to yield intermediate 45 (20 mg, crude product) as per specification page 143 / 247, CN 122461300 A. MS: m / z = 387.7 (M + 1).

[0395] Example 36: Synthesis of Intermediate 46 Step 1: 46-A 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 another...The reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (450 mL × 3) for 18 hours. 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). ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 1.7 Hz, 1H), 7.65–7.50 (m, 1H), 7.42–7.29 (m, 2H), 5.62 (s, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H).

[0396] Step 2: 46-B was prepared by cooling 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 to 5°C, and then adding lithium bis(trimethylsilyl)amino (1 M, 23.44 mL) 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).

[0397] Step 3: 46-C A mixture of 46-B (2 g, 6.0 mmol), sodium bicarbonate (2.52 g, 30.01 mmol), and hydroxylamine hydrochloride (2.09 g, 30.01 mmol) in DMSO (50 mL) was heated at 50 °C for 3 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).

[0398] Step 4: Add 1,1'-carbonyldiimidazole to the mixture of 46-D (2.66 g, 7.26 mmol) in DMSO (30 mL). (Instructions for use, pages 144 / 247, CN 122461300 A, 2.36 g, 14.53 mmol)1,8-diazabicyclo[5.4.0]undec-7-ene (2.21 g, 14.53 mmol). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give 46-D (2.2 g, 77.23% yield). MS: m / z = 391.6 (M + 1).

[0399] Step 5: 46-E A mixture of intermediate 26 (2.6 g, 9.99 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-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 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 added to a 2 M NaOH aqueous solution (26 mL) under ice bath conditions. The alkaline aqueous solution was extracted with MTBE (10 mL × 3), and the organic extracts were 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-dioxaborhexacyclopentane (1.5 g, 6.3 mmol).

[0400] 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) were mixed under a nitrogen atmosphere in dioxane (15 mL) and water (5 mL).The mixture in methanol (30 mL) 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).

[0401] Step 6: 46-F The mixture of 46-E (2.5 g, 6.38 mmol) and Rh / C (1.5 g) in methanol (30 mL) under H2 atmosphere (1 atm) was stirred at 25 °C for 16 hours. 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 H2 atmosphere (1 atm). The mixture was filtered and concentrated to a residue, which was purified by column chromatography (DCM / MeOH = 3 / 1) to give 46-F (700 mg, 28.63% yield). MS: m / z = 383.9 (M + 1).

[0402] Step 7: 46-G A mixture of 46-F (700 mg, 1.83 mmol), hydroxylamine hydrochloride (634.23 mg, 9.13 mmol), and TEA (1.85 g, 18.25 mmol) in ethanol (10 mL) was stirred at 25°C for 16 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).

[0403] Step 8: 46-H 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]acoxane (342.98 mg, 2.25 mmol) and di(imidazol-1-yl)methyl ketone (365.31 mg, 2.25 mmol) were added to a mixture of 46-G (450 mg, 1.13 mmol) in DMSO (5 mL). The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4Cl (15 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give 46-H (440 mg, 91.80% yield). MS: m / z = 425.7 (M + 1).

[0404] Step 9: Intermediate 46 Specification 145 / 247 pages 150 CN 122461300 A 46-H (440 mg, 1.03 mmol) was prepared in methanol (2 mL), water (2 mL) and THF.Lithium hydroxide hydrate (216.98 mg, 5.17 mmol) was added to a solution of (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).

[0405] Example 37: Separation of Intermediates 35-P1 and 35-P2 Intermediate 35 (5.3 g) was separated by SFC (column: CHIRALPAK®IE 4.6×250 mm 5 μm; mobile phase: hexane / EtOH = 30 / 70; column temperature: 25 °C; flow rate: 1 mL / min) to give intermediate 35-P1 (Rt=10.94 min) and intermediate 35-P2 (2.5 g, Rt=21.33 min).

[0406] Example 38: Separation of Intermediates 46-P1 and 46-P2 The compounds in Table 10 were separated by SFC to obtain intermediates 35-P1 and 35-P2. Example 39: Synthesis of Intermediate 47 146 / 247 pages 151 CN 122461300 A Step 1: 47-A 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).

[0407] Step 2: 47-B 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 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 solution.47-B (1.52 g, 4.19 mmol) 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).

[0408] Step 3: 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-dimethylimidazolidine-2-one (40 mL) in an ice-water bath. After 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).

[0409] Step 4: 47-D LiHMDS (1 M, 33.47 mL) was added to a solution of 47-C (1.68 g, 4.18 mmol) and (4R)-4-methyl-1,3,2-dioxane-2,2-dioxide (1.73 g, 12.55 mmol) in DMPU (20 mL) 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 (30 mL), and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with water (20 mL) and brine (15 mL), 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 (380 mg, 20.57% yield). MS: m / z = 442 (M + 1).

[0410] Step 5: 47-E Sodium bicarbonate (722.89 mg, 8.61 mmol) was added to a solution of 47-D (380 mg, 860.58 μmol), 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).The residue was 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. Then, 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). 1H NMR (400 MHz, CDCl3) δ 11.14 (s, 1H) , 7.60 - 7.23 (m, 5H) , 7.06 (t, J = 28.0 Hz, 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).

[0411] Step 6: Intermediate 47 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).

[0412] Example 40: Synthesis of Intermediates 48 and 49 The compounds in Table 11 were prepared according to the procedure for intermediate 47.

[0413] Table 11 Example 41: Synthesis of Intermediate 50, Specification 148 / 247 pages, 153 CN 122461300 A Step 1: 50-A Add NaOH (13.35 mmol, 10%) to a solution of 37-C (1 g, 2.67 mmol) in THF (30 mL).The reaction was carried out at 20°C with stirring 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).

[0414] Step 2: Intermediate 50 Dibal-H (1 M, 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 was poured into 5 mL of 1 M 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 (ACN: 0.1% HCOOH in H2O = 50:50) to give intermediate 50 (190 mg, 50% yield). MS: m / z = 350.2 (M + 1).

[0415] Example 42: Synthesis of intermediates 51-P1 and 51-P2 Step 1: 51-B 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 hour. Then, DMF (5.57 g, 76.21 mmol) was added to the resulting mixture, and the mixture was stirred at -60°C for 2 hours. 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).

[0416] Step 2: 51-C 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 and 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 analyzed by silica gel column chromatography (EA / DCM =1 / 3) Purification to give 51-C (0.9 g, 5.58 mmol, 88.87% yield). MS: m / 149 / 247 pages 154 CN 122461300 AZ = 161.9 (M + 1).

[0417] Step 3: 51-D 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). 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 4.80 (d, J = 0.5 Hz, 2H), 2.70 (s, 3H).

[0418] Step 4: 51-E 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).

[0419] Step 5: 51-F 51-E (800 mg, 1.8 mmol) was mixed in portions with mCPBA (776.28 mg, 85% purity) in DCM (20 mL) under an argon atmosphere and at 0 °C with stirring. 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 the 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).

[0420] Step 6: Intermediate 51-P1 and Intermediate 51-P2A 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). Intermediate 51-P1: 1H NMR (400 MHz, DMSO) δ 13.08 (bs, 1H), 11.03 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.52 (s, 1H), 7.27 (dd, J = 8.7, 1.5 Hz, 1H), 7.21 (s, 1H), 7.02 (d, J = 2.6 Hz, 1H), 5.64 (s, 2H), 3.71 (d, J = 7.3 Hz, 2H), 3.02 (t, J =12.4 Hz, 1H) , 1.69 (d, J = 12.8 Hz, 2H), 1.64 - 1.46 (m, 2H), 1.32 - 1.24 (m, 3H), 1.19 (s, 3H). MS: m / z = 387 (M + 1).

[0422] Intermediate 51-P2: ¹H NMR (400 MHz, DMSO) δ 13.03 (bs, ¹H), 11.03 (s, ¹H), 7.68 (d, J = 8.8 Hz, ¹H), 7.52 (s, ¹H), 7.27 (d, J = 8.6 Hz, ¹H), 7.21 (s, ¹H), 7.02 (s, ¹H), 5.64 (s, 2H), 3.72 (d, J = 7.7 Hz).Hz, 2H), 3.01 (d, J = 12.8 Hz, 2H), 1.68 (s, 2H), 1.56 (dt, J = 26.0, 10.9 Hz, 2H), 1.26 (d, J = 12.3 Hz, 3H), 1.19 (s, 3H).

[0423] Example 43: Synthesis of Intermediate 52, Specification 150 / 247 pages, 155 CN 122461300 A Step 1: 52-A 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).

[0424] Step 2: 52-B 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 a crude product. The crude product was purified by column chromatography (PE / EA = 1 / 10) to give 52-B (1 g, 83.48% yield).

[0425] Step 3: 52-C 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 with 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).

[0426] Step 4: 52-D 52-C (160 mg, 416.16 mg) was added to a mixture of 52-B (1 g, 2.62 mmol) in methanol (15 mL), and Pd / C (10%, 556.51 mg) was added.A mixture of 52-D (100 mg, 249.67 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).

[0427] Step 5: 52-E At 25 °C, s-chlorochloromethanethioate (163.51 mg, 1.25 mmol) was slowly added to the 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).

[0428] Step 6: 52-F 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 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).

[0429] Step 7: Intermediate 52 The 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).

[0430] Example 44: Synthesis of Intermediate 53 Step 1: 53-B 53-AThe mixture of 11 g (52.31 mmol) in thionyl chloride (180.40 g, 1.52 mol, 110.0 mL) was stirred at 70 °C for 16 hours. 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 hours. The mixture was concentrated under reduced pressure to provide 53-B (16.26 g, crude). MS: m / z = 208.9 (M +1).

[0431] Step 2: 53-C 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 organic matter was 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).

[0432] Step 3: 53-D 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 (see page 152 / 247 of the specification, CN 122461300 A) 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 (400 MHz, CDCl₃) δ 8.48 (d, J = 4.7 Hz, ¹H), 7.49 (dd, J = 7.7, 1.0 Hz, 2H), 7.45-7.32 (m, 3H), 6.67 (d, J = 4.7 Hz, ¹H), 5.45 (s, 2H); MS: m / z = 191.9 (M + 1).

[0433] Step 4: 53-E53-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). ¹H NMR (400 MHz, CDCl₃) δ 10.05 (s, 1H), 7.53 - 7.33 (m, 5H), 7.17 (s, 1H), 5.46 (s, 2H); MS: m / z = 220.1 (M + 1).

[0434] Step 5: 53-F 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).

[0435] Step 6: 53-G 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).

[0436] Step 7: 53-H A mixture of intermediate 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 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).

[0437] Step 8: 53-I A 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).

[0438] Step 9: Intermediate 53 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).

[0439] Example 45: Synthesis of Intermediate 54 153 / 247 pages 158 CN 122461300 A Step 1: 54-A 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; 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 give 54-A (590 mg, 1.71 mmol, 87.59% yield). MS: m / z = 346.2 (M + 1).

[0440] Step 2: Intermediate 54 The 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 hours. 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).

[0441] Example 46: Synthesis of Compound 1 Step 1: 1-1 NaOH (6 M, 2 mL) was added to a solution of 33-A (30 mg, 90.04 μmol) in MeOH (5 mL). The reaction mixture was stirred at 25 °C for 2 hours. The MeOH was removed, and the mixture was adjusted to pH ~ 5 with HCl (1 M). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under vacuum to give 1-1 (25 mg, 91% yield). MS: m / z = 305.0 (M + 1).

[0442] Step 2: 1-2 Add DIEA (52 mg, 409.67 μmol) 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). Stir the reaction mixture at 25 °C for 1 hour. Dilute the mixture with water (20 mL) and extract with ethyl acetate (20 mL × 3). Wash the combined organic phases with brine (30 mL) and filter. Concentrate the filtrate and purify by preparative TLC (DCM / MeOH = 10 / 1) to give 1-2 (30 mg, 47% yield). MS: m / z = 776.1 (M + 1).

[0443] Step 3: 1-3 Add 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) to a solution of 1-2 (30 mg, 38.63 μmol) in toluene (5 mL). The mixture was stirred at 100 °C for 16 hours. 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).

[0444] Step 4: 1-4 Add NH2OH·HCl (25 mg, 369.96 μmol) to the solution of 1-3 (10 mg, 12.33 μmol) in DMSO (2 mL).The mixture was stirred at 60°C for 16 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 1-4 (10 mg, 96% yield). MS: m / z = 844.3 (M + 1).

[0445] Step 5: Compound 1 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 5μm C18 150 × 19 mm, mobile phase: MeCN-H2O (0.1% FA)) to give compound 1 (1.0 mg, 9.70% yield). 1H NMR (400 MHz, CD3OD) δ 8.15 (d , J = 21.6 Hz, 1H) , 7.66 - 7.40 (m, 5H) , 7.16 (d , J = 6.0 Hz, 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).

[0446] Example 47: Synthesis of Compound 2 Step 1: 2-1 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).

[0447] Step 2: 2-2 Add NaHCO3 (23 mg, 284.76 μmol) and NH2OH·HCl (19 mg, 284.76 μmol) to the solution of 2-1 (12 mg, 14.24 μmol) in DMSO (1 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 dryness to give 2-2 (10 mg, 80% yield). MS: m / z = 876.2 (M + 1).

[0448] Step 3: Compound 2 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). 1H NMR (400 MHz, CD3OD) δ 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).

[0449] Example 48: Synthesis of Compounds 3-23 The compounds in Table 12 were prepared according to the procedure for Compound 2. Specification 156 / 247 pages 161 CN122461300 A Specification 157 / 247 pages 162 CN 122461300 A Specification 158 / 247 pages 163 CN 122461300 A Specification 159 / 247 pages 164 CN 122461300 A Specification 160 / 247 pages 165 CN 122461300 A Specification 161 / 247 pages 166 CN 122461300 A Specification 162 / 247 pages 167 CN 122461300 A Specification 163 / 247 pages 168 CN 122461300 A Specification 164 / 247 pages 169 CN 122461300 A Example 49: Synthesis of Compound 24 Specification 165 / 247 pages 170 CN 122461300 A 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 reversed-phase column chromatography (MeCN: 0.5% FA in H2O = 60:40) to give compound 24 (3.2 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.13 (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, 3H) , 3.90 (s , 2H) , 3.72 (d , J = 7.6 Hz, 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).

[0450] Example 50: Synthesis of Compounds 25-52 The compounds in Table 13 were prepared according to the procedure for Compound 24.

[0451] Table 13Instruction manual, pages 166 / 247, 171 CN 122461300 A; Instruction manual, pages 167 / 247, 172 CN 122461300 A; Instruction manual, pages 168 / 247, 173 CN 122461300 A; Instruction manual, pages 169 / 247, 174 CN 122461300 A; Instruction manual, pages 170 / 247, 175 CN 122461300 A; Instruction manual, pages 171 / 247, 176 CN 122461300 A; Instruction manual, pages 172 / 247, 177 CN 122461300 A; Instruction manual, pages 173 / 247, 178 CN 122461300 A; Instruction manual, pages 174 / 247, 179 CN 122461300 A; Instruction manual, pages 175 / 247, 180 CN. 122461300 A Specification 176 / 247 pages 181 CN 122461300 A Example 51: Synthesis of Compound 53 Step 1: 53-1 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). Instructions for Use, pages 177 / 247, 182 CN 122461300 A

[0452] Step 2: Compound 53 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 hours. 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 (400 MHz, CD3OD) δ 7.46 (s, 1H), 7.41 - 7.38 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 8.4 Hz, 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), 3.97 (d, J = 10.8 Hz, 2H), 3.73 (s, 1H) , 3.50 (td , J = 10.8, 3.6 Hz, 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).

[0453] Example 52: Synthesis of Compound 54 The compounds in Table 14 were prepared according to the procedure of Compound 53. Example 53: Synthesis of Compound 55 Specification 178 / 247 pages 183 CN 122461300 A Step 1: 55-1 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 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 reaction (0.1% FA: MeCN = 44: 56 in water) to give 55-1 (12 mg, 34% yield). MS: m / z = 801.2 (M + 23).

[0454] Step 2: Compound 55 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 chromatography (0.1% FA: MeCN = 43:57 in water) to give compound 55 (3.7 mg, 30% yield). ¹H NMR (400 MHz, MeOD) δ 8.28 (s, ¹H), 8.15 (s, ¹H).7.93(d, J=8.0 Hz, 1H) , 7.67 - 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, 2 H) , 4.10 - 4.03 (m, 4H) , 3.58 (t, J = 11.2 Hz, 2H) , 2.88 - 2.86 (m, 1 H) , 1.86 - 1.79 (m, 4 H); MS: m / z = 795.2 (M + 1).

[0455] Example 54: Synthesis of Compounds 56 and 57 The compounds in Table 15 were prepared according to the procedure for Compound 55. Specification 179 / 247 pages 184 CN 122461300 A Example 55: Synthesis of Compound 58 Specification 180 / 247 pages 185 CN 122461300 A 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%). 1H NMR (400 MHz, DMSO) δ 8.47 (d, J = 5.2 Hz, 1H), 8.26 (s, 1H), 8.13 (d, J = 13.2 Hz, 2H), 7.75 (s, 2H), 7.70 - 7.45 (m, 5H), 7.31 - 7.22 (m, 2H) , 7.10 (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).

[0456] Example 56: Synthesis of compound 59 Step 1: 59-1 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 hours. 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).

[0457] Step 2: 59-2 Add (4-methoxyphenyl)methylamine (1.85 g, 0.013 mol) and K2CO3 (9.88 g, 0.072 mol) to a solution of 59-1 (5.56 g, 0.013 mol) in DMF (30 mL). Heat the reaction at 80 °C for 1 hour. Dilute the reaction with 50 mL of ethyl acetate, wash with brine (30 mL × 3) and dry with sodium sulfate, and concentrate under low pressure to give 59-2 (3.2 g, 47% yield). MS: m / z = 530.1 (M + 1).

[0458] Step 3: 59-3 Add TFA (10 mL) to a solution of 59-2 (3.2 g, 0.006 mol) in DCM (20 mL). Stir the reaction at 40 °C for 2 hours. The reaction 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).

[0459] Step 4: 59-4 59-3 (2.16 g, 0.005 mol) was reacted with MeOH (40 mL) and H2O (10 mL) to give 59-3 (2.16 g, 0.005 mol).Reducing Fe (2.96 g, 0.052 mol) and NH4Cl (5.34 g, 0.1 mol) were added to a solution of 59-4 (950 mg, 2.5 mmol) in AcOH (10 mL) and H2O (5 mL). The reaction was heated at 80 °C for 4 hours. The reaction was filtered, concentrated, and diluted with 30 mL of water. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic layer was dried over sodium sulfate and concentrated to give 59-4 (950 mg, crude). MS: m / z = 380.2 (M + 1).

[0460] Step 5: 59-5 At 0 °C, NaNO2 (276 mg, 4 mmol) was added to a solution of 59-4 (950 mg, 2.5 mmol) in AcOH (10 mL) and H2O (5 mL). The reaction was stirred at 0 °C for 1 hour. The reaction was concentrated, diluted with 10 mL of water, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic layer was then dried over sodium sulfate and concentrated to give a residue, which was purified by silica gel chromatography (DCM / MeOH = 100 / 1 to 40 / 1) to give 59-5 (422 mg, 43% yield). MS: m / z = 391.2 (M + 1).

[0461] Step 6: 59-5 (422 mg, 1.08 mmol) in dioxane (2 mL) was added to a solution of 59-5 (422 mg, 1.08 mmol) in dioxane (2 mL) with (Boc)₂O (306 mg, 1.41 mmol), NaOH (43 mg, 1.08 mmol) and DMAP (2 mg, 16.37 μmol). The reaction was stirred at 25 °C for 2 hours. The reaction was quenched by water (5 mL) and the mixture was then extracted with ethyl acetate (10 mL × 3). The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 59-6 (500 mg, 94% yield). MS: m / z = 391.2 (M + 1 - 100).

[0462] Step 7: 59-7 NaOH (122 mg, 3.06 mmol) was added to a solution of 59-6 (500 mg, 1.02 mmol) in MeOH (5 mL). The reaction was heated at 60 °C for 2 hours. The reaction was concentrated, diluted with 5 mL of water, and the aqueous phase was washed with ethyl acetate (3 mL × 3) and then adjusted to pH ~ 6 with HCl (1 M). The mixture was extracted with ethyl acetate (5 mL × 3), and the organic layer was dried over sodium sulfate, filtered, and concentrated to give 59-7 (200 mg, 54% yield). MS: m / z = 363.2 (M + 1).

[0463] Step 8: 59-8 to 59-7 (200 mg, 551 mg)A solution of 0.91 μmol of (Boc)₂O (180.68 mg, 827.86 μmol), NaOH (22.08 mg, 551.91 μmol), and DMAP (2 mg, 16.37 μmol) was added to a solution in water (2 mL) and dioxane (8 mL). The reaction was stirred at 20 °C for 2 hours. The reaction mixture was concentrated, diluted with 5 mL of water, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by preparative TLC (DCM / MeOH = 20 / 1) to give 59-8 (48.7 mg, 19% yield). MS: m / z = 485.0 (M + 23).

[0464] Step 9: 59-9 Intermediate 4 (50 mg, 0.11 mmol) and HATU (63 mg, 0.17 mmol) were added to a solution of 59-8 (48.7 mg, 0.11 mmol) in DMF (5 mL). The solution was stirred for 5 min, and then DIEA (204 mg, 2.2 mmol) was introduced into the solution. The reaction was stirred at 25 °C for 16 h. The reaction was diluted with 50 mL of ethyl acetate and washed with brine (20 mL × 3), dried over sodium sulfate and concentrated to give 59-9 (65 mg, crude). MS: m / z = 820.2 (M+1-100).

[0465] Step 10: Compound 59 TFA (1 mL) was added to a solution of 59-9 (65 mg, 70.6 mmol) in DCM (5 mL). The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC (column: ACQUITY BEH C18, 50 × 2.1 mm, 1.7 μm; mobile phase: MeCN-H2O (0.05% FA); gradient: 5% - 95%) to give compound 59 (8 mg, 9% yield). 1H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H) , 7.84 - 7.83 (m, 1H) , 7.67 - 7.63 (m, 2H) , 7.55 (d, J = 7.2 Hz, 1H) , 7.50 - 7.47 (m , 1H) , 7.43 - 7.14 (m, 5H), 6.72 - 6.70 (m, 3H),4.14 - 4.04 (m, 5H), 3.67 - 3.56 (m, 3H), 3.52 - 3.49 (m, 1H), 2.93 - 2.91(m, 3H), 2.31 (s, 6H), 1.88 - 1.86 (m, 4H). MS: m / z = 820.2 (M + 1).

[0466] Example 57: Synthesis of Compounds 60 and 61 A solution of intermediate 46 (100 mg, 251.62 μmol) in DMF (3 mL) was supplemented with DIEA (260.16 mg, 2.01 mmol), N,N,N',N'-tetramethyl-1-(3-oxo-2,3-dihydrotriazolo[4,5-b]pyridin-3-onthiol-1-yl)methyldiamine hexafluorophosphate (192.36 mg, 503.24 μmol), and intermediate 16 (118.25 mg, 251.62 μmol). The resulting solution was stirred at 25 °C for 16 hours. The mixture was diluted with water (5 mL), and the aqueous layer was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, and concentrated to give a residue, which was purified by preparative HPLC (column: Gemini-C18 150 × 21.2 mm, 5 μm; mobile phase: MeCN-H2O (0.1% TFA); gradient: 60%–70%) to give a mixture of diastereomers. The mixture was further separated by SFC to give two desired isomers. The isomers were further purified by preparative HPLC (column: Gemini-C18 150 × 21.2 mm, 5 μm; mobile phase: MeCN-H2O (0.1% TFA); gradient: 50% - 70%) to give: (SFC column: chiralpak-OD (4.6 mm × 250 mm), mobile phase: 70% CO2 - 30% MeOH (0.2% NH3H2O); flow rate: 2.5 mL / min; retention time: 16.28 min, 30.0 mg, 14.67% yield); 1H NMR (400 MHz, DMSO) δ 12.10 (s, 1H), 8.32 (s, 1H), 7 .80 - 7.38 (m, 4H), 7.37 - 6.91 (m, 3H), 6.91 - 6.59 (m, 1H), 5.78 - 5.28 (m, 1H) , 5.18 - 4.56 (m, 1H) , 4.51 - 4.21 (m, 1H) , 4.13 (s, 3H) , 3.71 - 3.67 (m, 2H) , 3.59 - 3.34 (m, 1H) , 3.13 - 2.64 (m, 3H) , 2.63 - 2.55 (m, 1H) , 2.18 (s, 6H) , 1.98 - 1.40 (m, 8H) , 1.34 - 1.23 (m, 5H) , 1.19 (s, 3H); MS: m / z = 812.6 (M + 1).

[0467] Compound 61 (SFC column: chiralpak-OD (4.6 mm × 250 mm); mobile phase: 70% CO2 - 30% MeOH (0.2% NH3H2O); flow rate: 2.5 mL / min, retention time: 20.43 min, 30.0 mg, 14.67% yield); 1H NMR (400 MHz, DMSO) δ 12.11 (s, 1H), 8.32 (s, 1H), 7.82 - 7.37 (m, 4H), 7.32 - 6.89 (m, 3H), 6.89 - 6.56 (m, 1H), 5.77 - 5.31 (m, 1H), 5.20 - 4.50 (m , 1H) , 4.50 - 4.19 (m , 1H) , 4.13 (s , 3H) , 3.72 (d , J = 8.1 Hz, 2H) , 3.57 - 3.34 (m, 1H) , 3.12 - 2.63 (m, 3H) , 2.59 (d, J = 3.2 Hz, 1H), 2.18 (s, 6H), 1.91 - 1.42 (m, 8H), 1.34 - 1.22 (m, 5H), 1.19 (s, 3H); MS: m / z = 812.6 (M + 1).

[0468] Example 58: Synthesis of Compounds 62 and 63. The compounds in Table 16 were prepared according to the procedure for Compounds 60 and 61. Specification 184 / 247 pages 189 CN 122461300 A Specification 185 / 247 pages 190 CN 122461300 A Example 59: Synthesis of Compound 64 Specification 186 / 247 pages 191 CN 122461300 AStep 1: 64-1 Add Raney nickel (20.0 mg) to a solution of intermediate 48 (300.0 mg, 0.70 mmol) in MeOH (10 mL). Stir the resulting mixture at 35 °C for 5 hours under H2 atmosphere. Filter the reaction mixture and concentrate the filtrate under vacuum. Purify the residue by silica gel column chromatography (PE / EA = 1 / 1 to DCM / MeOH = 10 / 1) to provide 64-1 (200.0 mg, 66.04%). MS: m / z = 432.3 (M + 1).

[0469] Step 2: 64-2 Add MsCl (106.12 mg, 0.93 mmol) and DIEA (119.79 mg, 0.93 mmol) to a solution of 64-1 (200.0 mg, 0.46 mmol) in DCM (5 mL). After stirring at 25°C for 1 hour, the mixture was poured into ice water (50 mL) and extracted with DCM (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 and purified by silica gel column chromatography (PE / EA = 1 / 1) to provide 64-2 (210.0 mg, 88.91%). MS: m / z = 510.2 (M + 1).

[0470] Step 3: 64-3 KOH (462.39 mg, 8.24 mmol) was added to a solution of 64-2 (210.0 mg, 0.41 mmol) in 2-methoxyethanol (5 mL) and H2O (1 mL). The resulting mixture was heated to 100°C and stirred for 60 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with water (20 mL) and adjusted to pH ~ 3 with concentrated HCl. The aqueous mixture was 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 = 2 / 1 to DCM / MeOH = 10 / 1) to provide 64-3 (160.0 mg, 92.34%). MS: m / z = 421.2 (M + 1).

[0471] Step 4: Compound 64 was added to a solution of 64-3 (160.0 mg, 0.38 mmol) and intermediate 3 (240.15 mg, 0.46 mmol, HCl salt) in pyridine (10 mL) with EDCI (146.10 mg, 0.76 mmol). After stirring at 25°C for 16 hours...The solvent was removed under vacuum. The residue was diluted with 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 preparative HPLC (0.1% FA) to provide compound 64 (120.0 mg, 35.36%). 1H NMR (400 MHz, DMSO-d 6) δ 8.31 (s, 1H) , 7.67 - 7.63 (m, 2H) , 7.50 - 7.45 (m, 2H) , 7.22 - 7.17 (m, 3H) , 7.08 - 7.07 (m, 1H) , 6.96 (s, 1H) , 6.73 (s, 1H) , 4.12 - 4.08 (m, 3H) , 3.73 - 3.66 (m, 3H) , 3.53 - 3.40 (m, 1H) , 3.06 - 3.03 (m, 2H) , 2.44 - 2.43 (m , 3H) , 2.26 - 2.22 (m, 6H), 1.69 - 1.50 (m, 5H), 1.41 - 1.40 (m, 2H), 1.28 (s, 3H), 1.19 (s, 3H), 1.09 - 1.03 (m, 2H); MS: m / z = 892.4 (M + 1).

[0472] Example 60: Synthesis of intermediate 55 At 0°C, NaNO2 (492.89 mg, 7.14 mmol) in water (60 mL) was added to a mixture of 55-A (900 mg, 5.95 mmol) in HCl (concentrated, 30 mL) for 0.5 hours. The mixture was stirred at 0°C for 1 hour. Then, SnCl2 (3.39 g, 17.86 mmol) in HCl (concentrated, 50 mL) was added to the mixture at 0 °C for 1 hour. The reaction solution was stirred at 0 °C for 0.5 hours and quenched with water (150 mL) at 0 °C. The reaction mixture was neutralized with saturated aqueous NaOH until pH ~8, and ethyl acetate (200 mL) was added to it. The mixture was then filtered, and the organic layer was washed with brine (80 mL), dried over sodium sulfate, and concentrated to give intermediate 55 (500 mg, crude).

[0473] The compounds in Table 17 were prepared according to the procedure for intermediate 55.Example 61: Synthesis of Intermediate 57 Step 1: 57-B At 25°C, 57-A (812.88 mg, 3.53 mmol, HCl salt) and H2O (264.62 mg, 14.69 mmol) were added to a mixture of intermediate 2 (700 mg, 2.94 mmol) in ethanol (20 mL). The reaction solution was stirred at 80°C for 2 hours. The mixture was concentrated to give the residue, which was then added with H2O (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE / EA = 2 / 1) to give 57-B (750 mg, 1.81 mmol, 61.61% yield). MS: m / z = 163.1 (M + 1).

[0474] Step 2: 57-C At 25°C, phenyl chloroformate (368.37 mg, 2.35 mmol, 294.70 μL) was added to a mixture of 57-B (750 mg, 1.81 mmol) and DIEA (1.17 g, 9.05 mmol, 1.58 mL) in THF (16 mL). The reaction solution was stirred at 25°C for 1 hour. Then, 2,2-dimethoxyethylamine (761.12 mg, 7.24 mmol, 788.73 μL) was added to the reaction mixture at 25°C. The reaction solution was stirred at 25°C for 1 hour. The solution was concentrated using a rotary evaporator to give 57-C (950 mg, crude). MS: m / z = 546.3 (M + 1).

[0475] Step 3: 57-D At 25°C, CF3SO3H (214.46 mg, CN 122461300 A, page 193, specification 188 / 247, 2.61 mmol) was added to a mixture of 57-C (950 mg) and THF (15 mL). The reaction mixture was stirred at 60°C for 2 hours. Then, (Boc)2O (570.09 mg, 2.61 mmol) and TEA (528.65 mg, 5.22 mmol, 728.17 μL) were added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated to give a residue, which was purified by silica gel chromatography (PE / EA = 1 / 1) to obtain 57-D (500 mg, 1.04 mmol, 59.64% yield). MS: m / z = 482.2 (M + 1).

[0476] Step 4: 57-E at 25°C, to 57-D (500A mixture of (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (73.86 mg, 519.27 μmol, 81.89 μL) in NMP (6 mL) was supplemented with K2CO3 (430.60 mg, 3.12 mmol) and CuI (98.90 mg, 519.27 μmol). After removing O2 by bubbling N2 into the reaction solution, the reaction mixture was stirred at 135 °C for 2.5 h. The mixture was quenched with H2O (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, and concentrated to give a residue, which was purified by silica gel chromatography (PE / EA = 1 / 1) to give 57-E (380 mg, 603.58 μmol, 58.12% yield). MS: m / z = 630.3 (M + 1).

[0477] Step 5: Intermediate 57 HCl (4 M, 1.03 mL in MeOH) was added to a solution of 57-E (0.13 g, 206.49 μmol) in MeOH (4 mL), and the mixture was stirred at 25 °C for 6 hours. The reaction was concentrated to intermediate 57 (0.11 g, 194.37 μmol, 94.13% yield, HCl salt). MS: m / z = 530.1 (M + 1).

[0478] The compounds in Table 18 were prepared according to the procedure for intermediate 57. The compounds in Table 19 were prepared according to the procedure for intermediate 11. (Specification 189 / 247 pages 194 CN 122461300 A) The compounds in Table 20 were prepared according to the procedures for intermediates 19-P1 and 19-P2. The compounds in Table 21 were prepared according to the procedure for compound 24. Specification 190 / 247 pages 195 CN 122461300 A Specification 191 / 247 pages 196 CN 122461300 A Specification 192 / 247 pages 197 CN 122461300 A Specification 193 / 247 pages 198 CN 122461300 A Specification 194 / 247 pages 199 CN 122461300 A Specification 195 / 247 pages 200 CN 122461300 A Specification 196 / 247 pages 201 CN 122461300 A Example 65: Synthesis Step 1 of Intermediate 65: 65-BAt 25°C, 65-A (100 g, 632.93 mmol, 61.73 mL) was added to a solution of hydroxylamine-O-sulfonic acid (107.37 g, 949.39 mmol) in 300 mL of cold water. The mixture was heated at 90°C for 40 minutes, and after cooling to room temperature, potassium carbonate (138 g) was added, followed by evaporation to remove water under vacuum. The residue was treated with 300 mL of ethanol, and insoluble precipitates were removed by filtration. The filtrate was treated with 140 mL of 57% hydroiodic acid and stored at -20°C. The solid was then collected by filtration to give 65-B (40 g, 132.48 mmol, 20.9% yield, HI salt), which was used in the next step without further purification.

[0479] St...

Claims

1. Use of a compound of formula (I) in the preparation of a pharmaceutical composition for the treatment or prevention of non-insulin-dependent diabetes mellitus (type 2 diabetes) in a subject with corresponding need, wherein the compound of formula (I) is: (I)， Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer, wherein: yes or ; 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; Each R C It is independently H, C1-C3 alkyl, or C1-C3 haloalkyl; R2 is C3-C 10 Cycloalkyl, 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; It is selected from the following bicyclic heteroaryl rings: , , , , , , , , , , , and ; 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; 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; 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 are capable of forming a 5- or 6-membered ring, the 5- or 6-membered ring optionally containing 1 to 3 heteroatoms selected from N, O and S; R5 and R6 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen, or R5 and R6 together with the carbon 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 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 the two substituents together with the carbon atoms to which they are attached form a 5- or 6-membered ring, T is H. 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 the heteroaryl group is optionally substituted, and L is 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; The condition is when yes , yes T stands for oxadiazolone group, and L stands for... 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. The condition is when yes , yes T stands for oxadiazolone group, and L stands for... And when R5 and R6 are each 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 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.

2. The use according to claim 1, wherein the compound is selected from Table A or its pharmaceutically acceptable salts or tautomers.

3. The use according to claim 1, wherein the compound is selected from: 、 、 、 、 、 、 and Or, or its pharmaceutically acceptable salt or tautomer.