Benzo-condensed ring compound inhibitors, and their manufacturing methods and applications

Abstract

The present invention relates to benzo-condensed ring compound inhibitors, and to methods for producing the same and their applications. In particular, the present invention relates to compounds represented by general formula (I), methods for producing the same and pharmaceutical compositions containing the compound, and their uses in drugs for treating chronic kidney disease, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome, where each substituent in general formula (I) is as defined in the specification.

Description

[Technical Field]

[0001] This application is, Chinese Patent Application No. 202310384096.5, April 11, 2023. Chinese Patent Application No. 202310611392.4, May 26, 2023. Chinese Patent Application No. 202310907026.3, July 21, 2023. Chinese Patent Application No. 202311086944.0, August 25, 2023. This patent application claims priority dated December 1, 2023, in China Patent Application No. 202311645650.7.

[0002] This invention belongs to the field of biopharmaceuticals and specifically relates to benzo-condensed ring compound inhibitors, their manufacturing methods, and applications. [Background technology]

[0003] Aldosterone is a steroid hormone secreted by the adrenal glands that binds to and activates mineralocorticoid receptors (MRs). In the primary cells of the distal tubules and collecting ducts, MR activation causes sodium and water retention accompanied by potassium excretion, leading to plasma volume dilation and increased blood pressure (BP). The renin-angiotensin-aldosterone system (RAAS), as an endocrine system, regulates blood pressure and fluid balance in the human body. Current antihypertensive drugs—angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor blockers (MRAs)—regulate blood pressure by inhibiting this pathway. Patients taking ACEi or ARBs for extended periods may experience an "aldosterone breakthrough," where aldosterone levels temporarily decrease and then rise, damaging target organs. Currently, the only commercially available aldosterone inhibitor is spironolactone, which causes hyperkalemia. The detection of excessive aldosterone in the circulating blood is called primary aldosteronism (PA), which occurs when aldosterone production becomes uncontrolled in the renin-angiotensin-aldosterone system (RAAS). PA was first discovered in patients with adrenal adenoma, and recent evidence indicates an increased prevalence associated with obesity. PA is a common cause of secondary hypertension, accounting for 14%–21% of patients with refractory hypertension (RHTN), where blood pressure remains above the target blood pressure of 140 / 90 mmHg despite the use of three types of antihypertensive drugs (calcium channel blockers, angiotensin enzyme inhibitors, angiotensin receptor blockers, and diuretics). Refractory hypertension is a high-risk condition with a high multimorbidity prevalence, including diabetes, chronic kidney disease, ischemic heart disease, and cerebrovascular disease.

[0004] CYP11B2 is the gene encoded by aldosterone synthase and has high homology to the gene sequence encoding cortisol synthase CYP11B1. Developing highly selective CYP11B2 inhibitors to inhibit aldosterone synthesis is a major direction in the treatment of refractory hypertension and primary aldosteronism. [Overview of the project]

[0005] An object of the present invention is to provide a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

[0006] Alternatively, any two R1 atoms may form a 3-8 membered cycloalkyl group or a 4-7 membered heterocycline group with adjacent carbon atoms, and optionally, the 3-8 membered cycloalkyl group or 4-7 membered heterocycline group may further have an oxo group, -C(O)R b , -NR a C(O)R b -S(O)2R b -S(O)(NH)R b , -NR a S(O)2R b or -NR a S(O)(NH)R b Replaced by, R a or R bEach of these groups is independently selected from hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, aryl group, heteroaryl group, or heterocyclyl group, and optionally, the cycloalkyl group, aryl group, heteroaryl group, or heterocyclyl group is further substituted with one or more substituents selected from oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, or -S(O)2alkyl group. R2, R3, or R4 are each independently selected from hydrogen, deuterium, oxo group, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -NR a C(O)(CH2) n R b or - C(O)NR a (CH2) n R b This may be further replaced by an optional substitution. Alternatively, R2 and R3 may form a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group, or a 4-7 membered heterocyclyl group with an adjacent atom, and optionally, the 3-8 membered cycloalkyl group, the 5-6 membered heteroaryl group, or the 4-7 membered heterocyclyl group may be further substituted with one or more substituents selected from an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, or hydroxyalkyl group. Alternatively, any two R2 atoms may form a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group, or a 4-7 membered heterocyclyl group with an adjacent atom, and optionally, the 3-8 membered cycloalkyl group, the 5-6 membered heteroaryl group, or the 4-7 membered heterocyclyl group may be further substituted with one or more substituents selected from an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, or hydroxyalkyl group. Alternatively, R2 and R4 may form a 5-14 member cycloalkyl group, a 5-14 member heteroaryl group, or a 5-14 member heterocyclyl group with an adjacent atom, and optionally, the 5-14 member cycloalkyl group, the 5-14 member heteroaryl group, or the 5-14 member heterocyclyl group may be further substituted with one or more substituents selected from an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, or hydroxyalkyl group. p, x, y, and z are each independently selected from 1, 2, 3, or 4. n is selected from 0, 1, 2, or 3. [ka] but [ka] And M1 is N, and ring C is [ka] If so, R1 is -NR a C(O)R b and -NR a S(O)2R b Instead, M1 is N, and there is no ring C or [ka] If that is the case, [ka] teeth, [ka] isn't it.

[0007] In some embodiments of the present invention, a compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is provided. [ka] Here, [ka] These are single or double bonds, Ring A is selected from a phenyl group, a 4-7 membered heterocyclyl group, or a 5-6 membered heteroaryl group, or is absent. If ring A is absent, R2 is linked to ring B. Ring B is a 4-7 membered heterocyclyl group, a 5-6 membered heteroaryl group, or a phenyl group. Ring C is a cycloalkyl group, a heteroaryl group, a heterocyclyl group, or is absent. If ring C is absent, R1 is [ka] It is connected to, M1, M2, M4, M5, and M6 are each independently selected from N, NH, or CH. M3 is a bond, N or CH. R1 is independently a cycloalkyl group, a heterocyclyl group, a cycloalkyloxy group, a heterocyclyloxy group, a cycloalkylamino group, a heterocyclylamino group, a cycloalkylthio group, a heterocyclylthio group, or -C(O)(CH2) n R b , -NR a C(O)(CH2) n R b -S(O)2(CH2) n R b,-S(O)(NH)(CH2) n R b ,-NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b selected from, optionally, the cycloalkyl group, heterocyclyl group, cycloalkyloxy group, heterocyclyloxy group, cycloalkylamino group, heterocyclylamino group, cycloalkylthio group or heterocyclylthio group is further an oxo group, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, -C(O)(CH2) n R b ,-S(O)2(CH2) n R b ,-S(O)(NH)(CH2) n R b ,-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted with one or more substituents selected from, or, any two R1s form a 3- to 8-membered cycloalkyl group or a 4- to 7-membered heterocyclyl group with adjacent carbon atoms, and optionally, the 3- to 8-membered cycloalkyl group or 4- to 7-membered heterocyclyl group is further -C(O)R b ,-NR a C(O)R b ,-S(O)2R b ,-S(O)(NH)R b ,-NR a S(O)2R b or -NR a S(O)(NH)R b substituted with, R a or R bis independently selected from hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, aryl group, heteroaryl group or heterocyclyl group, R2, R3 or R4 is independently selected from hydrogen, deuterium, oxo group, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and the alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -NR a C(O)(CH2) n R b or - C(O)NR a (CH2) n R b is optionally further substituted, or R2 and R3 form a 3 - 8 member cycloalkyl group, 5 - 6 member heteroaryl group or 4 - 7 member heterocyclyl group with adjacent atoms, and optionally, the 3 - 8 member cycloalkyl group, 5 - 6 member heteroaryl group or 4 - 7 member heterocyclyl group is further substituted with one or more substituents selected from oxo group, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group or hydroxyalkyl group, Alternatively, any two R2 atoms may form a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group, or a 4-7 membered heterocyclyl group with an adjacent atom, and optionally, the 3-8 membered cycloalkyl group, the 5-6 membered heteroaryl group, or the 4-7 membered heterocyclyl group may be further substituted with one or more substituents selected from an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, or hydroxyalkyl group. p, x, y, and z are each independently selected from 1, 2, 3, or 4. n is selected from 0, 1, 2, or 3. If a ring of carbon is present or substituted with R1, then M5 or M6 is CH, and the H atom is further substituted with a ring of carbon or R1.

[0008] In a preferred embodiment of the present invention, [ka] but [ka] And M1 is N, and ring C is [ka] If so, R1 is -NR a C(O)R b and -NR a S(O)2R b Instead, M1 is N, and there is no ring C or [ka] If that is the case, [ka] teeth, [ka] isn't it.

[0009] In preferred embodiments of the present invention, ring A is not selected from a 5-10 membered heterocyclyl group or a 5-10 membered heteroaryl group containing 1-3 members selected from C(O), N, O, S, SO2, or SONH.

[0010] In a preferred embodiment of the present invention, ring A is selected from a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group containing 1-3 elements selected from C(O), N, O, S, SO2, or SONH.

[0011] In preferred embodiments of the present invention, ring B is selected from a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group containing 1-3 members selected from phenyl, C(O), N, O, or S.

[0012] In a preferred embodiment of the present invention, [ka] teeth, [ka] Selected from, here, [ka] teeth, [ka] This represents the connection point.

[0013] In a preferred embodiment of the present invention, [ka] teeth, [ka] Selected from.

[0014] In a preferred embodiment of the present invention, [Chemical formula] is [Chemical formula] selected from.

[0015] In a preferred embodiment of the present invention, [Chemical formula] is [Chemical formula] selected from.

[0016] In a preferred embodiment of the present invention, ring C is selected from a 3- to 10-member cycloalkyl group or a 4- to 10-member heterocyclyl group containing 1 to 3 selected from C(O), N, O, S, SO2 or SONH, In a preferred embodiment of the present invention, ring C is selected from a 5- to 7-member monocyclic cycloalkyl group, a 6- to 1- member bicyclic cycloalkyl group, a 5- to 7-member monocyclic heterocyclyl group containing 1 to 3 selected from C(O), N, O, S, SO2 or SONH, and a 7- to 10-member bicyclic heterocyclyl group containing 1 to 3 selected from C(O), N, O, S, SO2 or SONH.

[0017] In a preferred embodiment of the present invention, ring C is [Chemical formula] selected from the group of.

[0018] In a preferred embodiment of the present invention, ring C does not exist.

[0019] In preferred embodiments of the present invention, R1 is independently a 3-10 member cycloalkyl group, a 4-10 member heterocyclyl group, a 3-8 member cycloalkyloxy group, a 4-8 member heterocyclyloxy group, a 3-8 member cycloalkylamino group, a 4-8 member heterocyclylamino group, a 3-8 member cycloalkylthio group, a 4-8 member heterocyclylthio group, or -C(O)(CH2) n R b , -NR a C(O)(CH2) n R b -O(CH2) n R b , -NH(CH2) n R b -S(CH2) n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n R b , -NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Selected from, optionally, the 3-10 member cycloalkyl group, 4-10 member heterocyclyl group, 3-8 member cycloalkyloxy group, 4-8 member heterocyclyloxy group, 3-8 member cycloalkylamino group, 4-8 member heterocyclylamino group, 3-8 member cycloalkylthio group, and 4-8 member heterocyclylthio group may further be an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, or C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, -C(O)(CH2) n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n Rb -S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Substituted with one or more substituents selected from, R a or R b These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 A 5-8 membered heteroaryl group containing 1-3 members selected from a hydroxyalkyl group, a 3-8 membered cycloalkyl group, C(O), N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, optionally comprising an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, or C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group or -SO2-C 1-6 It is substituted with one or more substituents selected from alkyl groups.

[0020] In a preferred embodiment of the present invention, R a or R bThese are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 A 5-8 membered heteroaryl group containing 1-3 members selected from a hydroxyalkyl group, a 3-8 membered cycloalkyl group, C(O), N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, optionally comprising an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, or C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl groups, 3-6 membered cycloalkyl groups, or -SO2-C 1-6 It is substituted with one or more substituents selected from alkyl groups.

[0021] In preferred embodiments of the present invention, R1 is independently a 4-10 member heterocyclyl group containing 1-3 members selected from 3-10 member cycloalkyl groups, N, O, S, SO2, or SONH, a 3-8 member cycloalkyloxy group, a 4-8 member heterocyclyloxy group containing 1-3 members selected from N, O, S, SO2, or SONH, or -C(O)(CH2) n R b , -NR a C(O)(CH2) n Rb -O(CH2) n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n R b , -NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b A 4-10 member heterocyclyl group containing 1 to 3 members selected from the 3-10 member cycloalkyl group, N, O, S, SO2, or SONH, and a 4-8 member heterocyclyloxy group containing 1 to 3 members selected from the 3-8 member cycloalkyloxy group, N, O, S, SO2, or SONH, further comprising an oxo group, -C(O)(CH2) n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n R b -S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Substituted with one or more substituents selected from, R a or R b These are, independently, hydrogen, deuterium, and C. 1-3 Selected from alkyl groups, 3-8 membered cycloalkyl groups, 5-8 membered heteroaryl groups containing 1-3 members selected from N, O, or S, or 4-8 membered heterocyclyl groups containing 1-3 members selected from C(O), N, O, or S, and optionally the 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or the 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, further comprising an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group or -SO2-C 1-3 It is substituted with one or more substituents selected from alkyl groups.

[0022] In preferred embodiments of the present invention, R1 is independently a 3-8 member cycloalkyl group, a 4-8 member heterocyclyl group, a 3-8 member cycloalkyloxy group, a 4-8 member heterocyclyloxy group, a 3-8 member cycloalkylamino group, a 4-8 member heterocyclylamino group, a 3-8 member cycloalkylthio group, a 4-8 member heterocyclylthio group, or -C(O)(CH2) n R b , -NR a C(O)(CH2) n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n R b , -NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Selected from, optionally, the 3-8 member cycloalkyl group, 4-8 member heterocyclyl group, 3-8 member cycloalkyloxy group, 4-8 member heterocyclyloxy group, 3-8 member cycloalkylamino group, 4-8 member heterocyclylamino group, 3-8 member cycloalkylthio group, and 4-8 member heterocyclylthio group may further be an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, or C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6Hydroxyalkyl group, -C(O)(CH2) n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n R b -S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Substituted with one or more substituents selected from, R a or R b These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 The group is selected from a hydroxyalkyl group, a 3-8 membered cycloalkyl group, a 5-8 membered heteroaryl group containing 1-3 members selected from C(O), N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S.

[0023] In preferred embodiments of the present invention, R1 is independently a 4-8 member heterocyclyl group containing 1-3 members selected from 3-8 member cycloalkyl groups, N, O, S, SO2 or SONH, a 3-8 member cycloalkyloxy group, a 3-8 member cycloalkylamino group, a 4-8 member heterocyclyloxy group containing 1-3 members selected from N, O, S, SO2 or SONH, a 4-8 member heterocyclylamino group containing 1-3 members selected from N, O, S, SO2 or SONH, and -C(O)(CH2) n R b , -NR a C(O)(CH2) n R b -O(CH2) n Rb -S(O)2(CH2) n R b -S(O)(NH)(CH2) n R b , -NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b A 4-8 member heterocyclyl group containing 1 to 3 members selected from the 3-8 member cycloalkyl group, N, O, S, SO2, or SONH, a 3-8 member cycloalkyloxy group, a 3-8 member cycloalkylamino group, a 4-8 member heterocyclyloxy group containing 1 to 3 members selected from N, O, S, SO2, or SONH, or a 4-8 member heterocyclylamino group containing 1 to 3 members selected from N, O, S, SO2, or SONH, further contains an oxo group, -C(O)(CH2) n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n R b -S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Substituted with one or more substituents selected from, R a or R b These are, independently, hydrogen, deuterium, and C. 1-3 Selected from alkyl groups, 3-8 membered cycloalkyl groups, 5-8 membered heteroaryl groups containing 1-3 members selected from N, O, or S, or 4-8 membered heterocyclyl groups containing 1-3 members selected from C(O), N, O, or S, and optionally the 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or the 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, further comprising an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl alkyl group, C2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl groups, 3-6 membered cycloalkyl groups, or -SO2-C 1-3 It is substituted with one or more substituents selected from alkyl groups.

[0024] In preferred embodiments of the present invention, R1 is independently a 4-8 member heterocyclyl group containing 1-3 members selected from 3-8 member cycloalkyl groups, N, O, S, SO2, or SONH, a 4-8 member heterocyclyloxy group containing 1-3 members selected from 3-8 member cycloalkyloxy groups, N, O, S, SO2, or SONH, or -C(O)(CH2) n R b , -NR a C(O)(CH2) n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n R b , -NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b A 4-8 member heterocyclyl group containing 1 to 3 members selected from the 3-8 member cycloalkyl group, N, O, S, SO2, or SONH, and a 4-8 member heterocyclyloxy group containing 1 to 3 members selected from the 3-8 member cycloalkyloxy group, N, O, S, SO2, or SONH, further comprising an oxo group, -C(O)(CH2) n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n R b -S(O)2(CH2) n R bor -NR a S(O)(NH)(CH2) n R b Substituted with one or more substituents selected from, In a preferred embodiment of the present invention, R2, R3, or R4 are each independently hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Hydroxyalkyl group, 3-8 membered cycloalkyl group, 3-8 membered cycloalkyloxy group, 3-8 membered cycloalkylamino group, C 6-10 A 5-6 membered heteroaryl group containing 1-3 members selected from aryl groups, N, O, and S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, -NR a R b , -NR a C(O)R b or -C(O)NR a R b Selected from.

[0025] In a preferred embodiment of the present invention, R2, R3, or R4 are each independently hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 A hydroxyalkyl group, a 3-8 membered cycloalkyl group, or a 4-8 membered heterocyclyl group containing 1-3 elements selected from C(O), N, O, or S, -NR a C(O)R bor -C(O)NR a R b Selected from, R a or R b These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 The group is selected from a hydroxyalkyl group, a 3-8 membered cycloalkyl group, a 5-8 membered heteroaryl group containing 1-3 members selected from C(O), N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S.

[0026] In a preferred embodiment of the present invention, R2, R3, or R4 are each independently hydrogen, deuterium, halogen, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group or C 3-6 Selected from cycloalkyloxy groups.

[0027] In a preferred embodiment of the present invention, R2, R3, or R4 are each independently hydrogen, deuterium, halogen, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group or C 1-3 Selected from hydroxyalkyl groups.

[0028] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by general formula (III-a)-(III-i), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] Ring C is selected from a 5-7 member monocyclic cycloalkyl group, a 6-10 member bicyclic cycloalkyl group, a 5-7 member monocyclic heterocyclyl group containing 1-3 members selected from C(O), N, O, S, SO2, or SONH, and a 7-10 member bicyclic heterocyclyl group containing 1-3 members selected from C(O), N, O, S, SO2, or SONH. Alternatively, ring C does not exist. L stands for bond, -O-, -R c C(O)-, -R c S(O)NH- or -R c Selected from S(O)2, preferably -NHC(O)-, R c This is selected from a 4-8 membered heterocyclyl group containing 1-3 elements selected from a bond, NH, a 3-8 membered cycloalkyl group, N, O, S, SO2, or SONH, and a 4-8 membered heterocyclyloxy group containing 1-3 elements selected from a 3-8 membered cycloalkyloxy group, N, O, S, SO2, or SONH. R2, R3, or R4 are each independently hydrogen, deuterium, halogen, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group or C 3-6 Selected from cycloalkyl groups, R b These are hydrogen, deuterium, halogen, hydroxyl group, cyano group, and C 1-3Selected from an alkyl group, a 3- to 8-member cycloalkyl group, a 5- to 8-member heteroaryl group containing 1 to 3 members selected from N, O or S, or a 4- to 8-member heterocyclyl group containing 1 to 3 members selected from C(O), N, O, S, SO2 or SONH, y is 1, 2 or 3.

[0029] In a more preferred embodiment of the present invention, R b is hydrogen, deuterium, C 1-3 Selected from an alkyl group, a 3- to 8-member cycloalkyl group, a 5- to 8-member heteroaryl group containing 1 to 3 members selected from N, O or S, or a 4- to 8-member heterocyclyl group containing 1 to 3 members selected from C(O), N, O, S, SO2 or SONH, and optionally, the C 1-3 Selected from an alkyl group, a 3- to ochoalkyl group, a 5- to 8-member heteroaryl group containing 1 to 3 members selected from N, O or S, or a 4- to 8-member heterocyclyl group containing 1 to 3 members selected from C(O), N, O, S, SO2 or SONH is further substituted with a hydroxy group, an amino group, CN, C 1-3 alkyl group, C 1-3 deuterated alkyl group, C 1-3 haloalkyl group, C 1-3 alkoxy group, C 1-3 haloalkoxy group, C 1-3 hydroxyalkyl group or a 3- to 6-member cycloalkyl group.

[0030] In a more preferred embodiment of the present invention, R c When selected from a 3- to 8-member cycloalkyloxy group or a 4- to 8-member heterocyclyloxy group containing 1 to och members selected from N, O, S, SO2 or SONH, the exocyclic oxygen atom is linked to ring C, and when ring C is absent, the oxygen atom is

Chemical formula

[0031] In a more preferred embodiment of the present invention, R bis hydrogen, deuterium, C 1-3 A 5-8 membered heteroaryl group containing 1-3 elements selected from alkyl groups, 3-8 membered cycloalkyl groups, N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 elements selected from C(O), N, O, S, SO2, or SONH, optionally comprising the C 1-3 A 5-8 membered heteroaryl group containing 1-3 elements selected from alkyl groups, 3-8 membered cycloalkyl groups, N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 elements selected from C(O), N, O, S, SO2, or SONH, may further contain a hydroxyl group, an amino group, CN, or C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Substituted with a hydroxyalkyl group or a 3- to 6-membered cycloalkyl group.

[0032] In a more preferred embodiment of the present invention, R c However, if selected from a 3-8 membered cycloalkyloxy group or a 4-8 membered heterocyclyloxy group containing 1-3 members selected from N, O, S, SO2, or SONH, the oxygen atom is linked to the ring C, and if the ring C is absent, the oxygen atom is... [ka] It is connected to.

[0033] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by general formula (III') or general formula (IV'), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] Ring C is selected from a 5-7 member monocyclic cycloalkyl group, a 6-10 member bicyclic cycloalkyl group, a 5-7 member monocyclic heterocyclyl group containing 1-3 members selected from C(O), N, O, S, SO2, or SONH, and a 7-10 member bicyclic heterocyclyl group containing 1-3 members selected from C(O), N, O, S, SO2, or SONH. Alternatively, ring C does not exist. L stands for bond, -O-, -R c C(O)-, -R c S(O)NH- or -R c Selected from S(O)2, R c This is selected from a 4-8 membered heterocyclyl group containing 1-3 elements selected from a bond, NH, a 3-8 membered cycloalkyl group, N, O, S, SO2, or SONH, and a 4-8 membered heterocyclyloxy group containing 1-3 elements selected from a 3-8 membered cycloalkyloxy group, N, O, S, SO2, or SONH. R2 or R4 independently contain hydrogen, deuterium, halogen, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group or C 1-3 Selected from hydroxyalkyl groups, R b is hydrogen, deuterium, C 1-3 Selected from alkyl groups, 3-8 membered cycloalkyl groups, 5-8 membered heteroaryl groups containing 1-3 members selected from N, O, or S, or 4-8 membered heterocyclyl groups containing 1-3 members selected from C(O), N, O, S, SO2, or SONH, y is 1, 2, or 3.

[0034] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by general formula (IV-a) or (IV-b), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] Here, M2 or M3 is independently selected from N or CH, and if a ring C is present or substituted with R1, then M2 or M3 is CH, and the H atom is further substituted. Ring C is selected from a 5-7 member monocyclic cycloalkyl group, a 6-10 member bicyclic cycloalkyl group, a 5-7 member monocyclic heterocyclyl group containing 1-3 members selected from C(O), N, O, S, SO2, or SONH, or a 7-10 member bicyclic heterocyclyl group containing 1-3 members selected from C(O), N, O, S, SO2, or SONH, or is absent. R1 is -C(O)R b , -NR a C(O)R b , -OR b -S(O)2R b -S(O)(NH)R b , -NR a S(O)2R b , -NR a S(O)(NH)R b Alternatively, a 4- to 8-membered heterocyclyl group is selected, and the 4- to 8-membered nitrogen-containing heterocyclyl group is optionally further -C(O)R b Or -S(O)2R b Replaced by, R a or R b These are, independently, hydrogen, deuterium, halogen, hydroxyl group, cyano group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Selected from a haloalkoxy group, a 3-8 membered cycloalkyl group, a 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, optionally comprising the C 1-3A 5-8 membered heteroaryl group containing 1-3 elements selected from alkyl groups, 3-8 membered cycloalkyl groups, N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 elements selected from C(O), N, O, S, SO2, or SONH, may further contain a hydroxyl group, an amino group, CN, or C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Substituted with a hydroxyalkyl group or a 3-6 membered cycloalkyl group, R2 is hydrogen, deuterium, halogen, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group or C 3-6 Selected from cycloalkyloxy groups.

[0035] In a more preferred embodiment of the present invention, the general formula (IV-a) is further a compound represented by general formula (IV-a-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0036] In a more preferred embodiment of the present invention, R b is hydrogen, deuterium, C 1-3 A 5-8 membered heteroaryl group containing 1-3 elements selected from alkyl groups, 3-8 membered cycloalkyl groups, N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 elements selected from C(O), N, O, S, SO2, or SONH, optionally comprising the C 1-3A 5-8 membered heteroaryl group containing 1-3 elements selected from alkyl groups, 3-8 membered cycloalkyl groups, N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 elements selected from C(O), N, O, S, SO2, or SONH, may further contain a hydroxyl group, an amino group, CN, or C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Substituted with a hydroxyalkyl group or a 3- to 6-membered cycloalkyl group.

[0037] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by general formula (Va) or (Vb), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] Here, L is selected from a bond, NH, or O. Ring D is selected from 4-8 membered heterocyclyl groups containing 1-3 nitrogen atoms.

[0038] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by general formula (VI-a)-(VI-j), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] Here, L is NR a Selected from O or S, L1 is selected from C(O) or S(O)2. R a is hydrogen, deuterium, halogen, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3Hydroxyalkyl group or C 3-6 Selected from cycloalkyloxy groups, M2 is selected from N or CH. M5 is selected from N or CH. R2 is hydrogen, deuterium, halogen, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group or C 3-6 Selected from cycloalkyloxy groups, Alternatively, any two R2 atoms may form a 5-8 membered heteroaryl group containing 1-3 atoms selected from 3-8 membered cycloalkyl groups, N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 atoms selected from C(O), N, O, or S. R b These are, independently, hydrogen, deuterium, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Selected from a haloalkoxy group, a 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, optionally the 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or the 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, further comprising a halogen, hydroxyl group, amino group, CN, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Substituted with a hydroxyalkyl group or a 3-6 membered cycloalkyl group, R5 independently represents hydrogen, deuterium, halogen, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group or C 3-6 Selected from cycloalkyloxy groups, R6 is hydrogen, deuterium, halogen, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group or C 3-6 Selected from cycloalkyl groups, Alternatively, any two R5 atoms may form a 3-8 membered cycloalkyl group or a 3-8 membered heterocycline group with adjacent carbon atoms. Ring D is selected from a 3- to 8-membered cycloalkyl group or a 4- to 8-membered heterocyclyl group, preferably a 4- to 6-membered nitrogen-containing heterocyclyl group. q, r, s, and t are each independently selected from 1 or 2. k is independently selected from 1, 2, or 3.

[0039] In a more preferred embodiment of the present invention, q, r, s, and t are 1.

[0040] In a more preferred embodiment of the present invention, ring D is a 4-6 membered heterocyclyl group containing 1-2 nitrogen atoms.

[0041] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by general formula (VI-a)-(VI-i), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] Here, M2 is selected from N or CH. M5 is selected from N or CH. L is selected from NH, O, or S. R2 is hydrogen, deuterium, halogen, C 1-3 Alkyl alkyl group or C 1-3 Selected from deuterated alkyl groups, R b is hydrogen, deuterium, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Selected from a haloalkoxy group, a 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, optionally the 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or the 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, further comprising a halogen, hydroxyl group, amino group, CN, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Substituted with a hydroxyalkyl group or a 3-6 membered cycloalkyl group, Ring D is selected from a 4-6 membered heterocyclyl group containing 1-2 nitrogen atoms. q, r, s, and t are each independently selected from 1 or 2. y is independently selected from 0, 1, or 2.

[0042] In a more preferred embodiment of the present invention, R2 is selected from a methyl group or a methoxy group, and y is 1.

[0043] In a more preferred embodiment of the present invention, M2 is N and M3 is CH.

[0044] In a more preferred embodiment of the present invention, R b C 1-3 Selected from alkyl groups, 3-6 membered cycloalkyl groups, or 5-6 membered heteroaryl groups containing 1-3 members selected from N, O, or S, optionally the 5-6 membered heteroaryl group containing 1-3 members selected from N, O, or S may further contain a halogen, a hydroxyl group, CN, or C 1-3 It is replaced with an alkyl group.

[0045] In a more preferred embodiment of the present invention, q, r, s, and t are all 1.

[0046] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by the general formula (VI-k)-(VI-m), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] Here, M2 is selected from N or CH. M5 is selected from N or CH. R2 is hydrogen, deuterium, halogen, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group or C 3-6 Selected from cycloalkyloxy groups, Ring E is selected from a 3-10 membered cycloalkyl group or a 4-10 membered heterocyclyl group, preferably a 5-10 membered nitrogen-containing heterocyclyl group, and optionally further a halogen, hydroxyl group, amino group, CN, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3Substituted with a hydroxyalkyl group or a 3-6 membered cycloalkyl group, q, r, s, and t are each independently selected from 1 or 2. y is independently selected from 0, 1, or 2.

[0047] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by general formula (VII-a), (VII-b), (VII-c) or (VII-d), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] Here, M2 is selected from N or CH. R2 is hydrogen, deuterium, halogen, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group or C 3-6 Selected from cycloalkyloxy groups, R b These are, independently, hydrogen, deuterium, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Selected from a haloalkoxy group, a 5-8 membered heteroaryl group containing 1-3 members selected from 3-8 membered cycloalkyl groups, N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, optionally the 5-8 membered heteroaryl group containing 1-3 members selected from 3-8 membered cycloalkyl groups, N, O, or S, or the 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, further C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C1-3 Haloalkoxy group, C 1-3 Substituted with a hydroxyalkyl group or a 3-6 membered cycloalkyl group, R5 independently represents hydrogen, deuterium, halogen, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group or C 3-6 Selected from cycloalkyloxy groups, Alternatively, any two R5 atoms may form a 3-8 membered cycloalkyl group or a 3-8 membered heterocycline group with adjacent carbon atoms. Ring D is selected from 4- to 8-membered heterocyclyl groups, preferably a 4- to 6-membered nitrogen-containing heterocyclyl group. q, r, s, and t are each independently selected from 1 or 2. k is independently selected from 1, 2, or 3.

[0048] In a more preferred embodiment of the present invention, q, r, s, and t are 1.

[0049] In a more preferred embodiment of the present invention, ring D is a 4-6 membered heterocyclyl group containing 1-2 nitrogen atoms.

[0050] In another aspect, the present invention provides compounds represented by general formula (Xa) or (Xb), stereoisomers thereof, or pharmaceutically acceptable salts thereof. [ka] M2 or M5 is independently selected from N or CH. Each R is independently selected from hydrogen, a 3-10 member cycloalkyl group, a 4-10 member heterocyclyl group, a 3-8 member cycloalkyloxy group, a 4-8 member heterocyclyloxy group, a 3-8 member cycloalkylamino group, a 4-8 member heterocyclylamino group, a 3-8 member cycloalkylthio group, and a 4-8 member heterocyclylthio group. R2 independently consists of hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Hydroxyalkyl group, 3-8 membered cycloalkyl group, 3-8 membered cycloalkyloxy group, 3-8 membered cycloalkylamino group, C 6-10 A 5-6 membered heteroaryl group containing 1-3 members selected from aryl groups, N, O, and S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, -NR a R b , -NR a C(O)R b or -C(O)NR a R b Selected from, y is selected from 1, 2, or 3.

[0051] In a more preferred embodiment of the present invention, R is independently selected from a 4-8 member heterocyclyl group containing 1-3 elements selected from hydrogen, a 3-10 member cycloalkyl group, N, O, S, SO2, or SONH, a 3-8 member cycloalkyloxy group, a 3-8 member cycloalkyl mercapto group, a 4-8 member heterocyclyloxy group containing 1-3 elements selected from a 3-8 member cycloalkylamino group, N, O, S, SO2, or SONH, a 4-8 member heterocyclylamino group containing 1-3 elements selected from N, O, S, SO2, or SONH, and a 4-8 member heterocyclyl mercapto group containing 1-3 elements selected from N, O, S, SO2, or SONH.

[0052] In a more preferred embodiment of the present invention, R is independently selected from a 7-8 member heterocyclyl group containing 1-3 elements selected from hydrogen, a 3-8 member cycloalkyl group, N, O, S, SO2, or SONH, a 3-6 member cycloalkyloxy group, a 3-6 member cycloalkyl mercapto group, a 4-6 member heterocyclyloxy group containing 1-3 elements selected from a 3-6 member cycloalkylamino group, N, O, S, SO2, or SONH, a 4-6 member heterocyclylamino group containing 1-3 elements selected from N, O, S, SO2, or SONH, and a 4-6 member heterocyclyl mercapto group containing 1-3 elements selected from N, O, S, SO2, or SONH.

[0053] In a more preferred embodiment of the present invention, R2 is independently hydrogen, deuterium, halogen, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group or C 3-6 Selected from cycloalkyloxy groups.

[0054] In another aspect, the present invention provides compounds represented by general formula (Va-4) or (Vb-3), stereoisomers thereof, or pharmaceutically acceptable salts thereof. [ka] Here, M2, M5, L, R2, ring C, ring D, or y are defined in the general formula (Va) or (Vb).

[0055] In another embodiment, the present invention also relates to a pharmaceutical composition comprising any one general formula compound shown in therapeutically effective amounts, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0056] In some embodiments of the present invention, the pharmaceutical composition contains, with respect to the free base, the weight percentage of the compound, its stereoisomer, or its pharmaceutically acceptable salt is 0.1% to 95%, preferably 5% to 70%, for example, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%.

[0057] In some embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations or injections, and preferably further comprises a filler, optionally further comprising a disintegrant, or further comprising one or more of a fluidizer or a lubricant.

[0058] In some embodiments of the present invention, the pharmaceutical composition is either a rapid-release formulation or a sustained-release formulation.

[0059] In some embodiments of the present invention, the unit dose of the compound, its stereoisomer, or its pharmaceutically acceptable salt, based on a free base, in the pharmaceutical composition is 1 to 1000 mg, preferably 1 to 500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg.

[0060] In some embodiments of the present invention, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof may be administered by any convenient means, such as orally, parenterally, orally, sublingually, nasally, rectally, subarachnoidally, or transdermally, and in appropriately modified pharmaceutical compositions.

[0061] In some embodiments of the present invention, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof may be formulated as a liquid or solid preparation, such as a syrup, suspension, emulsion, tablet, capsule, powder, granule, or lozenge.

[0062] In another aspect, the present invention further relates to the application of any one of the general formula compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof, in the manufacture of drugs for treating CYP11B2-related disorders.

[0063] The present invention further relates to the use of compounds represented by any one of the general formulas shown, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the manufacture of drugs for the treatment or prevention of chronic kidney disease, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome.

[0064] In a preferred embodiment of the present invention, the hypertension is refractory hypertension.

[0065] In a preferred embodiment of the present invention, the chronic kidney disease is chronic kidney disease accompanied by type II diabetes.

[0066] In some embodiments, the EC of the compound of the present invention against CYP11B2 50 The values ​​range from 0.0001 μM to 50 μM, and the EC2 of preferred compounds relative to CYP11B2 50 The values ​​range from 0.0001 μM to 10 μM, and the EC2 of more preferred compounds relative to CYP11B2 50 The value is 0.0001 μM to 1 μM, and more preferably, the EC2 of the compound relative to CYP11B2. 50 The values ​​range from 0.0001 μM to 0.1 μM.

[0067] Furthermore, the compounds of the present invention exhibit good selectivity for CYP11B1, with a selectivity greater than 50, a selectivity greater than 100 for preferred compounds, a selectivity greater than 200 for more preferred compounds, and a selectivity greater than 500 for even more preferred compounds.

[0068] In another aspect, the present invention provides a method for producing a compound represented by formula (Va-3) or (Vb-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] By coupling formula (Va-1) and formula (Va-2), the compound shown in formula (Va-3), its stereoisomer, or a pharmaceutically acceptable salt thereof is produced, and optionally, by deprotecting formula (Va-3), the compound shown in formula (Va-4), its stereoisomer, or a pharmaceutically acceptable salt thereof is obtained. [ka] Optionally, equation (Va-4) and X2COR b The step of reacting to obtain a compound represented by general formula (Va), its stereoisomer, or a pharmaceutically acceptable salt thereof, or [ka] By coupling formula (Vb-1) and formula (Va-2), the compound shown in formula (Vb-2), its stereoisomer, or a pharmaceutically acceptable salt thereof is produced, and optionally, deprotection is performed to obtain the compound shown in formula (Vb-3), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] Optionally, use equation (Vb-3) and X2COR b The process includes reacting to obtain the compound shown in formula (Vb), its stereoisomer, or a pharmaceutically acceptable salt thereof, Here, X is a boranyl group, X1 is a halogen, X2 is a halogen or a hydroxyl group, and P is an amino protecting group. M2, M3, L, R2, R b ,r,q,s, ort are as defined in the general formula (Va) or (Vb).

[0069] In another aspect, the present invention provides a method for producing a compound represented by general formula (Va) or (Vb), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the method being [ka] Formula (Va-3) is produced by coupling formula (Va-1) and formula (Va-2), and formula (Va-4) is obtained by deprotection, and formula (Va-4) and X2COR b The steps involve reacting to obtain the general formula (Va), and optionally producing its stereoisomer or a pharmaceutically acceptable salt thereof, or [ka] Equation (Va-5) and X2COR b The steps involve reacting to obtain the general formula (Va-6), then further coupling it with formula (Va-1) to produce formula (Va), and optionally producing its stereoisomer or a pharmaceutically acceptable salt thereof, or [ka] Formula (Vb-2) is produced by coupling formula (Vb-1) and formula (Va-2), and formula (Vb-2) is obtained by deprotection, and formula (Vb-2) and X2COR b The steps involve reacting to obtain general formula (Vb), and optionally producing its stereoisomer or a pharmaceutically acceptable salt thereof, or [ka] Equation (Va-5) and X2COR b The process includes reacting to obtain the general formula (Va-6), then producing formula (Vb) by coupling reaction with formula (Vb-1), and optionally producing its stereoisomer or a pharmaceutically acceptable salt thereof. Here, X is a boranyl group, X1 is a halogen, X2 is a halogen or a hydroxyl group, and P is an amino protecting group. M2, M5, L, R2, R b Rings C, D, and y are defined by the general formulas (Va) or (Vb).

[0070] In a preferred embodiment of the present invention, the boranyl group is a dioxavoranyl group, X1 is chlorine or bromine, X2 is chlorine, bromine or a hydroxyl group, and P is a Boc protecting group.

[0071] In a preferred embodiment of the present invention, a method is provided for producing a compound represented by general formula (VI-a), (VI-c), or (VI-d), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] Formula (VI-a-3) is produced by coupling formula (VI-a-1) and formula (VI-a-2), and then formula (VI-a-5) is obtained by reacting it with formula (VI-a-4). After deprotecting formula (VI-a-5), X2COR is used. b The process involves manufacturing a product to obtain general formula (VI-a), and optionally further manufacturing its stereoisomer or a pharmaceutically acceptable salt thereof, or [ka] Formula (VI-c-2) is produced by coupling formula (VI-c-1) and formula (VI-a-2), and then formula (VI-c-3) is obtained by reacting it with formula (VI-a-4). After deprotecting formula (VI-c-3), X2COR is applied. b The process involves manufacturing a compound to obtain the general formula (VI-c), and optionally further manufacturing its stereoisomer or a pharmaceutically acceptable salt thereof, or [ka] Formula (VI-a-3) is produced by coupling formula (VI-a-1) and formula (VI-a-2), and then formula (VI-d-2) is obtained by reacting it with formula (VI-d-1). After deprotecting formula (VI-d-2), X2COR is used. b The process includes the step of producing a general formula (VI-a) and optionally further producing a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Here, X is a boranyl group, X1 is a halogen, X2 is a halogen or a hydroxyl group, and P is an amino protecting group. M2, M3, L, R2, R b , y, r, q, s, or t are as defined in the general formulas (VI-a), (VI-c), or (VI-d). [Modes for carrying out the invention]

[0072] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0073] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, and 5-methylhexyl group. Examples include 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.More preferably, the lower alkyl group contains 1 to 6 carbon atoms, and non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, and the like. The alkyl group may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking site, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups, and in the present invention, preferably methyl groups, ethyl groups, isopropyl groups, tert-butyl groups, haloalkyl groups, deuterated alkyl groups, alkyl groups substituted with alkoxy groups, and alkyl groups substituted with hydroxyl groups.

[0074] The term "alkylene group" refers to a group in which one hydrogen atom of an alkyl group is further substituted. For example, a "methylene group" refers to -CH2-, an "ethylene group" refers to -(CH2)2-, a "propylene group" refers to -(CH2)3-, and a "butylene group" refers to -(CH2)4-. The term "alkenyl group" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Examples include vinyl groups, 1-propenyl groups, 2-propenyl groups, and 1-, 2-, or 3-butenyl groups. The alkenyl group may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0075] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the ring of a cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, while polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings, and crosslinked rings, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl groups.

[0076] The term "spirocycloalkyl group" refers to a 5-20 membered polycyclic group in which monocyclic rings share one carbon atom (called a spiro atom), and which may contain one or more double bonds, but does not have any rings with a fully conjugated π-electron system. Preferably, it is 6-14 membered, and more preferably 7-10 membered. Depending on the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups, preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. More preferably, they are 3-membered / 6-membered, 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are: [ka] This includes, This also includes spirocycloalkyl groups in which monospirocycloalkyl groups and heterocycloalkyl groups share a spiro atom, and non-limiting examples include: [ka] This includes, among others.

[0077] The term "condensed cycloalkyl group" refers to a 5-20 member all-carbon polycyclic group in which each ring in the system shares one adjacent pair of carbon atoms with the other rings in the system, where one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, it is 6-14 member, more preferably 7-10 member. Depending on the number of constituent rings, it may be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyl group, preferably bicyclic or tricyclic, more preferably a 5-member / 5-member or 5-member / 6-member bicyclic cycloalkyl group. Non-limiting examples of condensed cycloalkyl groups are: [ka] This includes, among others.

[0078] A "crosslinked cycloalkyl group" refers to a 5-20 membered all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked. It may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, it has 6-14 members, more preferably 7-10 members. Depending on the number of rings, it may be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic crosslinked cycloalkyl group, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of crosslinked cycloalkyl groups include: [ka]

[0079] The cycloalkyl ring can be condensed onto an aryl group, a heteroaryl group, or a heterocycloalkyl ring, where the ring linked to the basic skeleton is a cycloalkyl group, and non-limiting examples include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0080] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, where one or more ring atoms are nitrogen, oxygen, or S(O). mThe heteroatoms are selected from (where m is an integer from 0 to 2), but do not contain the -OO-, -OS-, or -SS- ring portions, and the other ring atoms are carbon. Preferably, the 4-8 membered heterocyclyl group contains 3 to 12 ring atoms, where 1 to 4 are heteroatoms, more preferably 3 to 8 ring atoms, most preferably 3 to 8 ring atoms, and even more preferably 1 to 3 nitrogen atoms, which are optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, and include nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spiroheterocyclyl groups, or nitrogen-containing condensed heterocyclyl groups.

[0081] Non-limiting examples of monocyclic heterocyclyl groups include azetidine, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuryl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, azepanyl group, 1,4-diazacycloheptyl group, and pyranyl group, with pyrrolidinyl group, morpholinyl group, piperidinyl group, azepanyl group, 1,4-diazacycloheptyl group, and piperazinyl group being preferred. Polycyclic heterocyclyl groups include spiro rings, fused rings, and bridging ring heterocyclyl groups, where such spiro rings, fused rings, and bridging ring heterocyclyl groups are optionally linked to other groups via single bonds, or further linked in parallel to other cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups via any two or more atoms on the ring.

[0082] The term "spiroheterocyclyl group" refers to a 5-20 membered polycyclic heterocyclyl group in which monocyclic rings share one atom (called a spiro atom), where one or more ring atoms are nitrogen, oxygen, or S(O). mThe heteroatom is selected from (where m is an integer from 0 to 2), and the other ring atoms are carbon. It may contain one or more double bonds, but there are no rings having a fully conjugated π-electron system. Preferably, it is 6-14 member, more preferably 7-10 member. Depending on the number of covalent spiroatoms between the rings, the spiroheterocyclyl group is divided into a monospiroheterocyclyl group, a bisspiroheterocyclyl group, or a polyspiroheterocyclyl group, preferably a monospiroheterocyclyl group and a bisspiroheterocyclyl group. More preferably, it is a 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] This includes, among others.

[0083] The term "condensed heterocyclyl group" refers to a 5-20 membered polycyclic heterocyclyl group in which each ring in the system shares one adjacent pair of carbon atoms with the other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system, where one or more ring atoms are nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2) is a heteroatom selected from the above, and the other ring atoms are carbon. Preferably, it has 6 to 14 members, and more preferably, 7 to 10 members. Depending on the number of rings that make up the group, it may be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl group, preferably bicyclic or tricyclic, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups are: [ka] This includes, among others.

[0084] The term "bridged heterocyclyl group" refers to a 5-14 member polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, and which may contain one or more double bonds, but which have no rings having a fully conjugated π-electron system, where one or more ring atoms are nitrogen, oxygen, or S(O). m A heteroatom selected from (where m is an integer from 0 to 2), and the other ring atoms are carbon. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings it comprises, it may be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclyl group, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridging heterocyclyl groups are: [ka] This includes, among others.

[0085] The heterocyclyl ring may be condensed onto an aryl group, a heteroaryl group, or a cycloalkyl group, where the ring linked to the basic skeleton is a heterocyclyl group, and non-limiting examples include: [ka] This includes, but is not limited to, the following:

[0086] The heterocyclyl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0087] The term "aryl group" refers to a 6-14 member all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6-12 membered, such as a phenyl group and a naphthyl group. More preferably a phenyl group. The aryl group ring may be fused onto a heteroaryl group, a heterocyclyl group, or a cycloalkyl group, and includes a 5-10 membered benzoheteroaryl group, a 3-8 membered benzocycloalkyl group, and a 3-8 membered benzoheteroalkyl group, preferably a 5-6 membered benzoheteroaryl group, a 3-6 membered benzocycloalkyl group, and a 3-6 membered benzoheteroalkyl group, where the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, an oxygen atom, and a sulfur atom, or further includes a three-membered nitrogen-containing fused ring containing a benzene ring.

[0088] Here, the ring connected to the basic framework is an aryl ring, and a non-restrictive example of this is: [ka] This includes, among others.

[0089] The aryl group may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0090] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5- or 6-membered, and includes, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyridinyl, etc. Preferably, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl, more preferably pyrazolyl, pyrrolyl, and oxazolyl groups. The ring of the heteroaryl group may be condensed on an aryl, heterocyclyl, or cycloalkyl ring, where the ring linked to the basic skeleton is the heteroaryl ring, and non-limiting examples are: [ka] This includes, among others.

[0091] The heteroaryl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0092] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where the definition of alkyl group is as described above. Non-limiting examples of alkoxy groups include methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, and cyclohexyloxy group. The alkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0093] A "haloalkyl group" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.

[0094] A "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, where the alkoxy group is defined as described above.

[0095] "Hydroxyalkyl group" refers to an alkyl group substituted with a hydroxyl group, where the alkyl group is defined as described above.

[0096] "Alkenyl group" refers to a linear alkenyl group, also called an olefin group, and refers to a linear or branched unsaturated aliphatic hydrocarbon group that contains at least one carbon-carbon double bond, and the carbon-carbon double bond may be located at any position within the alkenyl group, and the alkenyl group is 2-20(C 2-20 ), 2~15(C 2-15 ), 2~12(C 2-12 ), 2~10(C 2-10 ), 2~8(C 2-8 ), 2~6(C2-6 ), 2~4(C 2-4 ) or 2-3 (C 2-3 It is a straight-chain or branched-chain unsaturated hydrocarbon group having ) carbon atoms. Non-limiting examples of alkenyl groups are: [ka] This includes the following: Here, the alkenyl group may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0097] An "alkynyl group" refers to (CH≡C-), which contains at least one carbon-carbon triple bond, and the carbon-carbon triple bond may be located at any position within the alkynyl group, and it contains at least one carbon-carbon double bond, and the carbon-carbon double bond may be located at any position within the alkynyl group, and the alkynyl group is 2-20(C 2-20 ), 2~15(C 2-15 ), 2~12(C 2-12 ), 2~10(C 2-10 ), 2~8(C 2-8 ), 2~6(C 2-6 ), 2~4(C 2-4 ) or 2-3 (C 2-3 It is a straight-chain or branched-chain unsaturated hydrocarbon group having ) carbon atoms. Non-limiting examples of alkynyl groups are: [ka] This includes the following: Here, the alkynyl group may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0098] The term "alkenylcarbonyl group" refers to -C(O)-(alkenyl group), where the definition of an alkenyl group is as described above. Non-limiting examples of alkenylcarbonyl groups include vinylcarbonyl groups, propenylcarbonyl groups, and butenylcarbonyl groups. Alkenylcarbonyl groups may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0099] [ka] This refers to a single bond or a double bond.

[0100] "Hydroxy group" refers to the -OH group.

[0101] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0102] The term "amino group" refers to -NH2.

[0103] The "cyano group" refers to -CN.

[0104] The term "nitro group" refers to -NO2.

[0105] The "carbonyl group" refers to -C(O)-.

[0106] The term "carboxyl group" refers to -C(O)OH.

[0107] "THF" refers to tetrahydrofuran.

[0108] ",''" refers to ethyl acetate.

[0109] "MeOH" refers to methanol.

[0110] "DMF" refers to N,N-dimethylformamide.

[0111] "DIPEA" refers to diisopropylethylamine.

[0112] "TFA" refers to trifluoroacetic acid.

[0113] "MeCN" refers to acetonitrile.

[0114] "DMA" refers to N,N-dimethylacetamide.

[0115] "Et2O" refers to ether.

[0116] "DCE" refers to 1,2-dichloroethane.

[0117] "DIPEA" refers to N,N-diisopropylethylamine.

[0118] "NBS" refers to N-bromosuccinimide.

[0119] "NIS" refers to N-iodosuccinimide.

[0120] Various phrases such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all express the same meaning, indicating that X can be one or more of A, B, or C.

[0121] Any formula or structure disclosed in the present invention is also intended to represent both the unlabeled and isotopically labeled forms of the compound. The isotopically labeled compound has the structure described in the general formula or specific compound disclosed in the present invention, except that one or more atoms are substituted by atoms having a selected atomic mass or mass number. Examples of isotopes of the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine.

[0122] "Optional" or "optionally" means that the event or environment described later may occur but is not required, and the description includes cases where the event or environment occurs or does not occur. For example, "optionally alkyl-substituted heterocyclyl group" means that the alkyl group may be present but is not required, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0123] "Substituting" means that one or more hydrogen atoms in a group, preferably up to five, more preferably one to three, are substituted independently of each other by a corresponding number of substituents. Needless to say, substituents exist only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) with little effort. For example, an amino or hydroxyl group with free hydrogen can become unstable if bonded to a carbon atom with an unsaturated (e.g., olefin) bond.

[0124] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, as well as other components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to a living organism, to facilitate the absorption of the active ingredient, and thereby to exert biological activity.

[0125] "Pharmacologically acceptable salt" refers to a salt of the compound of the present invention, which is safe and effective when used in the body of a mammal and possesses the desired biological activity. [Examples]

[0126] Examples The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR displacement (δ) is 10 -6 The values ​​were given in units of ppm. NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

[0127] A Finnigan LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX) was used for the MS measurements.

[0128] For HPLC measurements, we used an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6mm chromatography column).

[0129] Kinase mean inhibition rate and IC 50 A NovoStar plate reader (BMG GmbH, Germany) was used to measure the values.

[0130] Thin-layer chromatography (TLC) silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. Silica gel plates used for thin-layer chromatography were specified to be 0.15 mm to 0.2 mm in thickness, while plates of 0.4 mm to 0.5 mm were used for the separation and purification of products by thin-layer chromatography.

[0131] Column chromatography typically uses 200-300 mesh silica gel as the carrier.

[0132] The known starting materials of the present invention can be synthesized by methods known in the art, or purchased from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Dalui Chemicals, etc.

[0133] Unless otherwise specified in the examples, the reactions can all be carried out under an argon or nitrogen gas atmosphere.

[0134] An argon gas atmosphere or a nitrogen gas atmosphere is created by connecting a balloon containing approximately 1 liter of argon or nitrogen gas to the reaction flask.

[0135] A hydrogen gas atmosphere is created by connecting a hydrogen gas balloon with a volume of approximately 1 liter to the reaction flask.

[0136] For the pressurized hydrogenation reaction, a Parr 3916EKX type hydrogenator and either a QL-500 type hydrogen gas generator or an HC2-SS type hydrogenator were used.

[0137] The hydrogenation reaction was typically carried out under vacuum, with hydrogen gas being introduced, and repeated three times.

[0138] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0139] Unless otherwise specified in the examples, the solutions are aqueous solutions.

[0140] Unless otherwise specified in the examples, the reaction temperature is room temperature, between 20°C and 30°C.

[0141] Thin-layer chromatography (TLC) was used to monitor the reaction process in the examples. The developing solvent systems used in the reactions were A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0142] The eluent systems used for column chromatography and the developing solvent systems for thin-layer chromatography in the purification of the compounds include A: dichloromethane and methanol, B: n-hexane and ethyl acetate, and C: dichloromethane and acetone. The volume ratio of the solvents is adjusted according to the polarity of the compound, and can also be adjusted by adding small amounts of alkaline or acidic reagents such as triethylamine and acetic acid.

[0143] intermediate Intermediate Im-1 [ka]

[0144] Step 1: 5-Bromo-4-methylpyridine-3-carboxylate ethyl 5-bromo-4-methylpyridine-3-carboxylic acid (20 g, 92.58 mmol) was dissolved in anhydrous N,N-dimethylcarboxamide (200 mL), and anhydrous ethanol (42.65 g, 925.79 mmol, 54.06 mL), HATU (52.39 g, 138.87 mmol), and TEA (28.10 g, 277.74 mmol, 38.74 mL) were added to the solution. The reaction system was stirred at room temperature (20°C) for 16 hours. After the reaction was complete, water (50 mL) was added to quench the reaction, and the solution was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product 5-bromo-4-methylpyridine-3-carboxylic acid ethyl (21 g, crude). MS m / z(ESI):244.0, 246.0[M+1].

[0145] Step 2: 4-Bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylate methyl Ethyl 5-bromo-4-methylpyridine-3-carboxylate (7g, 28.68 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL), and lithium diisopropylamide (2M, 17.21 mL) was added dropwise at -78°C. The mixture was stirred at -78°C for 1 hour, and then methyl acrylate (6.17 g, 71.70 mmol, 6.46 mL) was slowly added. The reaction system was allowed to rise naturally to room temperature and stirred for 5 hours. After the reaction was complete, water (20 mL) was slowly added dropwise to quench the reaction, extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was subjected to column purification (PE / siRNA=3:1, uv=254nm) to obtain the final product 4-bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylate methyl (4g, 14.0 mmol, yield 48.8%). MS m / z(ESI):284.0, 286.0[M+1].

[0146] Step 3: 4-Bromo-6,7-dihydro-5H-isoquinoline-8-one 7 g, 24.64 mmol of 4-bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylate methyl methyl carboxylate was dissolved in 30 mL of 6 M hydrochloric acid. The reaction system was stirred in an oil bath at 100°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, the pH was adjusted to 7-8 with 6 M sodium hydroxide solution, washed with ethyl acetate (50 mL x 3) and saturated saline solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product 4-bromo-6,7-dihydro-5H-isoquinoline-8-one (4.8 g, 21.23 mmol, yield 86.17%). The crude product was used directly in the next step of the reaction. MS m / z(ESI):226.0, 228.0[M+1].

[0147] Step 4: 4-Bromo-5,6,7,8-tetrahydroisoquinoline-8-amine 4-Bromo-6,7-dihydro-5H-isoquinoline-8-one (7g, 30.96 mmol) was dissolved in ammonia-methanol solution (2M, 100 mL), and tetraisopropyl titanate (17.60 g, 61.93 mmol, 18.33 mL) was added. The reaction system was stirred at 20°C for 16 hours, and then sodium borohydride (1.76 g, 46.45 mmol) was gradually added in an ice bath. The reaction system was stirred at room temperature for 2 hours. After the reaction was complete, water (20 mL) was added to quench the reaction, filtered through diatomaceous earth, extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was subjected to column purification (Dichloromethane:Methanol = 10:1, uv = 254 nm) to obtain 4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine (4.5 g, 19.82 mmol, yield 63.99%). MS m / z(ESI):227.0, 229.0[M+1].

[0148] Step 5(R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine The following chiral separation was performed on 4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine (4.5 g, 19.82 mmol) to obtain the P1 and Im-1 products. [ka]

[0149] [Table 1] MS m / z (ESI): 227.0, 229.0 [M+1].

[0150] Example 1 [ka]

[0151] Step 1 6-Bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one In a 25 mL reaction flask, 6-bromo-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (500 mg, 2.19 mmol) and iodomethane (622.45 mg, 4.39 mmol) were dissolved in tetrahydrofuran (5 mL), and sodium hydride (78.92 mg, 3.29 mmol, 60% purity) was added at 0°C. The reaction mixture was then stirred at 25°C for 10 hours. The reaction was stopped, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 6-bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (410 mg, yellow solid) in yield of 77.2%. MS m / z(ESI):242.0, 244.0[M+1].

[0152] Step 2 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one 6-Bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (410 mg, 1.69 mmol), bis(pinacolato)diborone (860.2 mg, 3.39 mmol), palladium acetate (498.67 mg, 5.08 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (68.65 mg, 84.69 μmol) were dissolved in dioxane (10 mL), the mixture was purged three times with nitrogen gas, and the reaction mixture was stirred at 90°C for 10 hours. The reaction was stopped, cooled to room temperature, the reaction solution was filtered, concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (300 mg, yellow solid) in yield of 61.2%. MS m / z(ESI): 290.1[M+1].

[0153] Step 3 N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide In a 25 mL reaction flask, 4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine (500 mg, 2.20 mmol) and triethylamine (445.58 mg, 4.40 mmol) were dissolved in dichloromethane (5 mL), and propionyl chloride (224.07 mg, 2.42 mmol) was added dropwise. The reaction mixture was stirred at 25 °C for 3 hours. The reaction was stopped, water (5 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (5 mL x 2). The organic phases were combined, washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide (500 mg) in yield of 80.2%. MS m / z(ESI):283.0, 285.0[M+1].

[0154] Step 4 N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide (100 mg, 353.15 μmol), 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (102.11 mg, 353.15 μmol), Na2CO3 (112.29 mg, 1.06 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (14.31 mg, 17.66 μmol) were dissolved in dioxane (5 mL) and water (1 mL), the mixture was purged three times with nitrogen gas, and the reaction mixture was stirred at 90°C for 10 hours. The reaction was stopped, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide (75 mg) in yield of 58.2%. MS m / z(ESI): 366.2[M+1]. 1 HNMR(400MHz,DMSO)δ8.26(s,1H),8.22(d,1H),8.14(s,1H),7.30(dd,1H),7.23(d,1H),7.12(d,1H),5 .23(s,2H),5.02(q,1H),3.25(s,3H),2.53(q,2H),2.11-2.05(m,2H),1.84-1.61(m,4H),0.98(t,3H).

[0155] Example 1 was divided to obtain 1-A and 1-B.

[0156] [Table 2]

[0157] Example 2 [ka]

[0158] Step 1 4-Bromo-7,7-dimethoxy-6,7-dihydro-5H-cyclopentadiene[c]pyridine-6-ol Potassium hydroxide (5.29 g, 94.32 mmol) was dissolved in methanol (50 mL), and 4-bromo-5,6-dihydro-7H-cyclopentadiene[c]pyridine-7-one was added under cooling in an ice bath and protection with nitrogen gas. The mixture was stirred and reacted at 0°C for 5 minutes. Then, iodobenzene diacetate (6.08 g, 18.86 mmol) was added. The mixture was stirred and reacted at 18°C ​​for 4 hours. The reaction solution was evaporated to dryness at low temperature, and the reaction was quenched by adding saturated brine (100 mL) to the crude product. The mixture was extracted with ethyl acetate (50 mL x 3), the mixture was separated, the organic phases were combined, the organic phase was washed with saturated brine (100 mL x 2), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (dichloromethane:methanol = 100:0 to 95:5 elution) to obtain the target product 4-bromo-7,7-dimethoxy-6,7-dihydro-5H-cyclopentadiene[c]pyridine-6-ol (1.5 g, brown oily substance) with a yield of 58.02%. MS m / z(ESI):274.0, 276.0[M+1].

[0159] Step 2 4-Bromo-7,7-dimethoxy-7H-cyclopentadiene[c]pyridine 4-Bromo-7,7-dimethoxy-6,7-dihydro-5H-cyclopentadiene[c]pyridine-6-ol (1.5 g, 5.47 mmol) and triethylamine (2.77 g, 27.36 mmol, 3.82 mL) were dissolved in dichloromethane (60 mL), and trifluoroacetic anhydride (2.30 g, 10.94 mmol, 1.52 mL) was added under cooling in an ice bath and protection with nitrogen gas. The mixture was stirred at 20°C and reacted for 12 hours. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (150 mL) to the mixture, the organic phase was separated, washed sequentially with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 80:20 elution) to obtain the target product 4-bromo-7,7-dimethoxy-7H-cyclopentadiene[c]pyridine (1.3 g) with a yield of 92.76%. MS m / z(ESI):256.0, 258.0[M+1].

[0160] Step 3 4-Bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine Trimethylsulfoxonium iodide (3.35 g, 15.23 mmol) was dissolved in dimethyl sulfoxide (20 mL), and sodium hydrogen (609.09 mg, 15.23 mmol, 60% w / w) was added under nitrogen gas protection. The mixture was stirred and reacted at 18°C ​​for 3 hours. Under nitrogen gas protection, 4-bromo-7,7-dimethoxy-7H-cyclopentadiene[c]pyridine (1.30 g, 5.08 mmol) was added. The mixture was stirred and reacted at 18°C ​​for 12 hours. The reaction mixture was quenched with saturated saline (130 mL), extracted with ethyl acetate (50 mL x 2), separated the organic phase, washed with saturated saline (50 mL x 5), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product 4-bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine (1.1 g) was obtained, and the crude product was used directly in the next step. MS m / z(ESI):270.0, 272.0[M+1].

[0161] Step 4 4-Bromo-5,5a-dihydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6(4bH)-one 4-Bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine (1.1 g, 4.07 mmol) was dissolved in acetone (30 mL), and p-toluenesulfonic acid monohydrate (774.61 mg, 4.07 mmol) was added under nitrogen gas protection. The mixture was stirred at 18°C ​​and reacted for 2 hours. The mixture was evaporated to dryness at a low temperature, the reaction was quenched with saturated brine (50 mL), extracted with dichloromethane (50 mL x 2), the organic phases were combined and washed sequentially with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 75:25 elution) to obtain the target product 4-bromo-5,5a-dihydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6(4bH)-one (0.55 g, light brown solid) with a yield of 60.28%. MS m / z(ESI):224.0, 226.0[M+1].

[0162] Step 5 4-Bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6-amine 4-Bromo-5,5a-dihydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6(4bH)-one (0.55 g, 2.45 mmol) was dissolved in ammonia-methanol solution (2 M, 20 mL), and titanium tetraisopropoxide (2.16 g, 4.91 mmol) was added under nitrogen gas protection. The mixture was stirred at 60°C and reacted for 3 hours. The reaction solution was cooled to room temperature, and then sodium borohydride (185.74 mg, 4.91 mmol) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was evaporated to dryness, the crude product was dissolved in dichloromethane (60 mL), washed with saturated brine (30 mL x 2), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6-amine (0.44 g), which was used directly in the next step. MS m / z(ESI):225.0, 227.0[M+1].

[0163] Step 6 N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6-yl)propanamide N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6-amine)propanamide was synthesized using 4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6-yl)propanamide as starting materials, referring to step 3 of Example 1. MS m / z(ESI):281.0, 283.0[M+1].

[0164] Step 7 N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinoline-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6-yl)propanamide N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6-yl)propanamide and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-2(1H)-one were used as raw materials, and N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinoline-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6-yl)propanamide was synthesized by referring to step 4 of Example 1. MS m / z(ESI):362.2[M+1].

[0165] The sample was subjected to chiral separation as follows to obtain P1 and P2 products.

[0166] [Table 3]

[0167] Product P1 was chiral-resolved as follows to obtain P1A and P1B.

[0168] [Table 4]

[0169] Product P2 was chiral-resolved as follows to obtain P2A and P2B.

[0170] [Table 5]

[0171] The LCMS and HNMR results for sample P2B are as follows: 1H NMR(400MHz,CDCl3)δ8.48(s,1H),8.40(s,1H),7.50(dd,J=8.4,2.0Hz,1H),7.44-7.34(m,1H),7.11(d,J=8.4Hz,1H),6.04-5.88(m,1 H),5.77-5.58(m,1H),3.41(s,3H),3.00(t,J=7.4Hz,2H),2.79-2.64(m,2H),2.60-2.48(m,1H),2.40-2.21(m,3H),1.37-1.15(m,5H). MS m / z(ESI):362.2[M+1].

[0172] Example 3 [ka]

[0173] Referring to the synthesis route of Example 1, propionyl chloride was replaced with 1-methyl-1H-pyrazole-4-carbonyl chloride to obtain the title product 1-methyl-N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)-1H-pyrazole-4-carboxamide 3. MS m / z (ESI): 418.2 [M+1].

[0174] Example 4 [ka]

[0175] Step 1 tert-butyl 3-((5-bromopyridine-3-yl)oxo)azetidine-1-carboxylate To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate 4b (2 g, 11.56 mmol) in tetrahydrofuran (25 mL), sodium hydroxide (693 mg, 17.34 mmol, 60%) was added and stirred at room temperature for 30 minutes. Then, a solution of 3-bromo-5-fluoropyridine 4a (1.6 g, 9.25 mmol) in tetrahydrofuran (10 mL) was added dropwise and stirred at room temperature overnight. Water was added, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotated-dried, and separated by column chromatography to obtain the title product, tert-butyl 3-((5-bromopyridine-3-yl)oxo)azetidine-1-carboxylate 4c (1 g, pale yellow solid), in a yield of 33%. MS m / z (ESI): 329.0 [M+1].

[0176] Step 2 3-(azetidine-3-oxy)-5-bromopyridine To a solution of tert-butyl 3-((5-bromopyridine-3-yl)oxo)azetidine-1-carboxylate 4c (1 g, 3.04 mmol) in dichloromethane (15 mL), trifluoroacetic acid (5 mL) was added dropwise, the mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and dried to obtain the title product 3-(azetidine-3-oxy)-5-bromopyridine 4d (1.1 g, crude). MS m / z(ESI): 229.0[M+1].

[0177] Step 3 3-Bromo-5-((1-(ethylsulfonyl)azetidine-3-yl)oxopyridine Referring to step 3 of the synthesis route in Example 1, propionyl chloride was replaced with ethanesulfonyl chloride to obtain the title product 3-bromo-5-((1-(ethylsulfonyl)azetidine-3-yl)oxo)pyridine 4e. MS m / z(ESI): 321.0[M+1].

[0178] Step 4 6-(5-((1-(ethylsulfonyl)azetidine-3-yl)oxo)pyridine-3-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one Referring to step 4 of the synthesis route in Example 1, N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide was replaced with 3-bromo-5-((1-(ethylsulfonyl)azetidine-3-yl)oxo)pyridine to obtain the title product. MS m / z(ESI): 404.1[M+1].

[0179] Example 5 [ka]

[0180] Step 1 tert-butyl 6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3,3]heptan-2-carboxylate 3,5-Dibromopyridine 5a (3 g, 12.66 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate 5b (2.51 g, 12.66 mmol) were dissolved in 1,4-dioxane (50 mL), and sodium tert-butoxide (2.43 g, 25.33 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (733 mg, 1.27 mmol), and tri(dibenzylideneacetone)palladium (580 mg, 633 μmol) were added to the mixture. The reaction system was purged three times with nitrogen gas, and then stirred in an oil bath at 100 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by column chromatography to obtain the title product tert-butyl 6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-carboxylate 5c (2g, beige solid) in yield of 44.6%. MS m / z (ESI): 354.1 [M+1].

[0181] Step 2 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane Referring to step 2 of the synthetic route of Example 58, the title product 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane 5d was obtained. MS m / z(ESI): 254.1[M+1].

[0182] Step 3 (6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone Referring to step 3 of the synthesis route in Example 1, the title product 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane 5f was obtained. MS m / z (ESI): 362.1 [M+1].

[0183] Step 4 1-Methyl-6-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3,3]heptan-2-yl)pyridine-3-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one The title product was obtained by referring to step 4 of the synthesis route in Example 1. MS m / z(ESI): 445.2[M+1].

[0184] Example 6 [ka]

[0185] Step 1 7-Bromo-2H-benzo[b][1,4]oxazine-3(4H)-one (5g, 21.93 mmol) was dissolved in N,N-dimethylcarboxamide (50 mL), and potassium tert-butoxide (4.92 g, 43.85 mmol) was slowly added in an ice bath. After stirring for 0.5 hours, iodomethane (4.67 g, 32.89 mmol, 2.05 mL) was added dropwise. The reaction system was stirred at room temperature (20°C) for 5.5 hours. After the reaction was complete, the reaction was quenched by slowly adding H2O (20 mL) in an ice bath, extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by passing it through a column (PE / SiO₂ = 3:1, uv = 254 nm) to obtain a pale yellow solid, 7-bromo-4-methyl-2H-benzo[b][1,4]oxazine-3(4H)-one (4.5 g, yield 84.7%). MS m / z (ESI): 241.9 [M+1].

[0186] Step 2 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazine-3(4H)-one (4.5g, 18.59 mmol) was dissolved in dioxane (50 mL), and bis(pinacolato)diborone (5.66 g, 22.31 mmol), potassium acetate (1.95 g, 19.91 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.35 g, 1.86 mmol) were gradually added. After purging the reaction system several times with nitrogen gas, the mixture was stirred in an oil bath at 100°C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, slowly added H2O (20 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by passing it through a column (PE / siRNA=5:1, uv=254nm) to obtain a white solid 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazine-3(4H)-one (5g, 17.29 mmol, yield 93.02%). MS m / z(ESI): 290.1[M+1].

[0187] Step 3 4-Bromo-5,6,7,8-tetrahydroisoquinoline-8-amine (500 mg, 2.20 mmol) and 1-methyl-1H-pyrazole-4-carboxylic acid (333 mg, 2.64 mmol) were dissolved in N,N-dimethylcarboxamide (20 mL), and triethylamine (668 mg, 6.60 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.26 g, 3.30 mmol) were added to the mixture. The reaction mixture was stirred at 25°C for 4 hours. The reaction was stopped, water (10 mL) was added to quench the reaction, the mixture was extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by passing it through a column (PE / siRNA = 1:1, UV = 254 nm) to obtain the target product N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)-1-methyl-1H-pyrazole-4-carboxamide (400 mg, yield: 52.1%). MS m / z(ESI): 335.0[M+1].

[0188] Step 4 N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 285.6 μmol) and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazine-3(4H)-one (99.6 mg, 342.7 μmol) were dissolved in a mixed solvent of H2O (2 mL) and EtOH (10 mL). Sodium carbonate (91 mg, 857.0 μmol) and tetrakis(triphenylphosphine)palladium (33.0 mg, 28.6 μmol) were added sequentially. After purging the reaction system multiple times with nitrogen gas, the mixture was stirred in an oil bath at 100°C for 16 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (10 mL x 2), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was obtained. The crude product was purified by passing it through a column (DCM / MeOH = 10:1, UV = 254 nm) to obtain 1-methyl-N-(4-(4-methyl-3-carbonyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)-1H-pyrazole-4-carboxamide (50 mg, yield 41.7%). MS m / z (ESI): 418.1 [M+1].

[0189] Example 7 [ka]

[0190] Step 1 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazine-3(4H)-one 7-Bromo-2H-benzo[b][1,4]oxazine-3(4H)-one (5g, 21.93 mmol) was dissolved in N,N-dimethylcarboxamide (50 mL), and potassium tert-butoxide (4.92 g, 43.85 mmol) was slowly added in an ice bath. After stirring for 0.5 hours, iodomethane (4.67 g, 32.89 mmol, 2.05 mL) was added dropwise. The reaction system was stirred at room temperature (20°C) for 5.5 hours. After the reaction was complete, the reaction was quenched by slowly adding H2O (20 mL) in an ice bath, extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by passing it through a column (PE / SiO₂ = 3:1, uv = 254 nm) to obtain a pale yellow solid, 7-bromo-4-methyl-2H-benzo[b][1,4]oxazine-3(4H)-one (4.5 g, yield 84.7%). MS m / z (ESI): 241.9 [M+1].

[0191] Step 2 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazine-3(4H)-one 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazine-3(4H)-one (4.5g, 18.59 mmol) was dissolved in dioxane (50 mL), and bis(pinacolato)diborone (5.66 g, 22.31 mmol), potassium acetate (1.95 g, 19.91 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.35 g, 1.86 mmol) were gradually added. After purging the reaction system several times with nitrogen gas, the mixture was stirred in an oil bath at 100°C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, slowly added H2O (20 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by passing it through a column (PE / siRNA=5:1, uv=254nm) to obtain a white solid 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazine-3(4H)-one (5g, 17.29 mmol, yield 93.02%). MS m / z(ESI): 290.1[M+1].

[0192] Step 3 tert-butyl 6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3,3]heptan-2-carboxylate 3,5-Dibromopyridine (3 g, 12.66 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2.51 g, 12.66 mmol) were dissolved in dioxane (40 mL), and sodium tert-butoxide (2.43 g, 25.33 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (732.76 mg, 1.27 mmol), and tris(dibenzylideneacetone)dipalladium (579.83 mg, 633.20 μmol) were added to the mixture. The reaction system was purged multiple times with nitrogen gas, and then stirred in an oil bath at 100 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by passing it through a column (PE / Ã=5:1, uv=254 nm) to obtain a beige solid tert-butyl 6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-carboxylate (2 g, 5.65 mmol, yield 44.58%). MS m / z(ESI):354.0[M+1].

[0193] Step 4 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane 500 mg, 1.41 mmol of tert-butyl 6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate was dissolved in 10 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction system was stirred at room temperature for 4 hours. After the reaction of the starting materials was complete, the excess solvent was concentrated directly to obtain 360 mg, crude 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane. The crude product was directly dissolved in the reaction of the next step. MS m / z(ESI):254.0[M+1].

[0194] Step 5 (6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane (360 mg, crude) was dissolved in tetrahydrofuran (10 mL), and triethylamine (430 mg, 4.23 mmol) and 1-methyl-1H-pyrazole-4-carboxylic acid (270 mg, 2.12 mmol) were added to the solution. The reaction system was stirred at room temperature for 4 hours. After the reaction was complete, water (5 mL) was added to quench the reaction, and the solution was extracted with ethyl acetate (10 mL x 2). The solution was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by passing it through a column (PE / Â=3:1, uv=254nm) to obtain the target product (6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone (350 mg, yield: 68.7%). MS m / z (ESI): 362.1 [M+1].

[0195] Step 6 4-methyl-7-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3,3]heptan-2-yl)pyridine-3-yl)-2H-benzo[b][1,4]oxazine-3(4H)-one (6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3,3]heptan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone (100 mg, 276.2 μmol) and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazine-3(4H)-one (96.5 mg, 331.4 μmol) were dissolved in a mixed solvent of H2O (2 mL) and EtOH (10 mL). Sodium carbonate (88.0 mg, 828.6 μmol) and tetrakis(triphenylphosphine)palladium (32.0 mg, 27.6 μmol) were added sequentially. After purging the reaction system multiple times with nitrogen gas, the mixture was stirred in an oil bath at 100°C for 16 hours. After the reaction was complete, the solution was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (10 mL x 2), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was obtained. The crude product was purified by passing it through a column (DCM / MeOH = 10:1, UV = 254 nm) to obtain the target product (45 mg, yield 36.7%). MS m / z (ESI): 445.1 [M+1].

[0196] Example 8 [ka]

[0197] Starting with 6-bromo-3,4-dihydro-1,8-diazanaphthalene-2(1H)-one and 4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine, and referring to Example 6, the target product 1-methyl-N-(4-(8-methyl-7-carbonyl-5,6,7,8-tetrahydro-1,8-diazanaphthalene-3-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)-1H-pyrazole-4-carboxamide. MS m / z (ESI): 417.2 [M+1].

[0198] Example 9 [ka]

[0199] Starting with 6-bromo-3,4-dihydro-1,8-diazanaphthalene-2(1H)-one, 3,5-dibromopyridine, and tert-butyl 2,6-diazaspiro[3.3]heptan-2-carboxylate, and referring to Example 7, the target product 1-methyl-6-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridine-3-yl)-3,4-dihydro-1,8-diazanaphthalene-2(1H)-one. MS m / z(ESI): 444.2[M+1].

[0200] Example 10 [ka]

[0201] Using 7-(8-amino-5,6,7,8-tetrahydroisoquinoline-4-yl)-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one as a starting material, 1-methyl-N-(4-(1-methyl-2-carbonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)-1H-pyrazole-4-carboxamide was obtained in the same manner as in step 3 of Example 1. MS m / z (ESI): 430.2 [M+1].

[0202] Example 11 [ka]

[0203] Using 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one as a starting material, 1-methyl-7-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridine-3-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one was obtained in the same manner as in Example 5. MS m / z (ESI): 457.2 [M+1].

[0204] Example 12 [ka]

[0205] Referring to the synthetic route of Example 1, 6-bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was replaced with 3-(4-bromophenyl)oxetane to obtain the title product N-(4-(4-(oxetan-3-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide. MS m / z (ESI): 337.2 [M+1].

[0206] Example 13 [ka]

[0207] Step 1 5-(4-bromophenyl)-2-methyloxazole At room temperature, acetamide (0.50 g, 8.47 mmol) was heated to 120°C, and 2-bromo-1-(4-bromophenyl)ethanone (1.57 g, 5.65 mmol) was added. The mixture was reacted at 120°C for 3 hours until LC-MS showed the formation of the target product. The mixture was then cooled to room temperature, the reaction solution was dissolved in ethyl acetate (30 mL), and washed sequentially with saturated sodium bicarbonate solution (10 mL x 2) and saturated brine (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary dried. The residue was separated by flash column chromatography (eluted at PE:EA = 98:2 to 94:6) to obtain the target product 5-(4-bromophenyl)-2-methyloxazole (560 mg, pale yellow solid) with a yield of 41.6%. MS m / z (ESI): 238.0, 240.0 [M+1].

[0208] Step 2 2-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole At room temperature, bis(pinacolato)diborone (147.19 mg, 579.64 μmol), 5-(4-bromophenyl)-2-methyloxazole (92 mg, 386.42 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (31.56 mg, 38.64 μmol), and potassium acetate (75.74 mg, 772.85 μmol) were dissolved in 1'4-dioxane (5 mL), the mixture was purged with nitrogen gas, heated to 100 °C, reacted for 14 hours, and then cooled to room temperature. When LC-MS indicated the completion of the reaction, the mixture was filtered, the filtration residue was washed with ethyl acetate (15 mL x 2), the organic phase was combined, the organic phase was washed with saturated brine (10 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and rotary dried. The residue was purified by preparative thin-layer chromatography to obtain the target product, 2-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole (80 mg, pale yellow solid), with a yield of 72.6%. MS m / z(ESI):286.1[M+1].

[0209] Step 3 N-(4-(4-(2-methyloxazol-4-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide At room temperature, N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide (30 mg, 105.95 μmol), 2-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole (36.25 mg, 127.13 μmol), sodium carbonate (33.69 mg, 317.84 μmol), and tetrakistriphenylphosphine palladium (12.24 mg, 10.59 μmol) are dissolved in water (1 mL). The mixture was dissolved in ethanol (5 mL), purged with nitrogen gas, heated to 100 °C, reacted for 14 hours, cooled to room temperature, and when LC-MS indicated the end of the reaction, it was filtered, rotated dry, the residue was dissolved in ethyl acetate (15 mL), washed with saturated brine (15 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, rotated dry, the residue was separated by reverse-phase preparative chromatography (neutral), freeze-dried to obtain the target product (11 mg, white solid), with a yield of 28.7%. MS m / z(ESI):362.2[M+1]. 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.34(s,1H),8.30(d,1H),8.25(s,1H),7.85(d,2H),7.42(d,2H), 5.14-5.08(m,1H),2.63-2.60(m,2H),2.49(s,3H),2.21-2.20(m,2H),1.92-1.63(m,4H),1.06(t,3H).

[0210] Example 13 was divided to obtain 13-A and 13-B.

[0211] [Table 6]

[0212] Example 14 [ka]

[0213] Referring to the synthesis conditions of Example 1, N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide and 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)quinoline were used as raw materials to synthesize the title product N-(4-(2-methoxyquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide. MS m / z(ESI):362.2[M+1].

[0214] Example 14 was divided to obtain 14-A and 14-B.

[0215] [Table 7]

[0216] 14-A: 1 H NMR(400MHz,CDCl3)δ8.53(s,1H),8.37(s,1H),7.98(d,1H),7.90(d,1H),7.60(d,1H),7.52(dd,1H),6.95(d,1H),5. 84(d,1H),5.37(q,1H),4.10(s,3H),2.67(tdd,2H),2.30(q,2H),2.16-2.04(m,1H),1.92-1.73(m,2H),1.23(t,3H).

[0217] Example 15 [ka]

[0218] Referring to the synthesis conditions of Example 1, N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide and 2-duteromethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)quinoline were used as raw materials to synthesize the title product N-(4-(2-duteromethoxyquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide. MS m / z(ESI): 365.2[M+1].

[0219] Example 16 [ka]

[0220] Referring to the synthesis conditions of Example 1, N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide and 2-cyclopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)quinoline were used as raw materials to synthesize the title product N-(4-(2-cyclopropoxyquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide. MS m / z (ESI): 388.2 [M+1].

[0221] Example 17 [ka]

[0222] Referring to the synthesis conditions of Example 1, N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide and 2-difluoromethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)quinoline were used as raw materials to synthesize the title product N-(4-(2-difluoromethoxyquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide. MS m / z(ESI): 398.2[M+1].

[0223] Example 18 [ka]

[0224] Referring to the synthesis conditions of Example 1, N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide and 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)-1,8-naphthiridine were used as starting materials to synthesize the title product N-(4-(7-methoxy-1,8-naphthiridine-3-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide. MS m / z(ESI):363.2[M+1].

[0225] Example 19 [ka]

[0226] Referring to the synthesis conditions of Example 1, N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide and 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)-1,5-naphthopyridine were used as starting materials to synthesize the title product N-(4-(6-methoxy-1,5-naphthyridine-2-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide. MS m / z(ESI):363.2[M+1].

[0227] Example 20 [ka]

[0228] Referring to the synthesis conditions of Example 1, N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide and 7-fluoro-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)quinoline were used as raw materials to synthesize the title product N-(4-(7-fluoro-2-methoxyquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide. MS m / z (ESI): 380.2 [M+1].

[0229] Example 21 [ka]

[0230] Referring to the synthesis conditions of Example 3, the product was synthesized to obtain the title product N-(4-(2-methoxyquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)-1-methyl-1H-pyrazole-4-carboxamide. MS m / z(ESI): 414.2[M+1].

[0231] Example 22 [ka]

[0232] Referencing the synthesis conditions of Example 4, the product was synthesized to obtain the title product 6-(5-((1-(ethylsulfonyl)azetidine-3-yl)oxy)pyridine-3-yl)-2-methoxyquinoline. MS m / z (ESI): 400.1 [M+1]. 1 H NMR(400MHz,DMSO)δ8.62(d,1H),8.29-8.15(m,3H),8.01(dd,1H),7.81(d,1H),7.60(t,1H),7 .02(d,1H),5.23(td,1H),4.33(dd,2H),3.94(s,3H),3.92(dd,2H),3.14(q,2H),1.18(t,3H).

[0233] Example 23 [ka]

[0234] Referencing the synthesis conditions of Example 5, the product was synthesized to obtain the title product (6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone. MS m / z(ESI): 441.2[M+1]. 1 H NMR(400MHz,MeOD)δ8.28(s,1H),8.20(d,1H),8.06(d,2H),7.95-7.86(m,2H),7.82(d,2H), 7.23(t,1H),6.99(d,1H),4.68(s,2H),4.35(s,2H),4.22(s,4H),4.07(s,3H),3.93(s,3H).

[0235] Example 24 [ka]

[0236] Referring to the synthesis conditions of Example 14, the product was synthesized to obtain the title product N-(4-(2-methoxyquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)acetamide. MS m / z (ESI): 348.2 [M+1].

[0237] Example 24 was divided to obtain 24-A and 24-B.

[0238] [Table 8]

[0239] 81-A:1H NMR(400MHz,CDCl3)δ8.54(s,1H),8.36(s,1H),7.97(d,1H),7.90(d,1H),7.59(d,1H),7.51(dd,1H),6.95 (d,1H),5.93(d,1H),5.35(q,1H),4.10(s,3H),2.66(qt,2H),2.09(s,1H),2.08(s,3H),1.94-1.73(m,2H).

[0240] Example 25 [ka]

[0241] Step 1 In a 50 mL reaction flask, 4-bromo-6,7-dihydroisoquinoline-8(5H)-one (2 g, 8.85 mmol) was dissolved in tetrahydrofuran (20 mL), and LiHMDS (8.85 mL, 1 M) was added at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. Then, a tetrahydrofuran solution of 2-bromoethyl acetate (1.48 g, 8.85 mmol) was gradually added, and the reaction mixture was raised to room temperature and allowed to react for 10 hours. The reaction was stopped, water (10 mL) was added to quench the reaction, and after concentration, it was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product, 2-(4-bromo-8-carbonyl-5,6,7,8-tetrahydroisoquinoline-7-yl)ethyl acetate (1.1 g, yellow solid), with a yield of 39.8%. MS m / z (ESI): 312.0 [M+1].

[0242] Step 2 In a 50 mL reaction flask, 5-chloro-N-cyclopropyl-4-fluoro-2-nitroaniline (1 g, 3.2 mmol) was dissolved in methanol (10 mL), and an aqueous solution of NaOH (256.26 mg, 6.41 mmol) was added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was stopped, the pH was adjusted to 5 with HCl (1 M), the organic phase was extracted with ethyl acetate (10 mL x 2), the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with the eluent systems petroleum ether and ethyl acetate to obtain the title product 2-(4-bromo-8-carbonyl-5,6,7,8-tetrahydroisoquinoline-7-yl)acetic acid (800 mg, yellow solid) in a yield of 87.8%. MS m / z (ESI): 283.9 [M+1].

[0243] Step 3 In a 50 mL reaction flask, 2-(4-bromo-8-carbonyl-5,6,7,8-tetrahydroisoquinoline-7-yl)acetic acid (500 mg, 1.76 mmol), benzylamine (188.58 mg, 1.76 mmol), HATU (669.22 mg, 1.76 mmol), and triethylamine (356.18 mg, 3.52 mmol) were dissolved in DMF (5 mL), and the reaction mixture was stirred at 25°C for 10 hours. The reaction was stopped, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product N-benzyl-2-(4-bromo-8-carbonyl-5,6,7,8-tetrahydroisoquinoline-7-yl)propanamide (350 mg, yellow solid) in yield of 53.2%. MS m / z(ESI):373.0[M+1].

[0244] Step 4 In a 25 mL reaction flask, N-benzyl-2-(4-bromo-8-carbonyl-5,6,7,8-tetrahydroisoquinoline-7-yl)acetamide (350 mg, 937.71 μmol) was dissolved in acetonitrile (5 mL), and then triethylsilane (545.18 mg, 4.69 mmol) and triethylamine (284.67 mg, 2.81 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours. The reaction was stopped, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product, benzyl-6-bromo-1,3,3a,4,5,9b-hexahydro-2H-pyrrolo[3,2-h]isoquinoline-2-one (200 mg), with a yield of 59.7%. MS m / z (ESI): 357.0 [M+1].

[0245] Step 5 Using benzyl-6-bromo-1,3,3a,4,5,9b-hexahydro-2H-pyrrolo[3,2-h]isoquinoline-2-one as a starting material, the product benzyl-6-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinoline-6-yl)-1,3,3a,4,5,9b-hexahydro-2H-pyrrolo[3,2-h]isoquinoline-2-one was obtained by referring to step 4 of Example 1. MS m / z (ESI): 438.2 [M+1].

[0246] Step 6 6-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinoline-6-yl)-1,3,3a,4,5,9b-hexahydro-2H-pyrrolo[3,2-h]isoquinoline-2-one In a 25 mL reaction flask, benzyl-6-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinoline-6-yl)-1,3,3a,4,5,9b-hexahydro-2H-pyrrolo[3,2-h]isoquinoline-2-one (100 mg, 228.55 μmol) was dissolved in methanol (5 mL), and Pd / C (100 mg, 5% palladium carbon (55% water)) was added. The reaction mixture was stirred at 25 °C under a hydrogen gas atmosphere for 2 hours. After stopping the reaction, the mixture was filtered and concentrated. The resulting residue was then purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product, with a yield of 31.5%. MS m / z (ESI): 348.1 [M+1].

[0247] Example 26 [ka]

[0248] Step 1 4-Promo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (500 mg, 1.76 mmol), tetraisopropyl titanate (1.0 g, 3.52 mmol) in NH 3( The reaction was carried out by dissolving 7 mol in MeOH (10 mL) and stirring at room temperature for 24 hours. Sodium borohydride (200 mg, 5.28 mmol) was added to the reaction mixture, and the mixture was heated to 65°C and stirred for 18 hours. Heating was stopped, the reaction mixture was cooled to room temperature, saturated ammonium chloride solution was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product (8-amino-4-bromo-5,6,7,8-tetrahydroisoquinoline-7-yl)methanol (374 mg, yellow oily substance) with a yield of 82.7%. MS m / z(ESI):257.0[M+1].

[0249] Step 2 (8-amino-4-bromo-5,6,7,8-tetrahydroisoquinoline-7-yl)methanol (350 mg, 1.36 mmol), HATU (776 mg, 2.04 mmol), and 3-bromopropionic acid (248 mg, 1.63 mmol) were dissolved in DMF (10 mL), and the reaction mixture was heated to 50°C and stirred for 18 hours. The reaction mixture was cooled to room temperature, saturated ammonium chloride solution was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 3-bromo-N-(4-bromo-7-(hydroxymethyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide (411 mg, yellow oily substance) in a yield of 77.0%. MS m / z(ESI):391.0[M+1].

[0250] Step 3 3-Promo-N-(4-Promo-7-(hydroxymethyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide (400 mg, 1.02 mmol) and tert-butanol potassium (229 mg, 2.04 mmol) were dispersed in THF (10 mL), and the reaction mixture was heated to 50°C and stirred for 8 hours. The reaction mixture was cooled to room temperature, saturated ammonium chloride solution was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 9-bromo-1,3,4,6,6a,7,8,12b-octahydro-2H-[1,5]oxazino[3,4-h]isoquinoline-2-one (225 mg, yellow oily substance) in a yield of 70.9%. MS m / z(ESI):311.0[M+1].

[0251] Step 4 Referring to the synthesis conditions of Example 14, 9-bromo-1,3,4,6,6a,7,8,12b-octahydro-2H-[1,5]oxazino[3,4-h]isoquinoline-2-one (100 mg, 0.321 mmol) was used as a starting material to synthesize the title product, 9-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)-1,3,4,6,6a,7,8,12b-octahydro-2H-[1,5]oxazino[3,4-h]isoquinoline-2-one (102 mg, colorless oily substance), with a yield of 81.1%. MS m / z(ESI): 392.2[M+1].

[0252] Example 27 [ka]

[0253] Step 1 4-Promo-5,6,7,8-Tetrahydroisoquinoline-8-ol 4-Bromo-6,7-dihydroisoquinoline-8(5H)-one (0.1 g, 442.34 μmol) was dissolved in methanol (5 mL), and sodium borohydride (33.47 mg, 884.68 μmol) was added under nitrogen gas protection. The mixture was stirred and reacted at room temperature for 2 hours. The reaction solution was evaporated to dryness, the crude product was extracted with ethyl acetate (30 mL), washed with saturated brine (30 mL), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 4-Bromo-5,6,7,8-tetrahydroisoquinoline-8-ol (0.1 g). The crude product was used directly in the next step. MS m / z(ESI):228.0, 230.0[M+1].

[0254] Step 2 (4-Promo-5,6,7,8-Tetrahydroisoquinoline-8-yl)methanesulfonate 4-Promo-5,6,7,8-tetrahydroisoquinoline-8-ol (0.1 g, 438.43 μmol) and triethylamine (133.09 mg, 1.32 mmol) were dissolved in dichloromethane (4 mL), and methanesulfonic anhydride (114.56 mg, 657.65 μmol) was added under nitrogen gas protection. The mixture was stirred and reacted at room temperature for 12 hours. The reaction was quenched with saturated brine (30 mL), extracted with dichloromethane (30 mL), the organic phase was separated, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (4-promo-5,6,7,8-tetrahydroisoquinoline-8-yl)methanesulfonate (0.13 g). The crude product was used directly in the next step.

[0255] Step 3 (4-Promo-5,6,7,8-Tetrahydroisoquinoline-8-yl)imino-dimethylcarbonyl-sulfane (4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)methanesulfonate (0.13 g, 424.59 μmol) and dimethyl sulfimide (79.10 mg, 849.19 μmol) were dissolved in acetonitrile (6 mL), and cesium carbonate (415.02 mg, 1.27 mmol) was added under nitrogen gas protection. The mixture was stirred and reacted at 80°C for 12 hours. The reaction solution was evaporated to dryness and purified by high-performance silica gel chromatography (petroleum ether:ethyl acetate = 1:5) to obtain the target product (4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)imino-dimethyl-carbonyl-sulfan (16 mg, white solid) in a yield of 12.43%. MS m / z(ESI):303.0,305,0[M+1].

[0256] Step 4 6-(8-((dimethyl(carbonyl)-16-sulfanylidene)amino)-5,6,7,8-tetrahydroisoquinoline-4-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one (4-Promo-5,6,7,8-tetrahydroisoquinoline-8-yl)imino-dimethylcarbonyl sulfan (16 mg, 52.77 μmol), 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-2-one (30.31 mg, 105.53 μmol), and sodium carbonate (11.19 mg, 105.53 μmol) were dissolved in ethanol (10 mL) and water (2 mL). Tetrakistriphenylphosphine palladium (6.10 mg, 5.28 μmol) was added under nitrogen gas protection. The mixture was stirred and reacted at 90°C for 12 hours. The reaction solution was evaporated to dryness, and the crude product was separated by Prep-HPLC to obtain the target product. MS m / z(ESI):384.2[M+1].

[0257] Example 28 [ka]

[0258] Step 1 4-Promo-6,7,8,9-tetrahydro-5H-pyrido[3,4-c]azepine In a 50 mL reaction flask, 6,7,8,9-tetrahydro-5H-pyrido[3,4-c]azepine (1 g, 6.75 mmol) was dissolved in DMF (20 mL), and NBS (1.20 g, 6.75 mmol) was added at 25 °C. The reaction mixture was stirred at 80 °C for 3 hours. The reaction was stopped, water (10 mL) was added to quench the reaction, and after concentration, the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with the eluent systems petroleum ether and ethyl acetate to obtain the title product 4-bromo-6,7,8,9-tetrahydro-5H-pyrido[3,4-c]azepine (300 mg, yellow solid) in a yield of 19.5%. MS m / z(ESI): 227.0[M+1].

[0259] Step 2 (4-Promo-5,6,7,9-tetrahydro-8H-pyrido[3,4-c]azepine-8-yl)(1-methyl-1H-pyrazole-4-yl)methanone Using 4-bromo-6,7,8,9-tetrahydro-5H-pyrido[3,4-c]azepine as a starting material, the product (4-bromo-5,6,7,9-tetrahydro-8H-pyrido[3,4-c]azepine-8-yl)(1-methyl-1H-pyrazole-4-yl)methanone was obtained by referring to step 3 of Example 25. MS m / z(ESI): 335.0[M+1].

[0260] Step 3 Methyl-6-(8-(1-methyl-1H-pyrazole-4-carbonyl)-6,7,8,9-tetrahydro-5H-pyrido[3,4-c]azepine-4-yl)-3,4-dihydroquinoline-2(1H)-one (4-Promo-5,6,7,9-tetrahydro-8H-pyrido[3,4-c]azepine-8-yl)(1-methyl-1H-pyrazole-4-yl)methanone was used as a starting material, and the product was obtained by referring to step 4 of Example 1. MS m / z(ESI): 416.2[M+1].

[0261] Example 29 [ka]

[0262] Using 4-bromo-6,7,8,9-tetrahydro-5H-pyrido[3,4-c]azepine as a starting material, the product 1-methyl-6-(8-propan-6,7,8,9-tetrahydro-5H-pyrido[3,4-c]azepine-4-yl)-3,4-dihydroquinoline-2(1H)-one was obtained by referring to steps 2 and 3 of Example 28. MS m / z(ESI): 364.1[M+1].

[0263] Example 30 [ka]

[0264] Step 1 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene(form)aldehyde Referring to step 2 of the synthesis route in Example 1, the title product 30b was obtained. MS m / z (ESI): 248.1 [M+1].

[0265] Step 2 2-Chloro-N-(2-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide Referring to step 3 of the synthesis route in Example 1, the title product 30c was obtained. MS m / z(ESI): 324.1[M+1].

[0266] Step 3 2-Chloro-N-(2-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methylacetamide A mixture of 2-chloro-N-(2-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide 30c (2.1 g, 6.5 mmol), cesium carbonate (4.2 g, 13 mmol), iodomethane (1.8 g, 13 mmol), and acetonitrile (25 mL) was stirred at 80 degrees Celsius for 12 hours. Water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotated-dried, and separated by column chromatography to obtain the title product 30d (1.5 g, yellow solid) in 68% yield. MS m / z (ESI): 338.1 [M+1].

[0267] Step 4 4-Hydroxy-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-2(1H)-one 2-chloro-N-(2-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methylacetamide 30d (1.5 g, 4.45 mmol) was dissolved in tetrahydrofuran (20 mL), to which samarium iodide (89 mL, 8.9 mmol, 0.1 M) was added dropwise. The mixture was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotated-dried, and separated by column chromatography to obtain the title product 30e (700 mg, yellow solid) in a yield of 52%. MS m / z(ESI):304.2[M+1].

[0268] Step 5 4-Promo-8-carbonyl-5,6,7,8-tetrahydroisoquinoline 2-oxide 4-Bromo-6,7-dihydro-5H-isoquinoline-8-one 30f (2.5g, 11.06 mmol) was dissolved in dichloromethane (30 mL), and 3-chloro-benzoylperoxy acid (4.49 g, 22.12 mmol, 85%) was added. The mixture was stirred at room temperature for 1.5 hours, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotated-dried, and separated by column chromatography to obtain 30 g (1.1 g, pale yellow oily substance) with a yield of 41%. MS m / z (ESI): 242.0 [M+1].

[0269] Step 6 4-Bromo-3-(2-hydroxyethoxy)-6,7-dihydroisoquinoline-8(5H)-one 30 g (1.1 g, 4.54 mmol) of 4-bromo-8-carbonyl-5,6,7,8-tetrahydroisoquinoline 2-oxide was dissolved in carbon tetrachloride (15 mL), ethylene glycol (563 mg, 9.08 mmol) and N,N-diisopropylethylamine (1.2 g, 9.08 mmol) were added, and a solution of diethyl phosphite (1.25 g, 9.08 mmol) in acetonitrile (10 mL) was added dropwise. The mixture was stirred at 60 degrees Celsius for 12 hours, water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotated-dried, and separated by column chromatography to obtain 30 H (400 mg, pale yellow oily substance) with a yield of 31%. MS m / z (ESI): 286.0 [M+1].

[0270] Step 7 4-Hydroxy-6-(3-(2-hydroxyethoxy)-8-carbonyl-5,6,7,8-tetrahydroisoquinoline-4-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one Referring to step 4 of the synthesis route in Example 1, the title product 30i was obtained. MS m / z(ESI):383.2[M+1].

[0271] Step 8 2-((4-(4-hydroxy-1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinoline-6-yl)-8-carbonyl-5,6,7,8-tetrahydroisoquinoline-3-yl)oxo)ethylmethanesulfonate Referring to step 3 of the synthesis route in Example 1, propionyl chloride was replaced with methanesulfonyl chloride to obtain the title product 30j. MS m / z(ESI): 461.1[M+1].

[0272] Step 9 2-Methyl-4,4a,6,7,13,14-Hexahydro-1,15-(cyclohexane[1,2]diylidene)pyrido[3',4':9,10][1,4]dioxadecano[5,6-c]isoquinoline-3,11(2H,12H)-dione Sodium hydrogen (52 mg, 1.3 mmol, 60%) was added to a 30J (300 mg, 0.65 mmol) tetrahydrofuran solution, and the mixture was stirred at room temperature for 12 hours. Water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotated-dried, and separated by column chromatography to obtain 30K (100 mg, pale yellow oily substance) with a yield of 42%. MS m / z (ESI): 365.1 [M+1].

[0273] Step 10 11-Amino-2-methyl-4,4a,6,7,11,12,13,14-Octahydro-1,15-(cyclohexane[1,2]diylidene)pyrido[3',4':9,10][1,4]dioxadecano[5,6-c]isoquinoline-3(2H)-one 2-methyl-4,4a,6,7,13,14-hexahydro-1,15-(cyclohexane[1,2]diylidene)pyrido[3',4':9,10][1,4]dioxadecano[5,6-c]isoquinoline-3,11(2H,12H)-dione 30k (100 mg, 0.27 mmol) and tetraisopropyl titanate (153 mg, 0.54 mmol) are dissolved in methanol (5 mL). Ammonia alcohol (2 mL, 7.0 M) solution is added, and the mixture is stirred at 50 degrees Celsius for 5 hours. After cooling, water is added and dichloromethyl Extraction was performed with tung, the organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and rotary-dried to obtain an oily substance. Methanol (3 mL) was added to dissolve the oily substance, sodium borohydride (21 mg, 0.54 mmol) was added, the mixture was stirred for 1 hour, water was added, and the product was extracted with dichloromethane. The organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and rotary-dried. The product was then separated by column chromatography to obtain 30 L of the title product (20 mg, pale yellow oily substance) with a yield of 20%. MS m / z(ESI): 366.2[M+1].

[0274] Step 11 N-(2-methyl-3-carbonyl-2,3,4,4a,6,7,11,12,13,14-decahydro-1,15-(cyclohexane[1,2]diylidene)pyrido[3',4':9,10][1,4]dioxadecano[5,6-c]isoquinoline-11-yl)propanamide Referring to step 3 of the synthesis route in Example 1, the title product 30 was obtained. MS m / z(ESI): 422.2[M+1].

[0275] Example 31 [ka]

[0276] Step 1 5-Chloro-N-cyclopropyl-4-fluoro-2-nitroaniline In a 50 mL reaction flask, 1-chloro-2,5-difluoro-4-nitrobenzene (2 g, 10.33 mmol) was dissolved in ethanol (20 mL), and cyclopropylamine (590.04 mg, 10.33 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction was stopped, water (10 mL) was added to quench the reaction, and after concentration, the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product (1.5 g, yellow solid) with a yield of 62.9%. MS m / z(ESI):231.0[M+1].

[0277] Step 2 4-Chloro-N2-cyclopropyl-5-fluorobenzene-1,2-diamine In a 50 mL reaction flask, 5-chloro-N-cyclopropyl-4-fluoro-2-nitroaniline (1 g, 4.34 mmol) was dissolved in methanol (10 mL), and Zn (2.84 g, 43.36 mmol) and NH4Cl (1.16 g, 21.68 mmol) were added at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was stopped, filtered, and the organic phase was concentrated. After extraction with ethyl acetate (10 mL x 2), the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product (500 mg, yellow solid) with a yield of 57.5%. MS m / z(ESI):201.0[M+1].

[0278] Step 3 5-Chloro-3-cyclopropyl-6-fluoro-1H-benzoimidazole-2-one 4-chloro-N2-cyclopropyl-5-fluorobenzene-1,2-diamine (500 mg, 2.49 mmol) was dissolved in tetrahydrofuran (10 mL) in a 50 mL reaction flask, and 1,1'-carbonyldiimidazole (606.12 mg, 3.74 mmol) was added at 25°C. The reaction mixture was stirred at 25°C for 10 hours. The reaction was stopped, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with the eluent systems petroleum ether and ethyl acetate to obtain the title product (300 mg, yellow solid) with a yield of 53.1%. MS m / z(ESI): 227.0[M+1].

[0279] Step 4 2-Promo-6-chloro-1-cyclopropyl-5-fluoro-benzoimidazole In a 25 mL reaction flask, 5-chloro-3-cyclopropyl-6-fluoro-1H-benzimidazole-2-one (100 mg, 441.24 μmol) was dissolved in toluene (5 mL), and POBr3 (379.49 mg, 1.32 mmol) was added. The reaction mixture was stirred at 80°C for 3 hours. The reaction was stopped, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product (80 mg, yellow solid) with a yield of 62.6%. MS m / z (ESI): 288.9 [M+1].

[0280] Step 5 N-(4-(6-chloro-1-cyclopropyl-5-fluoro-1H-benzo[d]imidazole-2-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide Using 2-promo-6-chloro-1-cyclopropyl-5-fluoro-benzimidazole as a starting material, the product was obtained by referring to step 4 of Example 1. MS m / z(ESI): 413.1[M+1].

[0281] Example 32 [ka]

[0282] Step 1 N-(4-(dihydroindole-5-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide Using N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dihydroindole as raw materials, the target compound was obtained by referring to step 3 of Example 13. MS m / z(ESI): 322.1[M+1].

[0283] Step 2 N-(4-(1-acetyldihydroindole-5-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide Under ice bath conditions, N-(4-(dihydroindol-5-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide (0.08 g, 0.25 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine (0.05 g, 0.50 mmol) was added, and acetyl chloride (23.5 mg, 0.3 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours, and LC-MS indicated the completion of the reaction. The mixture was rotated dry, the residue was dissolved in ethyl acetate (30 mL), and washed sequentially with saturated sodium bicarbonate solution (10 mL x 2), then with saturated brine (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, rotated dry, and the residue was separated by reverse-phase preparative chromatography (neutral). The mixture was freeze-dried to obtain the target product (20 mg) with a yield of 22.1%. MS m / z(ESI): 364.1[M+1].

[0284] Example 33 [ka]

[0285] Step 1 Under ice bath conditions, 4-bromo-6,7-dihydroisoquinoline-8(5H)-one (2.26 g, 10 mmol) was dissolved in methanol (30 mL), and sodium borohydride (0.57 g, 15 mmol) was slowly added. The mixture was stirred under ice bath conditions for 1 hour. When LC-MS indicated the completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (30 mL), methanol was removed by distillation, the aqueous phase was extracted with ethyl acetate (20 mL x 3), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain the crude product 4-bromo-5,6,7,8-tetrahydroisoquinoline-8-ol (2.10 g) in a yield of 92%. MS m / z (ESI): 228.1, 230.1 [M+1].

[0286] Step 2 Under ice bath conditions, 4-bromo-5,6,7,8-tetrahydroisoquinoline-8-ol (2.10 g, 9.2 mmol) was dissolved in dichloromethane (30 mL), and triethylamine (2.79 g, 27.6 mmol) and trifluoroacetic anhydride (3.86 g, 18.4 mmol) were added. The mixture was stirred overnight at room temperature, and LC-MS indicated the completion of the reaction. The reaction solution was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (10 mL x 2), washed with saturated brine (20 mL x 1), the organic phase was dried over anhydrous sodium sulfate, filtered, and rotary dried. The residue was separated by flash column chromatography to obtain the target product, 4-bromo-5,6-dihydroisoquinoline (1.0 g), with a yield of 51.8%. MS m / z (ESI): 210.1, 212.1 [M+1].

[0287] Step 3 At room temperature, 4-bromo-5,6-dihydroisoquinoline (1.0 g, 4.76 mmol) was dissolved in methyl tert-butyl ether (20 mL), and then ethyl diazoethyl (1.09 g, 9.52 mmol), palladium acetate (0.107 g, 0.476 mmol), and triethylamine (1.44 g, 14.28 mmol) were added. The mixture was then purged with nitrogen gas, heated to 80°C, and reacted for 14 hours. After cooling to room temperature and LC-MS indicating the completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (20 mL x 3), combined with the organic phase, dried the organic phase over anhydrous sodium sulfate, filtered, and rotated-dried. The residue was separated by flash column chromatography to obtain ethyl 4-bromo-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]isoquinoline-7-carboxylate (0.50 g) with a yield of 35.7%. MS m / z (ESI): 296.1, 298.1 [M+1].

[0288] Step 4 At room temperature, 4-bromo-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]isoquinoline-7-carboxylate (0.50 g, 1.69 mmol) was dissolved in tetrahydrofuran (10 mL), and then aqueous sodium hydroxide solution (2 N, 5 mL) was added. The mixture was stirred at room temperature for 2 hours, and LC-MS indicated the completion of the reaction. The pH of the reaction solution was adjusted to 6-7 with dilute hydrochloric acid, the reaction solution was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain the crude product 4-bromo-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]isoquinoline-7-carboxylic acid (0.35 g) in yield of 77.8%. MS m / z (ESI): 268.1, 270.1 [M+1].

[0289] Step 5 At room temperature, 4-bromo-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]isoquinoline-7-carboxylic acid (0.35 g, 1.31 mmol) was dissolved in tetrahydrofuran (6 mL), then triethylamine (0.27 g, 2.62 mmol) was added, the mixture was purged with nitrogen gas, and then diphenyl phosphoryl azide (0.43 g, 1.57 mmol) was added. The mixture was heated to 70°C and reacted for 3 hours. When LC-MS indicated the end of the reaction, the mixture was cooled to room temperature and water was added. The mixture was quenched (5 mL), and the temperature was subsequently raised to 70°C for 3 hours. Once LC-MS indicated the completion of the reaction, the mixture was cooled to room temperature. The reaction solution was extracted with ethyl acetate (20 mL x 3), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and rotated-dried. The residue was separated by flash column chromatography to obtain 4-bromo-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]isoquinoline-7-amine (0.20 g) in yield of 51.9%. MS m / z (ESI): 239.1, 241.1 [M+1].

[0290] Step 6 Using 4-bromo-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]isoquinoline-7-amine as a starting material, the product N-(4-bromo-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]isoquinoline-7-yl)propanamide was obtained by referring to step 3 of Example 1. MS m / z (ESI): 295.1, 297.1 [M+1].

[0291] Step 7 Using N-(4-bromo-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]isoquinoline-7-yl)propanamide as a starting material, the product N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinoline-6-yl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]isoquinoline-7-yl)propanamide was obtained by referring to step 3 of Example 13. MS m / z(ESI): 376.2[M+1].

[0292] Example 34 [ka]

[0293] Using 2-amino-6-bromoquinoline as a starting material, and referring to Example 17, the product N-(4-(2-((methyl-d3)amino)quinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide was obtained. MS m / z(ESI): 364.2[M+1].

[0294] Example 35 [ka]

[0295] Using 6-bromo-1-methyl-1H-quinoline-2-one as a starting material, and referring to Example 1, the product N-(4-(1-methyl-2-oxo-1,2-dihydroquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide was obtained. MS m / z(ESI):362.2[M+1].

[0296] Example 35 was divided to obtain 35-A and 35-B.

[0297] [Table 9]

[0298] Example 36 [ka]

[0299] Referring to Example 23, the product 1-(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)propa-1-one was obtained. MS m / z (ESI): 389.2 [M+1]. 1 H NMR(400MHz,DMSO)δ8.29(d,1H),8.24(d,1H),8.17(d,1H),7.94(dd,1H),7.84-7.75(m,2H),7.11( t,1H),7.00(d,1H),4.24(s,2H),4.04(s,4H),3.98(s,2H),3.94(s,3H),1.99(q,2H),0.90(t,3H).

[0300] Example 37 [ka]

[0301] Referring to Example 1, the product N-(4-(9-fluoro-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-7-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide was obtained. MS m / z(ESI): 392.2[M+1].

[0302] Example 38 [ka]

[0303] Referring to Example 13, the product N-(4-(4-(4-methyloxazole-2-yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide was obtained. MS m / z(ESI):362.2[M+1].

[0304] Example 39 [ka]

[0305] Using 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline and N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6-yl)propanamide as raw materials, N-((4bR,5aS)-4-(2-methoxyquinoline-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6-yl)propanamide was synthesized by referring to step 7 of Example 2. MS m / z (ESI): 360.2 [M+1].

[0306] Example 40 [ka]

[0307] Using 3,5-dibromopyridine and tert-butyl-3-aminoazetidine-1-carboxylate as starting materials, and referring to Example 5, the product (3-((5-(2-methoxyquinoline-6-yl)pyridine-3-yl)amino)azetidine-1-yl)(1-methyl-1H-pyrazole-4-yl)methanone was obtained. MS m / z(ESI): 415.2[M+1]. 1 H NMR(400MHz,DMSO-d6)δ8.31(d,J=8.8Hz,1H),8.28(d,J=2.0Hz,1H),8.21(d,J=2. 0Hz,1H),8.16(s,1H),8.01-7.98(m,2H),7.87(d,J=8.8Hz,1H),7.75(s,1H),7.21 (d,J=2.0Hz,1H),7.07(d,J=8.8Hz,1H),6.77(d,J=7.2Hz,1H),4.79-4.72(m,1H), 4.53-4.37(m,2H),4.13-4.10(m,1H),4.01(s,3H),3.91-3.87(m,1H),3.85(s,3H),

[0308] Example 41 [ka]

[0309] Step 1 3,5-dibromopyridine (0.38 g, 1.60 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (496.00 mg, 1.60 mmol), and sodium carbonate (510.05 mg, 4.81 mmol) were dissolved in 1'4-dioxane (12 mL) and water (3 mL). Under nitrogen gas protection, bistriphenyldichloropalladium (56.30 mg, 80.21 μmol) was added. The mixture was stirred and reacted at 90°C for 5 hours. The reaction was quenched by adding saturated saline solution (50 mL) to the mixture, extracted with ethyl acetate (30 mL x 3), combined the organic phases, washed sequentially with saturated saline solution (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 70:30 elution) to obtain the target product tert-butyl 5-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (0.32 g, white solid) with a yield of 58.81%. MS m / z(ESI):339.1, 341.1[M+1].

[0310] Step 2 tert-butyl 5-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (0.2 g, 589.58 μmol) was dissolved in dioxane hydrochloride (4 M, 10 mL), and the mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product 5-bromo-1',2',3',6'-tetrahydro-3,4'-bipyridine hydrochloride (0.16 g). The crude product was used directly in the next step. MS m / z(ESI):239.0, 241.0[M+1].

[0311] Step 3 5-Bromo-1',2',3',6'-tetrahydro-3,4'-bipyridine hydrochloride (0.16 g, 580.61 μmol, CL) and triethylamine (293.76 mg, 2.90 mmol, 404.90 μL) were dissolved in dichloromethane (10 mL), and cyclopropanesulfonyl chloride (106.12 mg, 754.79 μmol) was added under nitrogen gas protection. The mixture was stirred at 20°C and reacted for 1 hour. The reaction solution was washed with saturated saline solution (30 mL x 2), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 5-bromo-1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine (0.19 g). The crude product was used directly in the next step. MS m / z(ESI):343.0, 345.0[M+1].

[0312] Step 4 Using 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one and 5-bromo-1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine as raw materials, and referring to step 4 of Example 1, 6-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-5-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was obtained. MS m / z(ESI): 426.1[M+1].

[0313] Example 42 [ka]

[0314] Step 1 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane (120 mg, 0.472 mmol), 1H-pyrazole-4-carboxylic acid (64 mg, 0.567 mmol), HATU (269 mg, 0.708 mmol), and triethylamine (143 mg, 1.42 mmol) were dissolved in DMF (5 mL) and reacted with stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with methanol and ethyl acetate as eluents to obtain the title product 42a (98 mg, colorless oily substance) with a yield of 59.6%. MS m / z(ESI):348.0, 350.0[M+1].

[0315] Step 2 42a (98 mg, 0.281 mmol), potassium carbonate (117 mg, 0.843 mmol), and deuterated iodomethane (49 mg, 0.338 mmol) were dispersed in DMF (5 mL) and reacted with stirring at room temperature for 18 hours. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with methanol and ethyl acetate as eluents to obtain the title product 42b (78 mg, colorless oily substance) with a yield of 75.9%. MS m / z(ESI):365.1, 367.1[M+1].

[0316] Step 3 Referring to the synthesis conditions of Example 5, the title product 6-(5-(2-ethoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-(methyl-d3)-1H-pyrazole-4-yl)methanone was synthesized. MS m / z (ESI): 458.2 [M+1].

[0317] Example 43 [ka]

[0318] Using 3,5-dibromopyridine and 2,6-diazaspiro[3.3]heptan-2-carboxylic acid tert-butyl ester as starting materials, and referring to Example 5, the product (1-cyclopropyl-1H-pyrazole-4-yl)(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone was obtained. MS m / z(ESI): 467.2[M+1]. 1 H NMR(400MHz,MeOD)δ8.28(s,1H),8.20(d,1H),8.13-8.06(m,2H),7.93(d,2H),7.81(s,2H),7.27-7.21(m,1H),6.99( d,1H),4.69(s,2H),4.34(s,2H),4.22(s,4H),4.07(s,3H),3.77-3.68(m,1H),1.16-1.12(m,2H),1.12-1.04(m,2H).

[0319] Example 44 [ka]

[0320] Referring to the synthesis conditions of Example 5, the title product (6-(5-(2-cyclopropoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone was synthesized. MS m / z(ESI): 467.2[M+1].

[0321] Example 45 [ka]

[0322] Step 1 Using tert-butyl 6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a starting material, the product tert-butyl 6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate was obtained by referring to step 4 of Example 1. MS m / z(ESI): 433.2[M+1].

[0323] Step 2 Using tert-butyl 6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a starting material, the product 6-(5-(2,6-diazaspiro[3.3]heptane-2-yl)pyridine-3-yl)-2-methoxyquinoline was obtained by referring to step 2 of Example 4. MS m / z(ESI): 333.2[M+1].

[0324] Step 3 Using 6-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridine-3-yl)-2-methoxyquinoline and 1H-pyrazole-1-carbonyl chloride as starting materials, the product (6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1H-pyrazole-1-yl)methanone was obtained by referring to step 3 of Example 1. MS m / z(ESI): 427.2[M+1].

[0325] Example 46 [ka]

[0326] Step 1 Using 6-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridine-3-yl)-2-methoxyquinoline and chloroacetyl chloride as starting materials, the product 2-chloro-1-(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethane-1-one was obtained by referring to step 3 of Example 1. MS m / z (ESI): 409.1 [M+1].

[0327] Step 2 At room temperature, 2-chloro-1-(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethane-1-one (40 mg, 0.1 mmol) is dissolved in N,N-dimethylcarboxamide (2 mL), then potassium carbonate (41.5 mg, 0.3 mmol) is added, followed by pyrazole (13.6 mg, 0.2 mmol). The mixture is heated to 100 °C and reacted for 14 hours, then cooled to room temperature. When the CMS indicated the end of the reaction, the reaction mixture was dissolved in ethyl acetate (30 mL), washed with saturated brine (10 mL x 2), dried the organic phase over anhydrous sodium sulfate, filtered, and rotated-dried. The residue was purified by reverse-phase preparative chromatography to obtain the product 1-(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(1H-pyrazole-1-yl)ethane-1-one. MS m / z(ESI): 441.2[M+1].

[0328] Example 47 [ka]

[0329] Referring to the synthesis conditions of Example 5, the title product (6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1H-pyrazole-4-yl)methanone was synthesized. MS m / z(ESI): 427.2[M+1].

[0330] Example 48 [ka]

[0331] Starting with 6-bromo-2-methoxyquinoline, 3,5-dibromopyridine, pyridazine-3-carboxylic acid, and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, and referring to Example 7, the target product (6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)(pyridazine-3-yl)methanone was obtained. MS m / z (ESI): 439.2 [M+1].

[0332] Example 49 [ka]

[0333] Starting with 6-bromo-2-methoxyquinoline, 3,5-dibromopyridine, pyridazine-4-carboxylic acid, and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, and referring to Example 7, the target product 6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)(pyridazine-4-yl)methanone was obtained. MS m / z (ESI): 439.2 [M+1].

[0334] Example 50 [ka]

[0335] Step 1 1-(5-bromopyridine-3-yl)piperazine (0.1 g, 413.03 μmol), 1-methylpyrazole-4-carboxylic acid (62.51 mg, 495.63 μmol), and N,N-diisopropylethylamine (160.14 mg, 1.24 mmol, 204.78 μL) were dissolved in N,N-dimethylcarboxamide (4 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (235.57 mg, 619.54 μmol) was added under nitrogen gas protection. The mixture was stirred and reacted at 20°C for 12 hours. The reaction was quenched by adding saturated saline solution (10 mL) to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with dichloromethane (15 mL x 2), the organic phase was added, and the mixture was sequentially washed with saturated saline solution (20 mL x 5). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (dichloromethane:methanol = 100:0 to 95:5 elution) to obtain the target product (4-(5-bromopyridine-3-yl)piperazin-1-yl)(1-methyl-1H-pyrazole-4-yl)methanone (0.1 g, white solid) with a yield of 69.13%. MS m / z (ESI): 350.1, 352.1 [M+1].

[0336] Step 2 (4-(5-bromopyridine-3-yl)piperazin-1-yl)(1-methyl-1H-pyrazole-4-yl)methanone (30 mg, 85.66 μmol), 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (24.43 mg, 85.66 μmol), and sodium carbonate (27.24 mg, 256.99 μmol) were dissolved in ethanol (3 mL) and water (0.5 mL). Tetrakistriphenylphosphine palladium (9.90 mg, 8.57 μmol) was added under nitrogen gas protection. The mixture was stirred and reacted at 90°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high-performance liquid chromatography to obtain (4-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)piperazine-1-yl)(1-methyl-1H-pyrazole-4-yl)methanone (7 mg), with a yield of 18.88%. MS m / z(ESI): 429.2[M+1]. 1 H NMR(400MHz,MeOD)δ8.43-8.33(m,1H),8.33-8.25(m,1H),8.24-8.15(m,1H),8.12-8.07(m,1H),8.00(s,1H),7.98-7 .90(m,2H),7.77(s,1H),7.76-7.70(m,1H),7.00(d,J=8.9Hz,1H),4.07(s,3H),4.00-3.88(m,7H),3.53-3.39(m,4H).

[0337] Example 51 [ka]

[0338] Using 3,5-dibromopyridine and 2,6-diazaspiro[3.4]octane-6-carboxylate tert-butyl ester as starting materials, and referring to Example 5, the product (2-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.4]octane-6-yl)(1-methyl-1H-pyrazole-4-yl)methanone was obtained. MS m / z (ESI): 455.2 [M+1]. 1H NMR(400MHz,MeOD)δ8.29-8.23(m,1H),8.19(dd,1H),8.13-8.04(m,2H),7.97-7.86(m,3H),7.84-7.77(m,1H),7.27-7.19(m,1H),7 .02-6.95(m,1H),4.09-3.96(m,8H),3.96-3.92(m,3H),3.92-3.82(m,2H),3.74-3.66(m,1H),2.40-2.32(m,1H),2.32-2.24(m,1H).

[0339] Example 52 [ka]

[0340] Referring to the synthesis conditions of Example 5, the title product (7-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone was obtained. MS m / z(ESI): 469.2[M+1].

[0341] Example 53 [ka]

[0342] Referring to Example 5, the product (5-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone was obtained. MS m / z (ESI): 455.2 [M+1].

[0343] Example 54 [ka]

[0344] Referring to Example 5, the product (1-cyclopropyl-1H-pyrazole-4-yl)(3-((5-(2-methoxyquinoline-6-yl)pyridine-3-yl)amino)azetidine-1-yl)methanone was obtained. MS m / z(ESI): 441.2[M+1]. 1 H NMR(400MHz,DMSO-d6)δ8.31(d,J=8.8Hz,1H),8.28(s,1H),8.22(s,1H),8.20(s,1H),8 .01-7.98(m,2H),7.87(d,J=8.8Hz,1H),7.75(s,1H),7.30-7.20(m,1H),7.07(d,J=8.8H z,1H),6.77(d,J=6.8Hz,1H),4.80-4.76(m,1H),4.50-4.39(m,2H),4.15-4.12(m,1H),4 .01(s,3H),3.90-3.86(m,1H),3.80-3.74(m,1H),1.09-1.06(m,2H),0.98-0.94(m,2H).

[0345] Example 55 [ka]

[0346] Referring to Example 5, the product (3-((5-(2-methoxyquinoline-6-yl)pyridine-3-yl)amino)pyrrolidine-1-yl)(1-methyl-1H-pyrazole-4-yl)methanone was obtained. MS m / z(ESI): 429.1[M+1].

[0347] Example 56 [ka]

[0348] Referring to Example 5, the product (4-((5-(2-methoxyquinoline-6-yl)pyridine-3-yl)amino)pyrimidine-1-yl)(1-methyl-1H-pyrazole-4-yl)methanone was obtained. MS m / z(ESI): 443.1[M+1]. 1 H NMR(400MHz,DMSO)δ8.31(d,J=8.9Hz,1H),8.18(dd,J=11.3,2.0Hz,2H),8.10-8.01(m, 2H),7.98(dd,J=8.7,2.1Hz,1H),7.87(d,J=8.7Hz,1H),7.66(s,1H),7.31(t,J=2.3Hz,1 H),7.08(d,J=8.8Hz,1H),5.98(d,J=8.2Hz,1H),4.20(s,2H),4.02(s,3H),3.86(s,3H), 3.76(d,J=9.6Hz,1H),3.26-3.10(m,2H),2.02(d,J=13.0Hz,2H),1.36(q,J=9.7Hz,2H).

[0349] Example 57 [ka]

[0350] Referring to Example 41, the product 6-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-5-yl)-1-methyl-3,4-dihydro-1,8-diazanaphthalene-2(1H)-one was obtained. MS m / z(ESI): 425.1[M+1].

[0351] Example 58 [ka]

[0352] Referring to Example 41, the product 1-(3-((5-(2-methoxyquinoline-6-yl)pyridine-3-yl)amino)azetidine-1-yl)propan-1-one was obtained. MS m / z(ESI):363.2[M+1].

[0353] Example 59 [ka]

[0354] Referring to Example 1, the product (R)-N-(4-(8-methyl-7-carbonyl-5,6,7,8-tetrahydro-1,8-diazanaphthalene-3-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)acetamide was obtained. MS m / z(ESI): 351.2[M+1].

[0355] Example 60 [ka]

[0356] Referring to Example 1, the product (R)-N-(4-(1-methyl-1H-indazole-5-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide was obtained. MS m / z(ESI): 335.2[M+1]. 1 H NMR(400MHz,DMSO)δ8.44(d,J=2.1Hz,1H),8.35-8.26(m,2H),8.07(dd,J=8.6,2.1Hz,1H),8.02(d,J=8.6Hz,1H),7.94(d,J=2.7Hz,1H),7.90 (d,J=8.7Hz,1H),7.74(d,J=8.6Hz,1H),7.42(s,1H),7.09(d,J=8.9Hz,1H),4.84(s,2H),4.38(s,2H),4.24(s,4H),4.02(s,3H),2.69(s,3H).

[0357] Example 61 [ka]

[0358] Starting with 6-bromo-2-methoxyquinoline, 3,5-dibromopyridine, 6-methylpyridazine-3-carboxylic acid, and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, and referring to Example 7, the target product 6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)(6-methylpyridazine-3-yl)methanone was obtained. MS m / z(ESI): 453.2[M+1].

[0359] Example 62 [ka]

[0360] Using 3,5-dibromopyridine and 2,7-diazaspiro[3.5]nonane-7-carboxylate tert-butyl ester as starting materials, and referring to Example 5, the product (2-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,7-diazaspiro[3.5]non-7-yl)(1-methyl-1H-pyrazole-4-yl)methanone was obtained. MS m / z(ESI): 469.2[M+1]. 1 H NMR(400MHz,DMSO)δ8.29-8.22(m,2H),8.18(d,J=2.1Hz,1H),8.01-7.93(m,2H),7.84-7.75(m,2H),7.58(s,1H),7.09(t, J=2.3Hz,1H),7.01(d,J=8.8Hz,1H),3.94(s,3H),3.79(s,3H),3.71(s,4H),3.52(t,J=5.3Hz,4H),1.75(t,J=5.2Hz,4H).

[0361] Example 63 [ka]

[0362] Using 3,5-dibromopyridine and (2-azaspiro[3.3]heptan-6-yl)aminocarboxylic acid tert-butyl ester as starting materials, and referring to Example 5, the product N-(2-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-1H-pyrazole-4-carboxamide was obtained. MS m / z (ESI): 455.2 [M+1].

[0363] Example 64 [ka]

[0364] Using 3,5-dibromopyridine and (2-azaspiro[3.3]heptan-6-yl)aminocarboxylic acid tert-butyl ester as starting materials, and referring to Example 5, the product N-(2-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2-azaspiro[3.3]heptan-6-yl)propanamide was obtained. MS m / z(ESI): 403.2[M+1]. 1 H NMR(400MHz,DMSO-d6)δ8.32-8.29(m,2H),8.23(s,1H),8.04-7.99(m,2H),7.86(d,J=8.8Hz,1H),7.81(s,1H),7.13-7.10(m,1H),7.07(d,J=8. 8Hz,1H),4.16-4.10(m,1H),4.02-3.99(m,5H),3.90(s,2H),2.49-2.45 (m,2H),2.15-2.10(m,2H),2.04(q,J=7.6Hz,2H),0.98(t,J=7.6Hz,3H).

[0365] Example 65 [ka]

[0366] Using 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)benzo[d]thiazole-2(3H)-one and (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide as starting materials, the title product (R)-N-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazole-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide was obtained by referring to step 4 of Example 1. MS m / z (ESI): 368.1 [M+1]. 1 H NMR(400MHz,MeOD)δ8.36(s,1H),8.20(s,1H),7.54(d,1H),7.35(s,2H),5.21(t,1H),3.51(s, 3H),2.78-2.59(m,2H),2.35-2.20(m,2H),2.09-1.97(m,1H),1.91-1.75(m,3H),1.19(t,3H).

[0367] Example 66 [ka]

[0368] Starting with N-((6R)-4-bromo-4b,5,5a,6-tetrahydrocyclopropyl[3,4]cyclopentadiene[1,2-c]pyridine-6-yl)propanamide and 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)benzo[d]thiazole-2(3H)-one, and referring to step 7 of Example 2, the product N-((6R)-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazole-6-yl)-4b,5,5a,6-tetrahydrocyclopropyl[3,4]cyclopentadiene[1,2-c]pyridine-6-yl)propanamide was obtained. The first chiral resolution of this product was performed to obtain products P1, P2, and P3, with the resolution conditions as follows.

[0369] [Table 10]

[0370] A second chiral splitting was performed on P1 to obtain products P1A and P1B, with the splitting conditions being as follows.

[0371] [Table 11]

[0372] MS m / z (ESI): 366.1 [M+1]. P2: 1 H NMR(400MHz,MeOD)δ8.41(s,1H),8.26(s,1H),7.91-7.80(m,1H),7.75-7.60(m,1H),7.45-7.35(m,1H),7.29-7.06(m,1H),5.84(d,J=6.6H z,1H),3.52(s,3H),2.63-2.49(m,1H),2.38-2.29(m,2H),2.29-2.20(m,1H),1.21(t,J=7.7Hz,3H),0.95-0.85(m,1H),0.69-0.60(m,1H).

[0373] Example 67 [ka]

[0374] Using 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)benzo[d]thiazole-2(3H)-one and (6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone as raw materials, the title product 3-methyl-6-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridine-3-yl)benzo[d]thiazole-2(3H)-one as raw materials, and referring to step 4 of Example 1, the title product 3-methyl-6-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridine-3-yl)benzo[d]thiazole-2(3H)-one. MS m / z(ESI): 447.1[M+1]. 1 H NMR(400MHz,MeOD)δ8.17(d,1H),8.06(s,1H),7.88-7.80(m,2H),7.78(d,1H),7.73-7.59(m,1H), 7.35(d,1H),7.16-7.07(m,1H),4.67(s,2H),4.33(s,2H),4.19(s,4H),3.93(s,3H),3.50(s,3H).

[0375] Example 68 [ka]

[0376] Using 4-bromoisoquinoline-8-amine as a starting material, the product N-(4-(2-methoxyquinoline-6-yl)isoquinoline-8-yl)propanamide was obtained by referring to steps 3 and 4 of Example 5. MS m / z (ESI): 358.1 [M+1].

[0377] Example 69 [ka]

[0378] Starting with 6-bromo-1-methylquinoline-2(1H)-one, 3,5-dibromopyridine, tert-butyl 2,6-diazaspiro[3.3]heptan-2-carboxylate and 1-methyl-1H-pyrazole-4-carboxylic acid, and referring to Example 7, the target product 1-methyl-6-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridine-3-yl)quinoline-2(1H)-one was obtained. MS m / z(ESI): 441.2[M+1].

[0379] Example 70 [ka]

[0380] Using 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)quinoline-2(1H)-one and 5-bromo-1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine as starting materials, the title product 6-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-5-yl)-1-methylquinoline-2(1H)-one was obtained by referring to step 4 of Example 1. MS m / z(ESI): 422.1[M+1]. 1 H NMR(400MHz,MeOD)δ8.79(d,1H),8.63(d,1H),8.18(t,1H),8.08(d,1H),8.02(dd,2H),7.73(d,1H),6.74(d,1H),6.4 4-6.37(m,1H),4.11-4.04(m,2H),3.79(s,3H),3.62(t,2H),2.81-2.73(m,2H),2.62-2.52(m,1H),1.16-1.00(m,4H).

[0381] Example 71 [ka]

[0382] Starting with 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)quinoline, 3,5-dibromopyridine, and pyrimidine-4-aminocarboxylic acid tert-butyl ester, and referring to Example 7, the target product N-(1-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)pyrimidine-4-yl)-1-methyl-1H-pyrazole-4-carboxamide was obtained. MS m / z(ESI): 443.2[M+1]. 1H NMR(400MHz,MeOD)δ8.34-8.30(m,1H),8.30-8.25(m,1H),8.21(d,J=8.9H z,1H),8.12-8.08(m,1H),8.04(s,1H),7.98-7.91(m,2H),7.90(s,1H),7. 77-7.69(m,1H),6.99(d,J=8.9Hz,1H),4.14-4.01(m,4H),4.02-3.92(m,2 H),3.91(s,3H),3.11-2.94(m,2H),2.15-1.99(m,2H),1.85-1.68(m,2H).

[0383] Example 72 [ka]

[0384] Step 1 Using deuterated iodomethane as a starting material, the product (1-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)pyrimidine-4-yl)(methyl-d3)aminocarboxylic acid tert-butyl ester was obtained by referring to Step 1 of Example 1. MS m / z (ESI): 452.2 [M+1].

[0385] Step 2 Using (1-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)pyrimidine-4-yl)(methyl-d3)aminocarboxylic acid tert-butyl ester as a starting material, and referring to Example 7, the product N-(1-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)pyrimidine-4-yl)-1-methyl-N-(methyl-d3)-1H-pyrazole-4-carboxamide was obtained. MS m / z (ESI): 460.2 [M+1].

[0386] Example 73 [ka]

[0387] Step 1 (5-Promo-3',6'-Dihydro-[3,4'-Bipyridine]-1'(2'H)-yl)(1-Methyl-1H-Pyrazole-4-yl)methanone Using 5-bromo-1',2',3',6'-tetrahydro-3,4'-bipyridine and 1-methyl-1H-pyrazole-4-carbonyl chloride as starting materials, the title product (5-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-yl)(1-methyl-1H-pyrazole-4-yl)methanone was obtained by referring to step 3 of Example 41. MS m / z (ESI): 347.0 [M+1].

[0388] Step 2 Using 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)quinoline-2(1H)-one and (5-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-yl)(1-methyl-1H-pyrazole-4-yl)methanone as raw materials, the title product 1-methyl-6-(1'-(1-methyl-1H-pyrazole-4-carbonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-5-yl)quinoline-2(1H)-one was obtained by referring to step 4 of Example 1. MS m / z(ESI): 426.1[M+1]. 1 H NMR(400MHz,DMSO)δ8.41(d,J=1.7Hz,1H),8.35(d,J=2.7Hz,1H),8.33-8.26(m,2H),8.11-8.02(m,2H),7.87(d,J=8.7Hz,1H),7.71(s,1H),7.67(t, J=2.4Hz,1H),7.08(d,J=8.8Hz,1H),4.05(s,1H),4.01(s,4H),3.87(s,3H) ),2.90(t,J=12.2Hz,2H),1.92(d,J=12.8Hz,2H),1.73(d,J=11.9Hz,2H).

[0389] Example 74 [ka]

[0390] Starting with 6-bromo-1-methylquinoline-2(1H)-one, 3,5-dibromopyridine, 1-methyl-1H-pyrazole-4-carboxylic acid, and tert-butyl ester of 3-aminoazetidine-1-carboxylic acid, and referring to Example 7, the target product 1-methyl-6-(5-(methyl(1-(1-methyl-1H-pyrazole-4-carbonyl)azetidine-3-yl)amino)pyridine-3-yl)quinoline-2(1)-one. MS m / z(ESI): 429.2[M+1].

[0391] Example 75 [ka]

[0392] Step 1 In a 25 mL reaction flask, trimethylsulfoxyiodide (693.27 mg, 3.15 mmol) was dissolved in DMSO (10 mL), and sodium hydride (142.80 mg, 3.57 mmol, 60% purity) was added at 0°C. The reaction mixture was stirred at 25°C for 1 hour, and then 6-bromo-1-methylquinoline-2-one (500 mg, 2.10 mmol) was added at 25°C. The reaction mixture was then allowed to react at 90°C for 10 hours. The reaction was stopped, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 6-bromo-3-methyl-1,1a,3,7b-tetrahydro-2H-cyclopropyl[c]quinoline-2-one (300 mg, yellow solid) in yield of 56.6%. MS m / z(ESI):252.0, 254.0[M+1].

[0393] Step 2 Using 6-bromo-3-methyl-1,1a,3,7b-tetrahydro-2H-cyclopropyl[c]quinoline-2-one as a starting material, N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propanamide was replaced with (6-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone, and referring to steps 2 and 4 of Example 1, the title product 3-methyl-6-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridine-3-yl)-1,1a,3,7b-tetrahydro-2H-cyclopropyl[c]quinoline-2-one was obtained. MS m / z (ESI): 455.2 [M+1].

[0394] Example 76 [ka]

[0395] Using 1-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-2(1H)-one as a starting material, and referring to Example 2, the product N-(4-(1-(methyl-d3)-2-carbonyl-1,2,3,4-tetrahydroquinoline-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopentadiene[1,2-c]pyridine-6-yl)propanamide was obtained. MS m / z(ESI): 365.2[M+1].

[0396] Example 77 [ka]

[0397] (S)-7-bromo-2,3-dihydrofluoro[3,2-c]pyridine-3-amine and 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)quinoline were used as starting materials, and the product (S)-N-(7-(2-methoxyquinoline-6-yl)-2,3-dihydrofuran[3,2-c]pyridine-3-yl)propanamide was obtained by referring to step 4 of Example 1. MS m / z (ESI): 350.1 [M+1].

[0398] Example 78 [ka]

[0399] Referring to the synthesis method of Example 42, the product (6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-(methyl-d3)-1H-pyrazole-4-yl)methanone was obtained. MS m / z(ESI): 444.2[M+1]. 1 H NMR(400MHz,CDCl3)δ8.37(s,1H),8.04(d,1H),7.95(d,1H),7.89(d,1H),7.87(s,1H),7.82(d, 2H),7.70(s,1H),7.09(s,1H),6.97(d,1H),4.60(s,2H),4.38(s,2H),4.23(s,4H),4.10(s,3H).

[0400] Example 79 [ka]

[0401] Using 3,5-dibromopyrazine as a starting material, the title product was obtained by referring to Example 5.

[0402] The specific method is as follows:

[0403] Step 1: tert-butyl 6-(6-bromopyrazine-2-yl)-2,6-diazaspiro[3.3]heptan-2-carboxylate A mixture of 2,6-dibromopyrazine (2.90 g, 12.21 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2.2 g, 11.10 mmol), potassium carbonate (4.59 g, 33.29 mmol), and N,N-dimethylcarboxamide (30 mL) was stirred at room temperature for 1 hour, rotated dry, and separated by column chromatography (PE / SiO=1:1) to obtain a white solid tert-butyl 6-(6-bromopyrazine-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (2.7 g, yield: 68.5%). MS m / z (ESI): 355.1 357.1 [M+1].

[0404] Step 2: tert-butyl 6-(6-(2-methoxyquinoline-6-yl)pyrazine-2-yl)-2,6-diazaspiro[3.3]heptan-2-carboxylate 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (2.09g, 7.32mmol), tert-butyl A mixture of 6-(6-bromopyrazine-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (2g, 5.63 mmol), sodium carbonate (1.79 g, 16.89 mmol), tetrakis(triphenylphosphine)palladium (390 mg, 0.34 mmol), ethanol (15 mL), and water (3 mL) was purged three times with nitrogen gas, and then stirred at 85°C for 12 hours under nitrogen gas protection. Separation by column chromatography (DCM / MeOH = 10:1) yielded a white solid tert-butyl 6-(6-(2-methoxyquinoline-6-yl)pyrazine-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (2g, yield: 81.9%). MS m / z (ESI): 434.2 [M+1].

[0405] Step 3: 6-(6-(2,6-diazaspiro[3,3]heptan-2-yl)pyrazine-2-yl)-2-methoxyquinoline A mixture of tert-butyl 6-[6-(2-methoxy-6-quinoline)pyrazine-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (2 g, 4.61 mmol), trifluoroacetic acid (5 mL), and DCM (15 mL) was stirred at room temperature for 15 minutes, rotated dry, water was added, and saturated NaHCO3 solution was added to adjust the pH to 10. A solid precipitated, which was filtered, and the filtered cake was dried to obtain 6-(6-(2,6-diazaspiro[3.3]heptane-2-yl)pyrazine-2-yl)-2-methoxyquinoline (1.5 g, crude product). MS m / z(ESI): 334.2[M+1].

[0406] Step 4: (6-(6-(2-methoxyquinoline-6-yl)pyrazine-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone Add a solution of 6-(6-(2,6-diazaspiro[3,3]heptan-2-yl)pyrazine-2-yl)-2-methoxyquinoline (1.5g, 4.50 mmol), triethylamine (1.36g, 13.50 mmol), and dichloromethane (15 mL) dropwise to a solution of 1-methyl-1H-pyrazole-4-carbonyl chloride (845 mg, 5.85 mmol) in dichloromethane (5 mL), stir at room temperature for 5 minutes, add water, and then add dichloromethane (30 mL x 3). Extraction was performed, the organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and rotatably dried. Separation was then performed by column chromatography (DCM / MeOH = 10:1) and then by preparative chromatography to obtain (6-(6-(2-methoxyquinoline-6-yl)pyrazine-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazole-4-yl)methanone (1.02 g, yield: 51.1%). MS m / z (ESI): 442.2 [M+1]. 1H NMR(400MHz,DMSO)δ8.60(d,J=3.9Hz,2H),8.42-8.26(m,2H),8.13(s,1H),7.95-7.81(m,2H),7.7 3(s,1H),7.08(d,J=8.9Hz,1H),4.60(s,2H),4.33(s,4H),4.21(s,2H),4.02(s,3H),3.87(s,3H).

[0407] Example 80 [ka]

[0408] Referring to Example 23, the product 2-methoxy-1-(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethane-1-one was obtained. MS m / z(ESI): 405.2[M+1]. 1 H NMR(400MHz,MeOD)δ8.46-8.38(m,1H),8.27-8.18(m,2H),8.05-7.93(m,2H),7.94-7.88(m,1H),7.83-7.74(m, 1H),7.04(d,J=8.9Hz,1H),4.54(s,2H),4.39-4.30(m,4H),4.27(s,2H),4.08(s,3H),4.00(s,2H),3.39(s,3H).

[0409] Example 81 [ka]

[0410] Using 3,5-dibromopyridine and 1-cyanocyclopropane-1-carboxylic acid as starting materials, the product 1-(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-carbonyl)cyclopropane-1-carbonyl was obtained by referring to steps 1 and 2 of Example 5 and steps 3 and 4 of Example 6. MS m / z(ESI): 426.1[M+1]. 1 H NMR(400MHz,DMSO-d6)δ8.57-8.55(m,1H),8.41-8.38(m,1H),8.32(d,J= 8.8Hz,1H),8.15-8.10(m,1H),8.06-8.02(m,1H),7.95-7.92(m,1H),7.84 -7.65(m,1H),7.12(dd,J1=8.8Hz,J2=2.0Hz,1H),4.76(s,2H),4.32-4.2 6(m,4H),4.20(s,2H),4.03(s,3H),1.60-1.55(m,2H),1.53-1.48(m,2H).

[0411] Example 82 [ka]

[0412] Referring to the synthesis route of Example 5, the title product cyclopropyl(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone was obtained. MS m / z (ESI): 401.2 [M+1]. 1 H NMR(400MHz,DMSO)δ8.36(d,J=1.9Hz,1H),8.31(d,J=8.9Hz,1H),8.25(d,J =2.1Hz,1H),8.02(dd,J=8.7,2.2Hz,1H),7.91-7.83(m,2H),7.18(t,J=2.3H z,1H),7.08(d,J=8.8Hz,1H),4.46(s,2H),4.19-4.10(m,4H),4.07(s,2H), 4.01(s,3H),1.53(tt,J=7.5,4.9Hz,1H),0.70(ddd,J=7.7,6.1,2.5Hz,4H).

[0413] Example 83 [ka]

[0414] Starting with 6-bromo-1-methylquinoline-2(1H)-one, 3,5-dibromopyridine, tert-butyl 3-aminoazetidine-1-carboxylate, and deuterated iodomethane, and referring to Example 7, the target product 1-methyl-6-(5-((methyl-d3)(1-propanezetidine-3-yl)amino)pyridine-3-yl)quinoline-2(1H)-one was obtained. MS m / z (ESI): 380.2 [M+1].

[0415] Example 84 [ka]

[0416] Using 3,5-dibromopyridine and 6-methylnicotinic acid as starting materials, the product (6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(6-methylpyridine-3-ylmethanone) was obtained by referring to steps 1 and 2 of Example 5 and steps 3 and 4 of Example 6. MS m / z (ESI): 452.1 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.58(s,1H),8.41(s,1H),8.20(d,J=8.8Hz,1H),8.15-8.05(m,3H),7.93(d,J=8.8H) z,1H),7.86(s,1H),7.60-7.50(m,1H),7.13(d,J=8.4Hz,1H),4.62(s,2H),4.32-4.24(m,6H),4.03(s,3H),2.60(s,3H).

[0417] Example 85 [ka]

[0418] Using 3,5-dibromopyridine and 3-amino-1-methyl-1H-pyrazole-4-carboxylic acid as starting materials, the product (3-amino-1-methyl-1H-pyrazole-4-yl)(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone was obtained by referring to steps 1 and 2 of Example 5 and steps 3 and 4 of Example 6. MS m / z (ESI): 456.1 [M+1].

[0419] Example 86 [ka]

[0420] Using 3,5-dibromopyridine and (2-azaspiro[3.3]heptan-6-yl)aminocarboxylic acid tert-butyl ester as starting materials, and referring to steps 1 and 2 of Example 5 and steps 3 and 4 of Example 6, the product 5-amino-N-(2-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-1H-pyrazole-4-carboxamide was obtained. MS m / z (ESI): 470.2 [M+1].

[0421] Example 87 [ka]

[0422] Step 1 At room temperature, 5-bromo-4-methoxy-2-methylpyridine (1.0 g, 5 mmol), triethylamine (5.06 g, 50 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.41 g, 0.5 mmol) were dissolved in N,N-dimethylcarboxamide (10 mL) and methanol (10 mL). The mixture was purged with carbon monoxide gas, heated to 100 °C, and reacted for 24 hours. After cooling to room temperature, methanol and triethylamine were removed by distillation. The residue was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The residue was separated by flash column chromatography (eluted at PE:EA = 10:1--3:1) to obtain the product methyl 4-methoxy-6-methylnicotinate (0.36 g, yield: 40%). MS m / z(ESI): 182.1[M+1].

[0423] Step 2 At room temperature, methyl 4-methoxy-6-methylnicotinate (0.36 g, 2 mmol) was dissolved in tetrahydrofuran (5 mL), and then aqueous sodium hydroxide solution (5 M, 2 mL) was added. The mixture was stirred overnight at room temperature, and when LC-MS indicated the completion of the reaction, the reaction mixture was neutralized with dilute hydrochloric acid (2 M) to adjust the pH to 5-6, and then extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotated-dried to obtain the target product, 4-methoxy-6-methylnicotinic acid (0.27 g, yield: 80%). MS m / z (ESI): 168.1 [M+1].

[0424] Step 3 Using 4-methoxy-6-methylnicotinic acid and 2-(5-bromopyridine-3-yl)-2-azaspiro[3.3]heptan-6-amine as starting materials, the product N-(2-(5-bromopyridine-3-yl)-2-azaspiro[3.3]heptan-6-yl)-4-methoxy-6-methylnicotinamide was obtained by referring to step 3 of Example 6. MS m / z(ESI): 417.1[M+1].

[0425] Step 4 Using N-(2-(5-bromopyridine-3-yl)-2-azaspiro[3.3]heptan-6-yl)-4-methoxy-6-methylnicotinamide and 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)quinoline as starting materials, the product 4-methoxy-N-(2-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2-azaspiro[3.3]heptan-6-yl)-6-methylnicotinamide was obtained by referring to step 4 of Example 6. MS m / z(ESI): 496.2[M+1].

[0426] Example 88 [ka]

[0427] Referring to the synthesis route of Example 5, the title product 3-methyl-6-(5-((1-(1-methyl-1H-pyrazole-4-carbonyl)azetidine-3-yl)amino)pyridine-3-yl)benzo[d]thiazole-2(3H)-one was obtained. MS m / z(ESI): 421.1[M+1].

[0428] Example 89 [ka]

[0429] Referring to the synthesis route of Example 5, the title product 3-methyl-6-(5-(methyl(1-(1-methyl-1H-pyrazole-4-carbonyl)azetidine-3-yl)amino)pyridine-3-yl)benzo[d]thiazole-2(3H)-one was obtained. MS m / z (ESI): 435.1 [M+1]. 1H NMR(400MHz,DMSO)δ8.38(d,J=1.7Hz,1H),8.20(d,J=2.7Hz,1H),8.17(s,1H ),8.14(d,J=2.1Hz,1H),7.82(dd,J=8.4,1.9Hz,1H),7.77(s,1H),7.61(s,1 H),7.44(d,J=8.5Hz,1H),4.89(t,J=6.6Hz,1H),4.67-4.64(m,1H),4.44(s, 1H),4.36-4.32(m,1H),4.07(s,1H),3.86(s,3H),3.46(s,3H),3.07(s,3H).

[0430] Example 90 [ka]

[0431] Referring to the synthesis route of Example 4, 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzothiazole-2-one was used as a starting material to obtain the title product 6-(5-((1-(ethylsulfonyl)azetidine-3-yl)oxy)pyridine-3-yl)-3-methylbenzo[d]thiazole-2(3H)-one. MS m / z(ESI): 406.1[M+1]. 1 H NMR(400MHz,DMSO)δ8.59(s,1H),8.25(d,J=2.7Hz,1H),8.13(s,1H),7.82(d,J=8.4Hz,1H),7.57(s,1H),7.43(d,J=8.4Hz,1H),5. 27(t,J=5.6Hz,1H),4.39(t,J=7.9Hz,2H),3.97(dd,J=9.4,4.6Hz,2H),3.46(s,3H),3.20(q,J=7.4Hz,2H),1.26(d,J=7.4Hz,3H).

[0432] Example 91 [ka]

[0433] Referring to the synthesis route of Example 4, the title product 3-methyl-6-(5-((1-(1-methyl-1H-pyrazole-4-carbonyl)azetidine-3-yl)oxy)pyridine-3-yl)benzo[d]thiazole-2(3H)-one was obtained.

[0434] The specific method is as follows: [ka]

[0435] Step 1: tert-butyl 3-((5-bromopyridine-3-yl)oxo)azetidine-1-carboxylate A mixture of 3-bromo-5-iodopyridine (2g, 7.04 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (1.46g, 8.45 mmol), cuprous iodide (66.93 mg, 352 μmol), 1,10-phenanthroline (126.96 mg, 704 μmol), cesium carbonate (6.89 g, 21.13 mmol), and toluene (20 mL) was purged three times with nitrogen gas, stirred at 110°C for 12 hours under nitrogen gas protection, rotated dry, and separated by column chromatography (PE / EtOAC = 3:1) to obtain tert-butyl 3-((5-bromopyridine-3-yl)oxo)azetidine-1-carboxylate (1.2 g, yield: 51.7%). MS m / z (ESI): 329.0 331.0 [M+H]

[0436] Step 2: tert-butyl 3-((5-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]thiazole-6-yl)pyridine-3-yl)oxo)azetidine-1-carboxylate A mixture of 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole-2(3H)-one (126 mg, 434 μmol), tert-butyl 3-((5-bromopyridine-3-yl)oxo)azetidine-1-carboxylate (110 mg, 334 μmol), sodium carbonate (106 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium (19 mg, 16 μmol), ethanol (5 mL), and water (1 mL) was purged three times with nitrogen gas, stirred at 90°C for 2 hours under nitrogen gas protection, rotated dry, and separated by column chromatography to obtain a pale yellow solid tert-butyl. 3-((5-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]thiazole-6-yl)pyridine-3-yl)oxo)azetidine-1-carboxylate (130 mg, yield: 94.1%) was obtained. MS m / z (ESI): 414.1 [M+H]

[0437] Step 3: 6-(5-(azetidine-3-oxy)pyridine-3-yl)-3-methylbenzo[d]thiazole-2(3H)-one A mixture of tert-butyl 3-((5-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]thiazole-6-yl)pyridine-3-yl)oxo)azetidine-1-carboxylate (130 mg, 314 μmol), trifluoroacetic acid (1 mL), and DCM (3 mL) was stirred at room temperature for 0.5 hours, rotated dry, water was added, pH was adjusted to 10 with saturated NaHCO3 solution, and the mixture was extracted with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried to obtain a pale yellow oily substance, 6-(5-(azetidine-3-oxy)pyridine-3-yl)-3-methylbenzo[d]thiazole-2(3H)-one (100 mg, crude). MS m / z (ESI): 314.1 [M+H]

[0438] Step 4: 3-methyl-6-(5-((1-(1-methyl-1H-pyrazole-4-carbonyl)azetidine-3-yl)oxo)pyridine-3-yl)benzo[d]thiazole-2(3H)-one 6-(5-(azetidine-3-oxy)pyridine-3-yl)-3-methylbenzo[d]thiazole-2(3H)-one (50 mg, 159 μmol), (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 319 μmol), triethylamine (48.44 mg, 478 μmol), in a solution of DMF (3 mL) 1-methyl-1H-pyrazole-4-carboxylic acid (30 mg, 239 μmol) was added, stirred at room temperature for 2 hours, water was added, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and rotary dried. Acidic separation by preparative chromatography yielded 3-methyl-6-(5-((1-(1-methyl-1H-pyrazole-4-carbonyl)azetidine-3-yl)oxo)pyridine-3-yl)benzo[d]thiazole-2(3H)-one (32.7 mg, yield: 48.1%). MS m / z(ESI): 422.1[M+1]. 1 H NMR(400MHz,DMSO)δ8.59(d,J=1.8Hz,1H),8.25(d,J=2.6Hz,1H),8.18(s,1H),8 .12(d,J=1.9Hz,1H),7.81(dd,J=8.4,2.0Hz,1H),7.77(s,1H),7.56(t,J=2.3Hz ,1H),7.43(d,J=8.4Hz,1H),5.33(tt,J=6.7,3.7Hz,1H),4.87-4.81(m,1H),4.5 4-4.51(m,1H),4.39-4.37(m,1H),4.10-3.93(m,1H),3.86(s,3H),3.45(s,3H).

[0439] Example 92 [ka]

[0440] Using 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane and acetic acid as starting materials, the title product 1-(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethane-1-one was obtained by referring to the synthesis method of Example 42. MS m / z (ESI): 375.1 [M+1]. 1 H NMR(400MHz,DMSO)δ8.36(d,J=1.9Hz,1H),8.31(d,J=8.9Hz,1H),8.24(d,J=2.1Hz,1H),8.01(dd,J=8.7,2.2Hz,1H),7.90- 7.83(m,2H),7.18(t,J=2.3Hz,1H),7.07(d,J=8.8Hz,1H),4.32(s,2H),4.11(s,4H),4.04(s,2H),4.01(s,3H),1.76(s,3H).

[0441] Example 93 [ka]

[0442] Using 3,5-dibromopyrazine as a starting material, and referring to Example 5, 1-methyl-1H-pyrazole-4-carbonyl chloride and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one were replaced with acetyl chloride and 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline to obtain the title product 1-(6-(6-(2-methoxyquinoline-6-yl)pyrazine-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethane-1-one. MS m / z (ESI): 376.1 [M+1]. 1H NMR(400MHz,DMSO)δ8.52(d,J=3.0Hz,2H),8.37-8.16(m,2H),7.81(t,J=4.4Hz,2H),7 .01(d,J=8.9Hz,1H),4.27(s,2H),4.22(s,4H),3.99(s,2H),3.95(s,3H),1.70(s,3H).

[0443] Example 94 [ka]

[0444] Using 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane and 1-fluorocyclopropane-1-carboxylic acid as starting materials, the title product (1-fluorocyclopropyl)(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)methanone was obtained by referring to the synthesis method of Example 42. MS m / z(ESI): 419.1[M+1]. 1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.33-8.30(m,2H),8.07(d,J=8.8Hz,1H),7.95(s,1H),7.90(d,J=8.8Hz,1H),7.48( s,1H),7.11(d,J=8.8Hz,1H),4.61(s,2H),4.22(s,4H),4.19(s,2H),4.02(s,3H),1.30-1.26(m,2H),1.21-1.18(m,2H).

[0445] Example 95 [ka]

[0446] Using 3,5-dibromopyrazine as a starting material, and referring to Example 5, 1-methyl-1H-pyrazole-4-carbonyl chloride and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one were replaced with 1-fluorocyclopropane-1-carbonyl chloride and 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline to obtain the title product (1-fluorocyclopropyl)(6-(6-(2-methoxyquinoline-6-yl)pyrazine-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone. MS m / z (ESI): 420.1 [M+1].

[0447] Example 96 [ka]

[0448] Using 3,5-dibromopyrazine as a starting material, and referring to Example 5, 1-methyl-1H-pyrazole-4-carbonyl chloride and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one were replaced with 1-cyanocyclopropane-1-carbonyl chloride and 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline to obtain the title product 1-(6-(6-(2-methoxyquinoline-6-yl)pyrazine-2-yl)-2,6-diazaspiro[3.3]heptan-2-carbonyl)cyclopropane-1-carbonyl. MS m / z (ESI): 427.1 [M+1].

[0449] Example 97 [ka]

[0450] Using 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane and 1-hydroxycyclopropane-1-carboxylic acid as starting materials, the title product (1-hydroxycyclopropyl)(6-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)methanone was obtained by referring to the synthesis method of Example 42. MS m / z(ESI): 417.1[M+1]. 1 H NMR(400MHz,DMSO)δ8.36(d,J=1.9Hz,1H),8.31(d,J=8.9Hz,1H),8.25(d,J=2.1Hz,1H),8.02(dd,J=8.7,2.2Hz,1H),7.90-7.83(m,2H),7.18( t,J=2.3Hz,1H),7.08(d,J=8.9Hz,1H),6.04(s,1H),4.64(s,2H),4.13- 4.10(m,6H),4.01(s,3H),1.03(q,J=4.1Hz,2H),0.79(q,J=4.1Hz,2H).

[0451] Example 98 [ka]

[0452] Using 3-(azetidine-3-oxy)-5-bromopyridine and 1-methyl-1H-pyrazole-4-carbonyl chloride as starting materials, and referring to steps 3 and 4 of Example 4, 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was replaced with 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2(1H)-one to obtain the title product 1-methyl-6-(5-((1-(1-methyl-1H-pyrazole-4-carbonyl)azetidine-3-yl)oxo)pyridine-3-yl)quinoline-2(1H)-one. MS m / z(ESI): 416.1[M+1]. 1H NMR(400MHz,DMSO)δ8.66(d,J=1.8Hz,1H),8.27(d,J=2.7Hz,1H),8.19(d,J=2. 2Hz,1H),8.17(s,1H),8.06(dd,J=8.8,2.2Hz,1H),7.97(d,J=9.5Hz,1H),7.77 (s,1H),7.70-7.60(m,2H),6.69(d,J=9.5Hz,1H),5.35(tt,J=6.9,3.9Hz,1H), 4.85(s,1H),4.53(s,1H),4.39(s,1H),4.02(s,1H),3.85(s,3H),3.67(s,3H).

[0453] Example 99 [ka]

[0454] Using 2-bromo-6-fluoropyrazine as a starting material, and referring to Example 4, ethanesulfonyl chloride and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one were replaced with 1-methyl-1H-pyrazole-4-carbonyl chloride and 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole-2(3H)-one to obtain the title product 3-methyl-6-(6-((1-(1-methyl-1H-pyrazole-4-carbonyl)azetidine-3-yl)oxo)pyrazine-2-yl)benzo[d]thiazole-2(3H)-one. MS m / z(ESI): 423.1[M+1]. 1H NMR(400MHz,DMSO)δ8.93(s,1H),8.50(d,J=1.8Hz,1H),8.34(s,1H),8.20(dd,J=8.5,1.9Hz,1H),8.17(s,1H),7.77(s,1H),7.46(d, J=8.5Hz,1H),5.66-5.61(m,1H),4.87(s,1H),4.56(s,1H),4.45(d,J=9.7Hz,1H),4.06(d,J=11.2Hz,1H),3.85(s,3H),3.47(s,3H).

[0455] Example 100 [ka]

[0456] Using 3,5-dibromopyrazine as a starting material, and referring to Example 5, 1-methyl-1H-pyrazole-4-carbonyl chloride and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one were replaced with 6-methylnicotinoyl chloride and 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline to obtain the title product (6-(6-(2-methoxyquinoline-6-yl)pyrazine-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(6-methylpyridine-3-yl)methanone. MS m / z(ESI): 453.2[M+1]. 1 H NMR(400MHz,DMSO)δ8.72(d,J=2.3Hz,1H),8.59(d,J=3.0Hz,2H),8.36(dd,J=8.7,2.1Hz,1H),8.33(d,J=9.1Hz,1H),7.95(dd,J=8.1,2. 3Hz,1H),7.88(d,J=8.4Hz,2H),7.38(d,J=8.1Hz,1H),7.08(d,J=8.9Hz,1H),4.60(s,2H),4.42-4.19(m,6H),4.02(s,3H),2.53(s,3H).

[0457] Example 101 [ka]

[0458] Using 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane and 6-methylnicotinic acid as raw materials, and referring to the synthesis method of Example 42, 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline was replaced with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole-2(3H)-one to obtain the title product 3-methyl-6-(5-(6-(6-methylnigronoyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridine-3-yl)benzo[d]thiazole-2(3H)-one. MS m / z (ESI): 458.1 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ8.70(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),8.05(d,J=2 .0Hz,1H),7.93(dd,J1=8.0Hz,J2=2.0Hz,1H),7.82(d,J=2.0Hz,1H),7.74(dd,J1 =8.0Hz,J2=2.0Hz,1H),7.40(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),7.08(t,J=2 .0Hz,1H),4.57(s,2H),4.28(s,2H),4.13-4.10(m,4H),3.44(s,3H),2.52(s,3H).

[0459] Example 102 [ka]

[0460] Using 3,5-dibromopyrazine as a starting material, and referring to Example 5, 1-methyl-1H-pyrazole-4-carbonyl chloride and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one were replaced with 6-methylnicotinoyl chloride and 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole-2(3H)-one to obtain the title product 3-methyl-6-(6-(6-(6-methylnigronoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrazine-2-yl)benzo[d]thiazole-2(3H)-one. MS m / z (ESI): 459.1 [M+1].

[0461] Example 103 [ka]

[0462] Using 3,5-dibromopyridine and 2,7-diazaspiro[3.5]nonane-7-carboxylate tert-butyl ester as starting materials, and referring to Example 5, 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was replaced with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole-2(3H)-one to obtain the title product 3-methyl-6-(5-(7-(1-methyl-1H-pyrazole-4-carbonyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyridine-3-yl)benzo[d]thiazole-2(3H)-one. MS m / z(ESI): 475.1[M+1]. 1H NMR(400MHz,DMSO)δ8.23(d,J=1.9Hz,1H),8.06(d,J=1.9Hz,1H),8.04(s,1H),7.81(d,J=2.6Hz,1H),7.74(dd,J=8.4,1.9Hz,1H),7.65( s,1H),7.40(d,J=8.5Hz,1H),7.06(t,J=2.3Hz,1H),3.86(s,3H),3.75(s,4H),3.58(t,J=5.5Hz,4H),3.45(s,3H),1.81(t,J=5.5Hz,4H).

[0463] Example 104 [ka]

[0464] Using 3,5-dibromopyrazine and 2,7-diazaspiro[3.5]nonane-7-carboxylate tert-butyl ester as starting materials, and referring to Example 5, 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was replaced with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole-2(3H)-one to obtain the title product 3-methyl-6-(6-(7-(1-methyl-1H-pyrazole-4-carbonyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyrazine-2-yl)benzo[d]thiazole-2(3H)-one. MS m / z (ESI): 476.1 [M+1].

[0465] Example 105 [ka]

[0466] Using 2-(5-bromopyridine-3-yl)-2,6-diazaspiro[3.3]heptane and 1-cyanocyclopropane-1-carboxylic acid as starting materials, and referring to the synthesis method of Example 42, 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline was replaced with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole-2(3H)-one to obtain the title product 1-(6-(5-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]thiazole-6-yl)pyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)cyclopropane-1-carbonil. MS m / z(ESI): 432.1[M+1]. 1 H NMR(400MHz,DMSO)δ8.25(d,J=1.9Hz,1H),8.05(d,J=1.9Hz,1H),7.82(d,J=2.6Hz,1H),7.73(dd,J=8.4,1.9Hz,1H),7.41( d,J=8.4Hz,1H),7.07(t,J=2.3Hz,1H),4.72(s,2H),4.30-4.03(m,6H),3.45(s,3H),1.60-1.54(m,2H),1.53-1.46(m,2H).

[0467] Example 106 [ka]

[0468] Using 3,5-dibromopyrazine as a starting material, and referring to Example 5, 1-methyl-1H-pyrazole-4-carbonyl chloride and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one were replaced with 1-cyanocyclopropane-1-carbonyl chloride and 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole-2(3H)-one to obtain the title product 1-(6-(6-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]thiazole-6-yl)pyrazine-2-yl)-2,6-diazaspiro[3.3]heptan-2-carbonyl)cyclopropane-1-carbonil. MS m / z (ESI): 433.1 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.36(s,1H),8.10(d,J=8.4Hz,1H),7.84(s,1H),7.43(d,J=8.4Hz ,1H),4.73(s,2H),4.33-4.29(m,4H),4.18(s,2H),3.45(s,3H),1.60-1.55(m,2H),1.52-1.46(m,2H).

[0469] Example 107 [ka]

[0470] Using 3,5-dibromopyrazine as a starting material, and referring to Example 5, 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was replaced with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole-2(3H)-one to obtain the title product 3-methyl-6-(6-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrazine-2-yl)benzo[d]thiazole-2(3H)-one. MS m / z (ESI): 448.1 [M+1]. 1 H NMR(400MHz,MeOD)δ8.35(s,1H),8.25(d,1H),8.11-8.04(m,2H),7.83(s,1H),7.75( s,1H),7.33(d,1H),4.72-4.62(m,2H),4.39-4.33(m,6H),3.93(s,3H),3.50(s,3H).

[0471] Example 108 [ka]

[0472] Step 1 Methyl 6-methyl-4-vinylnicotinate Dissolve 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.52g, 3.39 mmol), 4-bromo-6-methylpyridine-3-carboxylate methyl (0.65g, 2.83 mmol), sodium carbonate (0.89g, 8.48 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.12g, 0.14 mmol) in water (2 mL) and 1'4-dioxane (8 mL) at room temperature. The reaction was dissolved, purged with nitrogen gas, heated to 80°C, reacted for 14 hours, cooled to room temperature, diluted with ethyl acetate (25 mL), filtered, washed the organic phase with saturated brine (25 mL x 2), dried the organic phase over anhydrous sodium sulfate, filtered, and rotary dried. The residue was separated by flash column chromatography (eluted at PE:EA = 90:10 to 70:30) to obtain the target compound (0.39 g, yield: 77.9%), which was a pale yellow oily substance. MS m / z (ESI): 178.1 [M+1].

[0473] Step 2 6-(6-methyl-1-carbonyl-3,4-dihydro-2,7-diazanaphthalene-2(1H)-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester At room temperature, 6-amino-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (0.09 g, 0.43 mmol), acetic acid (0.15 mL), and methyl 6-methyl-4-vinylnicotinate (0.04 g, 0.21 mmol) were dissolved in methanol (2 mL), the mixture was purged with nitrogen gas, heated to 100 °C, and reacted for 14 hours. After cooling to room temperature, when LC-MS indicated the completion of the reaction, the mixture was rotated dry, the residue was dissolved in ethyl acetate (25 mL), and then sequentially washed with saturated sodium bicarbonate solution (25 mL x 1), saturated brine (25 mL x 1), the organic phase was dried over anhydrous sodium sulfate, filtered, rotated dry, and the residue was separated by preparative thin-layer chromatography (DCM:MeOH = 20:1) to obtain the target product (0.06 g, yield: 78.3%), which was a colorless oily substance. MS m / z (ESI): 358.2 [M+1].

[0474] Step 3 6-Methyl-2-(2-azaspiro[3,3]heptan-6-yl)-3,4-dihydro-2,7-diazanaphthalene-1(2H)-one At room temperature, 6-(6-methyl-1-carbonyl-3,4-dihydro-2,7-diazanaphthalene-2(1H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (0.10 g, 0.28 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. When LC-MS indicated the completion of the reaction, the mixture was rotated dry, the residue was neutralized with saturated sodium bicarbonate solution, and freeze-dried. The resulting solid was dissolved in dichloromethane (25 mL), filtered, and the resulting solution was rotate-dried. The resulting solid was used directly in the next step (0.06 g, yield: 83.3%). MS m / z (ESI): 258.1 [M+1].

[0475] Step 4 2-(2-(5-(2-methoxyquinoline-6-yl)pyridine-3-yl)-2-azaspiro[3,3]heptan-6-yl)-6-methyl-3,4-dihydro-2,7-diazanaphthalene-1(2H)-one At room temperature, 6-(5-bromo-3-pyridine)-2-methoxyquinoline (0.025g, 0.07mmol), 6-methyl-2-(2-azaspiro[3,3]heptan-6-yl)-3,4-dihydro-2,7-diazanaphthalene-1(2H)-one (0.02g, 0.078mmol), tris(dibenzylideneacetone)dipalladium (10mg, 0.012mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (13.5mg, 0.024mmol), and sodium tert-butoxide (11.19mg, 0. Dissolve 12 mmol of (DCM) in 2 mL of 1',4-dioxane, purge with nitrogen gas, heat to 100°C, react for 14 hours, cool to room temperature, dilute the reaction solution with ethyl acetate (25 mL), filter, and wash with saturated brine (25 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, and rotatably dry. Separate the residue by preparative thin-layer chromatography (DCM:MeOH = 15:1), separate the resulting crude product by reverse-phase preparative chromatography, freeze-dry, and obtain the target compound as a pale yellow solid (5.0 mg, yield: 13%). MS m / z(ESI): 492.2[M+1].

[0476] Example 109 [ka]

[0477] Using 3,5-dibromopyrazine and pyrimidine-4-ylaminocarboxylic acid tert-butyl ester as starting materials, and referring to Example 5, 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was replaced with 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline to obtain the title product N-(1-(6-(2-methoxyquinoline-6-yl)pyrazine-2-yl)pyrimidine-4-yl)-1-methyl-1H-pyrazole-4-carboxamide. MS m / z(ESI): 444.2[M+1]. 1 H NMR(400MHz,DMSO)δ8.63(d,1H),8.57(s,1H),8.42-8.32(m,3H),8.11(s,1H),7.87(t,2H),7.82(s,1H),7.08(d,1H),4 .57-4.49(m,2H),4.14-4.05(m,1H),4.02(s,3H),3.83(s,3H),3.17-3.06(m,2H),2.04-1.94(m,2H),1.62-1.50(m,2H).

[0478] Biological Test Evaluation The present invention will be further described below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0479] Test Example 1 We used the G-402 cell line as a host cell to express (transiently or stably transfect) human CYP11 family enzymes. Specifically, we established G-402 cell lines that stably express human CYP11B1 and human CYP11B2, respectively. The G-402 cell line expresses cofactors (adrenodoxin and adrenodoxin reductase) that are quite important for CYP11 family activity, and it was demonstrated that the cell line itself does not have CYP11 family-related enzyme activity (compared to H295R cells). Therefore, the G-402 cell line is very suitable as a host cell for ectopic expression of CYP11 family enzymes.

[0480] The G-402 cell line was initially derived from renal myoblastoma and is available from ATCC (CRL-1440). The main motif of the expression plasmid contains the ORF of human CYP11B1 or human CYP11B2, a suitable promoter (CMV promoter), and a suitable resistance marker (neomycin). The expression plasmid was transfected into G-402 cells using standard techniques, and then screened with specific antibiotics. The activity of enzymes expressed by the screened monoclonal cells was evaluated using 11-desoxycorticosterone (a substrate of CYP11B2) and 11-desoxycortisol (a substrate of CYP11B1).

[0481] G-402 cells expressing the CYP11 plasmid established in the above scheme were cultured in McCoy's 5a modified medium (ATCC Catalog No. 30-2007) containing 10% FCS and 400 μg / ml G418 at 37°C in a 5% CO2 incubator. Cell enzyme experiments were performed using DMEM / F12 medium containing 2.5% charcoal-treated FBS and appropriate substrate concentrations (1 μM 11-desoxycorticosterone or 1 μM 11-desoxycortisol). To detect cell enzyme activity, cells were seeded in 96-well plates and incubated for 16 hours. The supernatant was then transferred, and the concentrations of the desired products (CYP11B2 product: aldosterone; CYP11B1 product: cortisol) were analyzed. The concentrations of these products were measured by CisBio HTRF experiment.

[0482] In cell-enzyme experiments, the inhibitory effect of a test compound on the generated product can indicate its inhibitory effect on the enzyme. The dose-dependent inhibition of enzyme activity by a compound was calculated by plotting the concentration of the test compound (x-axis) against the measured product level (y-axis). The raw data was then fitted to a four-parameter s-type function using the least squares method (Morgan-Mercer-Flodin, MMF model): y=(AB+Cx D ) / (B+x D ) Here, A is the maximum y value, B is the EC50 determined using XLFit, C is the minimum y value, and D is the slope value. The maximum value A corresponds to the amount of product detected in the absence of an inhibitor, and C corresponds to the amount of product detected from G402 cells expressing an empty vector plasmid.

[0483] EC of the compound of the present invention 50 The values ​​were measured using the G-402 experimental system described above. CYP11B2 enzyme activity was measured under conditions of 1 μM 11-desoxycorticosterone and a variable amount of inhibitor, and CYP11B1 enzyme activity was measured under conditions of 1 μM 11-desoxycortisol and a variable amount of inhibitor.

[0484] [Table 12]

[0485] [Table 13] Note: hSF is an abbreviation for human selective factor, and refers to the selectivity of the compound CYP11B2 for CYP11B1. The hSF value is equal to CYP11B1 EC. 50 and CYP11B2 EC 50 This is the ratio.

[0486] From the above data, it was found that the compound of the present invention has good CYP11B2 activity and high selectivity compared to the CYP11B1 enzyme.

[0487] Test Example 2: Pharmacokinetic Measurement in Rats 1. Research purpose: The pharmacokinetic behavior of the compound of the present invention in vivo (plasma) of rats was investigated using SD rats as test animals.

[0488] 2. Test Scheme 2.1 Test chemicals: The compound of this invention is manufactured in-house.

[0489] 2.2 Test animals: SD rats, 3 males per group.

[0490] 2.3 Drug composition: Preparation of orally administered drugs: 0.5% CMC-Na (1% Tween80) 5 g of sodium capoxymethylcellulose (CMC-Na, viscosity: 800-1200 Cps) was weighed and dissolved in 1000 mL of purified water, and 10 g of Tween 80 was added. The mixture was then thoroughly mixed to obtain a clear solution.

[0491] The compounds of the examples were weighed, dissolved in the solution, shaken well to make homogeneous, and sonicated for 15 minutes to obtain a colorless clarified liquid with a concentration of 0.5 mg / mL.

[0492] Preparation of intravenous medication: 5% DMSO + 10% Solutol HS15 + 85% PBS The compound of the example was weighed, and in proportion to the total volume administered, first 5% DMSO was added, vortexed, and sonicated for 2 minutes to completely dissolve it. Next, 10% Solutol HS15 was added, vortexed, and sonicated for 2 minutes to completely dissolve it. Finally, 85% PBS was added, vortexed, and sonicated for 5 minutes. The solution was then passed through a 0.22 μm filter membrane to obtain a colorless, clear clarified solution with a concentration of 0.2 mg / mL.

[0493] 2.4 Administration: SD rats, 3 males per group. After an overnight fast, each rat was administered PO at a dose of 5 mg / kg and a volume of 10 mL / kg.

[0494] SD rats, 3 males per group. Each rat was administered intravenously after an overnight fast, with a dose of 1 mg / kg and a volume of 5 mL / kg.

[0495] 2.5 Sample collection: 0.2 mL of blood was collected from the jugular vein of experimental animals before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24.0 hours after administration. The blood was placed in an EDTA-2K test tube, centrifuged at 4°C and 8000 rpm for 6 minutes to separate the plasma, stored at -80°C, and fed to the animals 4 hours after administration.

[0496] 3. Experimental Results: The final measurement results were obtained using the LC-MS / MS method.

[0497] [Table 14]

[0498] Test Example 3: Ki Measurement Human CYP11 family enzymes were expressed (transiently or stably transfected) using the G-402 cell line as the host cell. Specifically, G-402 cell lines that stably express human CYP11B1 and human CYP11B2 were established. To detect the repression constants of the target compounds in CYP11B2 and CYP11B1, cells were incubated for 16 hours at different substrate concentrations (CYP11B2 cell line: 0.125-4 μM 11-DOC, CYP11B1 cell line: 0.3125-10 μM 11-desoxycortisol) and different inhibitor concentrations (CYP11B2 cell line: 0-100 nM, CY11B1 cell line: 0-10000 nM). Product levels (CYP11B2 cell line: aldosterone, CYP11B1 cell line: cortisol) were measured using CisBio's homogeneous time-resolved fluorescence (HTRF) assay. Ki was determined using the fitting algorithm provided by the GraphPad Prism program.

[0499] The compounds of the present invention have a better affinity for CYP11B2, have a Ki of less than 5 nM, and preferably have a compound concentration of less than 1 nM. Compared to CYP11B2, the compounds of the present invention have a selectivity for CYP11B1 that is more than 200 times greater, preferably more than 500 times greater, and more preferably more than 2000 times greater.

[0500] Test Example 4: In vivo drug efficacy measurement 1. Experimental Objective In vivo PD efficacy of compounds in a monkey ACTH Challenge model

[0501] 2. Experimental Instruments and Reagents 2.1 Equipment Refrigerator, biosafety cabinet, clean bench, electric pipette helper, constant temperature water bath, ultrasonic cleaner, pure water system, magnetic stirrer, electronic balance, electronic balance, ultrasonic cell disruptor, LC-MS / MS-BT

[0502] 2.2 Reagents ACTH, physiological saline, CMC-Na, Tween 80, HP-β-CD, HPMC

[0503] 3. Experimental Procedures and Data Processing 3.1 Animals Crab-eating macaque, male, 35-61 months old.

[0504] 3.2 Animal Models After the animals reached the barrier system, they were allowed to adapt for 14 days, followed by intravenous injection of ACTH.

[0505] 3.3 Grouping and Administration a. The subjects were grouped using a random grouping method.

[0506] b. Based on the group assignment results, administration of the test drug was initiated (method of administration: oral administration, volume of administration: 5 mL / kg, frequency of administration: single dose on the same day, vehicle: 0.5% CMC-Na + 1% Tween80, 20% HP-β-CD + 0.25% HPMC K4M).

[0507] c. ACTH was administered intravenously 1 hour after administration to create a monkey ACTH Challenge model (administration method: intravenous injection, administration volume: 1 mL / kg, dose: 5 μg / kg, vehicle: physiological saline).

[0508] d. After ACTH injection, blood was collected at a series of blood sampling points, and plasma was prepared.

[0509] e. The content of the four related hormones in plasma was detected at each time point using LC / MS-MS.

[0510] f. Data was processed, plotted, and analyzed using software such as Excel and Graphpad Prism 9. Hormone changes were observed, the point in time when each hormone level was highest was determined, and these points were selected for group comparisons.

[0511] 4. Experimental conclusion: In the monkey ACTH Challenge experiment, the compound of the present invention was able to effectively reduce aldosterone content at a low dose of 0.1 mg / kg without causing significant changes in hormones such as cortisol.

[0512] 5. Pharmacokinetic evaluation study of cynomolgus monkeys 1. Research purpose: Cynomolgus monkeys were used as test animals, and the pharmacokinetic behavior of the compound of the present invention in the body (plasma) of cynomolgus monkeys after oral administration at a dose of 3 mg / kg was investigated.

[0513] 2. Experimental plan: 2.1 Laboratory chemicals: Compounds of the embodiments of the present invention, manufactured in-house.

[0514] 2.2 Laboratory animals: Crab-eating macaques, 3 males per group.

[0515] 2.3 Formulation prescription: Preparation of orally administered drugs: 0.5% CMC-Na (1% Tween80) 0.5 g of CMC-Na (viscosity 800-1200) and 1.0 g of Tween 80 were weighed, placed in a 100 ml volumetric flask, vortexed, and mixed uniformly. The mixture was then sonicated to obtain a clear solution.

[0516] The compound of the present invention was weighed, placed in a 100 mL glass bottle, the solution was added, vortexed for 10 minutes, and sonicated to obtain a white suspension with a concentration of 0.6 mg / mL.

[0517] 2.4 Administration: Three male cynomolgus monkeys were administered PO after fasting overnight. The dose was 3 mg / kg, and the administered volume was 5 mL / kg.

[0518] 2.5 Sample collection: Blood collection: 0.3 mL of blood was collected from the forelimb veins of cynomolgus monkeys before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an EDTA-K2 anticoagulation tube, centrifuged at 4°C and 6000 rpm for 6 minutes to separate the plasma, stored at -80°C, and fed 4 hours after administration.

[0519] 2.6 Sample preparation: 1) 40 μL of plasma sample was added to 160 μL of acetonitrile and allowed to precipitate. After mixing, the mixture was centrifuged at 3500 × g for 5 to 20 minutes.

[0520] 2) The treated supernatant solution was taken, and the concentration of the test compound was analyzed by LC / MS / MS. The LC / MS / MS analyzer used was an AB Sciex API 4000 Qtrap.

[0521] 2.7 Liquid phase analysis: ● Liquid phase conditions: Shimadzu LC-20AD pump ● Chromatography column: Agilent ZORBAX XDB-C18 (50 × 2.1 mm, 3.5 μm) Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and Solution B is acetonitrile. ● Flow rate: 0.4mL / min ● The elution time is 0 to 4.0 minutes, and the eluate is as follows:

[0522] [Table 15]

[0523] 3. Experimental conclusion: The compound of the present invention exhibits excellent metabolic behavior in cynomolgus monkeys, and under a PO dose of 3 mg / kg, the plasma exposure AUC is high. 0-∞ The concentration was able to reach 7000-12000 ng / mL × h.

Claims

1. A compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Here, 【Chemistry 2】 These are single or double bonds, Ring A is selected from a phenyl group, a 4- to 7-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group, or is absent. Ring B is a 4-7 membered heterocyclyl group, a 5-6 membered heteroaryl group, or a phenyl group. Ring C is either a cycloalkyl group, a heteroaryl group, a heterocyclyl group, or is absent. M １ M ２ M ４ M ５ M ６ Each is independently selected from N, NH, or CH. M ３ It is a bond, N or CH, R １ is, independently of each other, a cycloalkyl group, a heterocyclyl group, a cycloalkyloxy group, a heterocyclyloxy group, a cycloalkylamino group, a heterocyclylamino group, a cycloalkylthio group, a heterocyclylthio group, -C(O)(CH ２ ) ｎ R ｂ , -NR ａ C(O)(CH ２ ) ｎ R ｂ , -O(CH ２ ) ｎ R ｂ , -NH(CH ２ ) ｎ R ｂ , -S(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ , -S(O)(NH)(CH ２ ) ｎ R ｂ , -NR ａ S(O) ２ (CH ２ ) ｎ R ｂ , -NR ａ S(O)(NH)(CH ２ ) ｎ R ｂ or -NS(O)(CH ２ ) ｎ R ａ R ｂ selected from, and optionally, the cycloalkyl group, the heterocyclyl group, the cycloalkyloxy group, the heterocyclyloxy group, the cycloalkylamino group, the heterocyclylamino group, the cycloalkylthio group or the heterocyclylthio group further has an oxo group, deuterium, a halogen, an amino group, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, -C(O)(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ , -S(O)(NH)(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ or -NR ａ S(O)(NH)(CH ２ ) ｎ R ｂ Substituted with one or more substituents selected from, Or, any two R １ It forms a 3-8 membered cycloalkyl group or a 4-7 membered heterocycline group with an adjacent carbon atom, and optionally, the 3-8 membered cycloalkyl group or the 4-7 membered heterocycline group may further have an oxo group, -C(O)R ｂ , -NR ａ C(O)R ｂ , -S(O) ２ R ｂ , -S(O)(NH)R ｂ , -NR ａ S(O) ２ R ｂ or -NR ａ S(O)(NH)R ｂ Replaced by, R ａ or R ｂ Each is independently selected from hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, aryl group, heteroaryl group, or heterocyclyl group, and optionally the cycloalkyl group, aryl group, heteroaryl group, or heterocyclyl group may further be an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, or -S(O) ２ Substituted with one or more substituents selected from alkyl groups, R ２ , R ３ or R ４ Each is independently selected from hydrogen, deuterium, oxo group, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -NR ａ C(O)(CH ２ ) ｎ R ｂ or - C(O)NR ａ (CH ２ ) ｎ R ｂ This may be further replaced by an optional substitution. Or, R ２ and R ３ It forms a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group, or a 4-7 membered heterocyclyl group with an adjacent atom, and optionally, the 3-8 membered cycloalkyl group, the 5-6 membered heteroaryl group, or the 4-7 membered heterocyclyl group is further substituted with one or more substituents selected from an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, or hydroxyalkyl group. or, any two Rs ２ form an adjacent atom and a 3- to 8-membered cycloalkyl group, 5- to 6-membered heteroaryl group or 4- to 7-membered heterocyclyl group, and optionally, the 3- to 8-membered cycloalkyl group, 5- to 6-membered heteroaryl group or 4- to 7-membered heterocyclyl group is further substituted with one or more substituents selected from an oxo group, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group or hydroxyalkyl group, Or, R ２ and R ４ It forms a 5-14 member cycloalkyl group, a 5-14 member heteroaryl group, or a 5-14 member heterocyclyl group with an adjacent atom, and optionally, the 5-14 member cycloalkyl group, the 5-14 member heteroaryl group, or the 5-14 member heterocyclyl group is further substituted with one or more substituents selected from an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, or hydroxyalkyl group. p, x, y, and z are each independently selected from 1, 2, 3, or 4. n is selected from 0, 1, 2, or 3. 【Transformation 3】 but 【Chemistry 4】 And M １ N is and ring C is 【Transformation 5】 When it is, R １ is -NR ａ C(O)R ｂ and -NR ａ S(O) ２ R ｂ but not M １ If N is present, then the ring C does not exist or 【Transformation 6】 If that is the case, 【Transformation 7】 teeth, 【Transformation 8】 Not a compound, its stereoisomer, or its pharmaceutically acceptable salt.

2. Ring A either does not exist, or it consists of C(O), N, O, S, SO ２ Alternatively, it is selected from a 5-10 membered heterocyclyl group or a 5-10 membered heteroaryl group containing 1 to 3 selected from SONH, preferably C(O), N, O, S, SO ２ The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that it is a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group containing 1 to 3 members selected from SONH.

3. The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that ring B is selected from a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group containing 1 to 3 members selected from phenyl groups, C(O), N, O, or S.

4. Ring A is a 5-7 membered heterocyclyl group containing C(O), N, or S, or C(O), N, O, S, SO ２ Alternatively, it is selected from a 5-6 membered heteroaryl group containing 1-3 selected from SONH, and ring B is selected from a phenyl group. Or, 【Chemistry 9】 teeth, 【Chemistry 10】 Selected from, more, 【Chemistry 11】 The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt.

5. The carbon ring is either absent or consists of a 3- to 10-membered cycloalkyl group or C(O), N, O, S, SO ２ Alternatively, selected from 4-10 membered heterocyclyl groups containing 1-3 selected from SONH, Preferably, ring C is a 5-7 member monocyclic cycloalkyl group, a 6-10 member bicyclic cycloalkyl group, C(O), N, O, S, SO ２ Alternatively, a 5-7 membered monocyclic heterocyclyl group containing 1-3 selected from SONH, C(O), N, O, S, SO ２ Alternatively, the compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from a 7-10 membered bicyclic heterocyclyl group containing 1-3 members selected from SONH.

6. R １ Each of these is independently a 3-8 member cycloalkyl group, a 4-8 member heterocyclyl group, a 3-8 member cycloalkyloxy group, a 4-8 member heterocyclyloxy group, a 3-8 member cycloalkylamino group, a 4-8 member heterocyclylamino group, a 3-8 member cycloalkylthio group, a 4-8 member heterocyclylthio group, and -C(O)(CH ２ ) ｎ R ｂ , -NR ａ C(O)(CH ２ ) ｎ R ｂ , -O(CH ２ ) ｎ R ｂ ,-NH(CH ２ ) ｎ R ｂ , -S(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ , -S(O)(NH)(CH ２ ) ｎ R ｂ , -NR ａ S(O) ２ (CH ２ ) ｎ R ｂ or -NR ａ S(O)(NH)(CH ２ ) ｎ R ｂ Selected from, and optionally, the 3-8 member cycloalkyl group, 4-8 member heterocyclyl group, 3-8 member cycloalkyloxy group, 4-8 member heterocyclyloxy group, 3-8 member cycloalkylamino group, 4-8 member heterocyclylamino group, 3-8 member cycloalkylthio group, and 4-8 member heterocyclylthio group may further be an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, or C １－６ Alkyl alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Hydroxyalkyl group, -C(O)(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ , -S(O)(NH)(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ or -NR ａ S(O)(NH)(CH ２ ) ｎ R ｂ Substituted with one or more substituents selected from, R ａ or R ｂ These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－６ Alkyl alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ A 5-8 membered heteroaryl group containing 1-3 members selected from a hydroxyalkyl group, a 3-8 membered cycloalkyl group, C(O), N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, optionally comprising an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C １－６ Alkyl alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Hydroxyalkyl group or -SO ２ -C １－６ Substituted with one or more substituents selected from alkyl groups, Preferably, R １ Each of these is independently a 3- to 8-membered cycloalkyl group, N, O, S, SO ２ Alternatively, it contains 1 to 3 selected from SONH, a 4-8 membered heterocyclyl group, a 3-8 membered cycloalkyloxy group, N, O, S, SO ２ Alternatively, a 4-8 membered heterocyclyloxy group containing 1-3 selected from SONH, -C(O)(CH ２ ) ｎ R ｂ , -NR ａ C(O)(CH ２ ) ｎ R ｂ , -O(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ , -S(O)(NH)(CH ２ ) ｎ R ｂ , -NR ａ S(O) ２ (CH ２ ) ｎ R ｂ or -NR ａ S(O)(NH)(CH ２ ) ｎ R ｂ Selected from, optionally, the 3-8 member cycloalkyl groups, N, O, S, SO ２ Alternatively, it contains 1 to 3 selected from SONH, a 4-8 membered heterocyclyl group, a 3-8 membered cycloalkyloxy group, N, O, S, SO ２ Alternatively, a 4-8 membered heterocyclyloxy group containing 1-3 selected from SONH may further contain an oxo group, -C(O)(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ , -S(O)(NH)(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ or -NR ａ S(O)(NH)(CH ２ ) ｎ R ｂ Substituted with one or more substituents selected from, R ａ or R ｂ These are, independently, hydrogen, deuterium, and C. １－３ Selected from an alkyl group, a 3-8 membered cycloalkyl group, a 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, and optionally the 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or the 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, further comprising an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C １－３ Alkyl alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group or -SO ２ -C １－３ The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being substituted with one or more substituents selected from alkyl groups.

7. R １ Each of these is independently a 3-10 membered cycloalkyl group, N, O, S, SO ２ Alternatively, it contains 1 to 3 selected from SONH: a 4-10 membered heterocyclyl group, a 3-8 membered cycloalkyloxy group, a 3-8 membered cycloalkylamino group, N, O, S, SO ２ Alternatively, a 4-8 member heterocyclyloxy group containing 1-3 selected from SONH, N, O, S, SO ２ Alternatively, a 4-8 membered heterocyclylamino group containing 1-3 selected from SONH, -C(O)(CH ２ ) ｎ R ｂ , -NR ａ C(O)(CH ２ ) ｎ R ｂ , -O(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ , -S(O)(NH)(CH ２ ) ｎ R ｂ , -NR ａ S(O) ２ (CH ２ ) ｎ R ｂ or -NR ａ S(O)(NH)(CH ２ ) ｎ R ｂ Selected from, optionally, the 3-10 member cycloalkyl groups, N, O, S, SO ２ Alternatively, it contains 1 to 3 selected from SONH: a 4-10 membered heterocyclyl group, a 3-8 membered cycloalkyloxy group, a 3-8 membered cycloalkylamino group, N, O, S, SO ２ Alternatively, a 4-8 membered heterocyclyloxy group containing 1-3 selected from SONH or N, O, S, SO ２ Alternatively, a 4-8 membered heterocyclylamino group containing 1-3 selected from SONH may further contain an oxo group, -C(O)(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ , -S(O)(NH)(CH ２ ) ｎ R ｂ , -S(O) ２ (CH ２ ) ｎ R ｂ or -NR ａ S(O)(NH)(CH ２ ) ｎ R ｂ Substituted with one or more substituents selected from, R ａ or R ｂ These are, independently, hydrogen, deuterium, halogen, hydroxyl group, cyano group, and C １－３ Selected from an alkyl group, a 3-8 membered cycloalkyl group, a 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, and optionally the 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or the 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, further comprising an oxo group, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C １－３ Alkyl alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl groups, 3-6 membered cycloalkyl groups, or -SO ２ -C １－３ The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being substituted with one or more substituents selected from alkyl groups.

8. R ２ , R ３ or R ４ These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－６ Alkyl alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Deuterated alkoxy group, C １－６ Hydroxyalkyl group, 3-8 membered cycloalkyl group, 3-8 membered cycloalkyloxy group, 3-8 membered cycloalkylamino group, C ６－１０ A 5-6 membered heteroaryl group containing 1-3 members selected from aryl groups, N, O, and S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, -NR ａ R ｂ , -NR ａ C(O)R ｂ or -C(O)NR ａ R ｂ Selected from, Preferably, R ２ , R ３ or R ４ These are, independently, hydrogen, deuterium, halogen, and C. １－３ Alkyl alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group or C ３－６ A compound according to claim 1, characterized by being selected from cycloalkyloxy groups, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Request Item 9】 【Chemistry 12】 teeth, 【Chemistry 13】 A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the following groups.

10. Furthermore, the compound represented by general formula (IV-a) or (IV-b), its stereoisomer, or its pharmaceutically acceptable salt, 【Chemistry 14】 Here, M ２ or M ３ Each is independently selected from N or CH. Ring C is a 5-7 member monocyclic cycloalkyl group, a 6-10 member bicyclic cycloalkyl group, C(O), N, O, S, SO ２ Alternatively, a 5-7 membered monocyclic heterocyclyl group containing 1-3 selected from SONH, C(O), N, O, S, SO ２ Alternatively, it may be selected from a 7-10 membered bicyclic heterocyclyl group containing 1-3 members selected from SONH, or it may not be present. R １ is -C(O)R ｂ , -NR ａ C(O)R ｂ , -OR ｂ , -S(O) ２ R ｂ , -S(O)(NH)R ｂ , -NR ａ S(O) ２ R ｂ , -NR ａ S(O)(NH)R ｂ , selected from a 4-8 member nitrogen-containing heterocyclyl group, a 4-8 member nitrogen-containing heterocyclyloxy group, a 4-8 member nitrogen-containing heterocyclylthio group, or a 4-8 member nitrogen-containing heterocycloamino group, wherein the 4-8 member nitrogen-containing heterocyclyl group, the 4-8 member nitrogen-containing heterocyclyloxy group, the 4-8 member nitrogen-containing heterocyclylthio group, or the 4-8 member nitrogen-containing heterocycloamino group is optionally -C(O)R ｂ or -S(O) ２ R ｂ It is further replaced by, R ａ or R ｂ These are, independently, hydrogen, deuterium, halogen, hydroxyl group, cyano group, and C １－３ Alkyl alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Selected from a haloalkoxy group, a 3-8 membered cycloalkyl group, a 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, optionally, the C １－３ A 5-8 membered heteroaryl group containing 1-3 elements selected from alkyl groups, 3-8 membered cycloalkyl groups, N, O, or S, or C(O), N, O, S, SO ２ Alternatively, a 4-8 membered heterocyclyl group containing 1-3 selected from SONH may further contain a hydroxyl group, an amino group, CN, and C. １－３ Alkyl alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Substituted with a hydroxyalkyl group or a 3-6 membered cycloalkyl group, R ２ is hydrogen, deuterium, halogen, C １－３ Alkyl alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group or C ３－６ A compound according to any one of claims 1 to 9, selected from cycloalkyloxy groups, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. Furthermore, the compound represented by general formula (V-a) or (V-b), its stereoisomer, or its pharmaceutically acceptable salt, 【Chemistry 15】 Here, L is selected from a bond, NH, or O. The compound according to claim 10, its stereoisomers, or its pharmaceutically acceptable salts, wherein ring D is selected from a 4-8 membered heterocyclyl group containing 1-3 nitrogen atoms.

12. Furthermore, the compounds represented by general formulas (VI-a), (VI-c), (VI-d), (VI-e), (VI-f), (VI-g), and (VI-i), their stereoisomers, or pharmaceutically acceptable salts thereof, 【Chemistry 16】 Here, L stands for NR ａ Selected from O or S, L １ is C(O) or S(O) ２ Selected from, R ａ is hydrogen, deuterium, halogen, C １－３ Alkyl alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group or C ３－６ Selected from cycloalkyloxy groups, M ２ It is selected from N or CH, M ５ It is selected from N or CH, R ２ is hydrogen, deuterium, halogen, C １－３ Alkyl alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group or C ３－６ Selected from cycloalkyloxy groups, Or, any two R ２ It forms a 5-8 membered heteroaryl group containing one to three atoms selected from a 3-8 membered cycloalkyl group, N, O, or S, or a 4-8 membered heterocyclyl group containing one to three atoms selected from C(O), N, O, or S. R ｂ These are, independently, hydrogen, deuterium, halogen, hydroxyl group, cyano group, and C １－３ Alkyl alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Selected from a haloalkoxy group, a 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, optionally the 5-8 membered heteroaryl group containing 1-3 members selected from N, O, or S, or the 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, further comprising a hydroxyl group, an amino group, CN, C １－３ Alkyl alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Substituted with a hydroxyalkyl group or a 3-6 membered cycloalkyl group, R ５ These are, independently, hydrogen, deuterium, halogen, and C. １－３ Alkyl alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group or C ３－６ Selected from cycloalkyloxy groups, R ６ is hydrogen, deuterium, halogen, C １－３ Alkyl alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group or C ３－６ Selected from cycloalkyl groups, or any two R ５ It forms a 3-8 membered cycloalkyl group or a 3-8 membered heterocycline group with an adjacent carbon atom. Ring D is selected from a 3- to 8-membered cycloalkyl group or a 4- to 8-membered heterocycline group, preferably a 4- to 6-membered nitrogen-containing heterocycline group, and more preferably a 4- to 6-membered heterocycline group containing 1 to 2 nitrogen atoms. q, r, s, and t are each independently selected from 1 or 2. k is independently selected from 1, 2, or 3, a compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Request Item 13】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 Any one of the compounds, its stereoisomer, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

15. A compound represented by general formula (X-a) or (X-b), its stereoisomer, or a pharmaceutically acceptable salt thereof, 【Chemistry 22】 M ２ or M ５ Each is independently selected from N or CH. R is independently selected from hydrogen, a 3-10 member cycloalkyl group, a 4-10 member heterocyclyl group, a 3-8 member cycloalkyloxy group, a 4-8 member heterocyclyloxy group, a 3-8 member cycloalkylamino group, a 4-8 member heterocyclylamino group, a 3-8 member cycloalkylthio group, and a 4-8 member heterocyclylthio group. R ２ These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－６ Alkyl alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Deuterated alkoxy group, C １－６ Hydroxyalkyl group, 3-8 membered cycloalkyl group, 3-8 membered cycloalkyloxy group, 3-8 membered cycloalkylamino group, C ６－１０ A 5-6 membered heteroaryl group containing 1-3 members selected from aryl groups, N, O, and S, or a 4-8 membered heterocyclyl group containing 1-3 members selected from C(O), N, O, or S, -NR ａ R ｂ , -NR ａ C(O)R ｂ or -C(O)NR ａ R ｂ Selected from, Preferably, R ２ These are, independently, hydrogen, deuterium, halogen, and C. １－３ Alkyl alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group or C ３－６ Selected from cycloalkyloxy groups, y is a compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, selected from 1, 2, or 3.

16. Uses of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 in the manufacture of drugs for treating or preventing chronic kidney disease, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome, preferably wherein the hypertension is refractory hypertension and the chronic kidney disease is chronic kidney disease accompanied by type II diabetes.

17. Application of a compound of the general formula shown in any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 14, in the manufacture of a drug for treating CYP11B2-related diseases.

18. A method for producing a compound represented by formula (V-a-3), (V-a-6), or (V-b-2), its stereoisomer, or a pharmaceutically acceptable salt thereof, 【Chemistry 23】 By coupling formula (V-a-1) and formula (V-a-2), the compound shown in formula (V-a-3), its stereoisomer, or a pharmaceutically acceptable salt thereof is produced, and optionally, by deprotecting formula (V-a-3), the compound shown in formula (V-a-4), its stereoisomer, or a pharmaceutically acceptable salt thereof is obtained. 【Chemistry 24】 Selectively, equation (V-a-4) and X ２ COR ｂ A step of reacting to obtain a compound represented by general formula (V-a), its stereoisomer, or a pharmaceutically acceptable salt thereof, Or, 【Chemistry 25】 By coupling formula (V-b-1) and formula (V-a-2), the compound shown in formula (V-b-2), its stereoisomer, or a pharmaceutically acceptable salt thereof is produced, and optionally, deprotection is performed to obtain the compound shown in formula (V-b-3), its stereoisomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 26】 Selectively, equation (V - b - 3) and X ２ COR ｂ The step of reacting to obtain the compound shown in formula (V-b), its stereoisomer, or its pharmaceutically acceptable salt, Or, 【Chemistry 27】 Equation (V-a-5) and X ２ COR ｂ By reacting them, the compound shown in formula (V-a-6), its stereoisomer, or its pharmaceutically acceptable salt is obtained. 【Chemistry 28】 The process includes the optional step of further coupling formula (V-a-6) with formula (V-a-1) or (V-b-1) to obtain the compound shown in formula (V-a) or formula (V-b), its stereoisomer, or a pharmaceutically acceptable salt thereof. Here, X is a boranyl group, and X １ It is a halogen, and X ２ is a halogen or hydroxyl group, and P is an amino protecting group. M ２ M ５ , L, R ２ , R ｂ A method wherein ring C, ring D, and y are as defined in claim 11.

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