Pyridine polycyclic compound inhibitors, and methods for their preparation and use

Abstract

The present invention relates to pyridine polycyclic compound inhibitors, and their preparation and use. In particular, the present invention relates to compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing the compounds, and their use in drugs for treating chronic kidney disease, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, primary aldosteronism, and Cushing's syndrome, wherein each substituent in general formula (I) is defined as described in the specification.

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 2022114779612, filed November 23, 2022. This application incorporates all of the above Chinese patent applications by reference.

[0002] The present invention belongs to the field of biopharmaceuticals, and specifically relates to a pyridine polycyclic compound inhibitor and its preparation method and use. [Background technology]

[0003] Aldosterone is a steroid hormone secreted by the adrenal gland that binds to and activates the mineralocorticoid receptor (MR). In primary cells of the distal convoluted tubule and collecting duct, MR activation causes sodium and water retention accompanied by potassium excretion, resulting in plasma volume expansion and elevated blood pressure (BP). The renin-angiotensin-aldosterone system (RAAS) is an endocrine system that regulates blood pressure and fluid balance in the human body. Current antihypertensive drugs, including angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), regulate blood pressure by inhibiting this pathway. Patients who take ACEi or ARBs for long periods of time experience "aldosterone breakthrough," in which aldosterone levels temporarily decrease followed by a subsequent increase, causing damage to target organs. The only aldosterone inhibitor currently available on the market is spironolactone, which causes hyperkalemia. Excess aldosterone measured in the circulation is called primary aldosteronism (PA) and occurs when aldosterone production becomes uncontrolled in the renin-angiotensin-aldosterone system (RAAS). PA was first identified in patients with adrenal adenoma, and recent evidence suggests its prevalence is associated with obesity. PA is a common cause of secondary hypertension, occurring in 14%–21% of patients with refractory hypertension (RHTN). Refractory hypertension is characterized by blood pressure still exceeding the target blood pressure of 140 / 90 mmHg despite treatment with three types of antihypertensive medication (calcium channel blockers, angiotensin enzyme inhibitors, angiotensin receptor blockers, and diuretics). Refractory hypertension is a high-risk condition, with a high prevalence of diabetes, chronic kidney disease, and multimorbidity including ischemic heart disease and cerebrovascular disease.

[0004] CYP11B2 is the gene encoding the aldosterone synthase, and has high homology with the gene sequence encoding the cortisol synthase CYP11B1. Developing highly selective CYP11B2 inhibitors to inhibit aldosterone synthesis is the main direction for the treatment of refractory hypertension and primary aldosteronism. Summary of the Invention [Means for solving the problem]

[0005] An object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: [ka] where: [ka] is a single or double bond, Ring A is selected from a phenyl group, a 4- to 7-membered heterocyclyl group, a 5- to 6-membered heteroaryl group, or is absent; Ring B is a 4- to 7-membered heterocyclyl group, a 5- or 6-membered heteroaryl group, or a phenyl group; Ring C is a cycloalkyl group, a heteroaryl group, a heterocyclyl group, or is absent; M1, M2, M4, M5, and M6 are each independently selected from N, NH, or CH; M3 is a bond, N or CH; Each R1 independently represents 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 , -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 , -NR aS(O)(NH)(CH2) n R b or -NS(O)(CH2) n R a R b and optionally the cycloalkyl group, heterocyclyl group, cycloalkyloxy group, heterocyclyloxy group, cycloalkylamino group, heterocyclylamino group, cycloalkylthio group or heterocyclylthio group may further be selected from the group consisting of 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 and is substituted with one or more substituents selected from Or, any two R1's together with adjacent carbon atoms form a 3- to 8-membered cycloalkyl group or a 4- to 7-membered heterocyclyl group, and optionally, the 3- to 8-membered cycloalkyl group or the 4- to 7-membered heterocyclyl group may further include 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 is replaced by R a or R bare each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups, optionally the cycloalkyl, aryl, heteroaryl, or heterocyclyl groups are further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or —S(O)2 alkyl; R2, R3 and R4 are each 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 and 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 together with adjacent atoms form a 3- to 8-membered cycloalkyl group, a 5- to 6-membered heteroaryl group, or a 4- to 7-membered heterocyclyl group, optionally the 3- to 8-membered cycloalkyl group, the 5- to 6-membered heteroaryl group, or the 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 any two R2 together with adjacent atoms form a 3- to 8-membered cycloalkyl group, a 5- to 6-membered heteroaryl group, or a 4- to 7-membered heterocyclyl group, optionally the 3- to 8-membered cycloalkyl group, the 5- to 6-membered heteroaryl group, or the 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 R2 and R4 together with adjacent atoms form a 5- to 14-membered cycloalkyl group, a 5- to 14-membered heteroaryl group, or a 5- to 14-membered heterocyclyl group, optionally the 5- to 14-membered cycloalkyl group, the 5- to 14-membered heteroaryl group, or the 5- to 14-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; 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] When R1 is -NR a C(O)R b and NR a S(O)2R b Instead, M1 is N and ring C is absent, or [ka] If [ka] teeth, [ka] isn't it.

[0006] In some embodiments of the present invention, there is provided a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] where: [ka] is a single or double bond, Ring A is selected from a phenyl group, a 4- to 7-membered heterocyclyl group, a 5- to 6-membered heteroaryl group, or is absent, and when Ring A is absent, R2 is linked to Ring B; Ring B is a 4- to 7-membered heterocyclyl group, a 5- or 6-membered heteroaryl group, or a phenyl group; Ring C is a cycloalkyl group, a heteroaryl group, a heterocyclyl group, or is absent, and when Ring C is absent, R1 is [ka] 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; Each R1 independently represents 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 and optionally the cycloalkyl group, heterocyclyl group, cycloalkyloxy group, heterocyclyloxy group, cycloalkylamino group, heterocyclylamino group, cycloalkylthio group or heterocyclylthio group may further be selected from the group consisting of 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 and is substituted with one or more substituents selected from Or, any two R1's together with adjacent carbon atoms form a 3- to 8-membered cycloalkyl group or a 4- to 7-membered heterocyclyl group, optionally, the 3- to 8-membered cycloalkyl group or the 4- to 7-membered heterocyclyl group further comprises -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 is replaced by R a or R bare each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R2, R3 and R4 are each 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 and 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 together with adjacent atoms form a 3- to 8-membered cycloalkyl group, a 5- to 6-membered heteroaryl group, or a 4- to 7-membered heterocyclyl group, optionally the 3- to 8-membered cycloalkyl group, the 5- to 6-membered heteroaryl group, or the 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 any two R2 together with adjacent atoms form a 3- to 8-membered cycloalkyl group, a 5- to 6-membered heteroaryl group, or a 4- to 7-membered heterocyclyl group, optionally the 3- to 8-membered cycloalkyl group, the 5- to 6-membered heteroaryl group, or the 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; p, x, y, and z are each independently selected from 1, 2, 3, or 4; n is selected from 0, 1, 2 or 3.

[0007] In a preferred embodiment of the present invention, ring A is not selected from a 5- to 10-membered heterocyclyl group or a 5- to 10-membered heteroaryl group containing 1 to 3 selected from C(O), N, O, S, SO2, or SONH.

[0008] In a preferred embodiment of the present invention, ring A is selected from a 5- to 7-membered heterocyclyl group containing 1 to 3 heteroatoms selected from C(O), N, O, S, SO2, and SONH, or a 5- to 6-membered heteroaryl group, preferably a 5- to 7-membered heterocyclyl group containing 2 to 3 heteroatoms selected from N, O, and S, and ring A contains at least one oxygen atom.

[0009] In a preferred embodiment of the invention, ring A is absent.

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

[0011] In a preferred embodiment of the present invention, [ka] teeth, [ka] is selected from.

[0012] In a preferred embodiment of the present invention, ring C is selected from a 3- to 10-membered cycloalkyl group or a 4- to 10-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, S, SO or SONH; In a preferred embodiment of the present invention, ring C is selected from a 5- to 7-membered monocyclic cycloalkyl group, a 6- to 10-membered bicyclic cycloalkyl group, a 5- to 7-membered monocyclic heterocyclyl group containing 1 to 3 groups selected from C(O), N, O, S, SO2, or SONH, and a 7- to 10-membered bicyclic heterocyclyl group containing 1 to 3 groups selected from C(O), N, O, S, SO2, or SONH.

[0013] In a preferred embodiment of the present invention, ring C is [ka] is selected from the group:

[0014] In a preferred embodiment of the present invention, ring C is absent.

[0015] In a preferred embodiment of the present invention, each R1 independently represents a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocyclyl group, a 3- to 8-membered cycloalkyloxy group, a 4- to 8-membered heterocyclyloxy group, a 3- to 8-membered cycloalkylamino group, a 4- to 8-membered heterocyclylamino group, a 3- to 8-membered cycloalkylthio group, a 4- to 8-membered 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 and optionally, the 3- to 10-membered cycloalkyl group, 4- to 10-membered heterocyclyl group, 3- to 8-membered cycloalkyloxy group, 4- to 8-membered heterocyclyloxy group, 3- to 8-membered cycloalkylamino group, 4- to 8-membered heterocyclylamino group, 3- to 8-membered cycloalkylthio group, and 4- to 8-membered heterocyclylthio group may further be selected from the group consisting of an oxo group, a deuterium atom, a halogen atom, an amino group, a hydroxy group, a cyano group, a nitro group, a C 1-6 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 R b , -S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b and is substituted with one or more substituents selected from R a or R b are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 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 1-6a hydroxyalkyl group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 selected from C(O), N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, and optionally the 3- to 8-membered cycloalkyl group, the 5- to 8-membered heteroaryl group containing 1 to 3 selected from C(O), N, O, or S, or the 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S may further include an oxo group, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 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.

[0016] In a preferred embodiment of the present invention, R a or R b are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 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 1-6a hydroxyalkyl group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 selected from C(O), N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, and optionally the 3- to 8-membered cycloalkyl group, the 5- to 8-membered heteroaryl group containing 1 to 3 selected from C(O), N, O, or S, or the 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S may further include an oxo group, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 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, 3- to 6-membered cycloalkyl group or -SO2-C 1-6 It is substituted with one or more substituents selected from alkyl groups.

[0017] In a preferred embodiment of the present invention, each R1 is independently selected from a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, S, SO2, and SONH, a 3- to 8-membered cycloalkyloxy group, a 4- to 8-membered heterocyclyloxy group containing 1 to 3 atoms selected from N, O, S, SO2, and SONH, -C(O)(CH2) n R b , -NR a C(O)(CH2) n R b , -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 Rb and optionally, the 3- to 10-membered cycloalkyl group, the 4- to 10-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, S, SO2 or SONH, the 3- to 8-membered cycloalkyloxy group, and the 4- to 8-membered heterocyclyloxy group containing 1 to 3 atoms selected from N, O, S, SO2 or SONH may further include 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 and is substituted with one or more substituents selected from R a or R b are independently hydrogen, deuterium, and C 1-3 and a 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, and optionally the 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or the 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, may further include an oxo group, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 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 -SO2-C 1-3 It is substituted with one or more substituents selected from alkyl groups.

[0018] In a preferred embodiment of the present invention, each R1 independently represents a 3- to 8-membered cycloalkyl group, a 4- to 8-membered heterocyclyl group, a 3- to 8-membered cycloalkyloxy group, a 4- to 8-membered heterocyclyloxy group, a 3- to 8-membered cycloalkylamino group, a 4- to 8-membered heterocyclylamino group, a 3- to 8-membered cycloalkylthio group, a 4- to 8-membered 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 and optionally, the 3- to 8-membered cycloalkyl group, 4- to 8-membered heterocyclyl group, 3- to 8-membered cycloalkyloxy group, 4- to 8-membered heterocyclyloxy group, 3- to 8-membered cycloalkylamino group, 4- to 8-membered heterocyclylamino group, 3- to 8-membered cycloalkylthio group, and 4- to 8-membered heterocyclylthio group may further be selected from an oxo group, a deuterium atom, a halogen atom, an amino group, a hydroxy group, a cyano group, a nitro group, a C 1-6 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 R b , -S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R band is substituted with one or more substituents selected from R a or R b are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 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 It is selected from a hydroxyalkyl group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 selected from C(O), N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S.

[0019] In a preferred embodiment of the present invention, each R1 is independently selected from a 3- to 8-membered cycloalkyl group, a 4- to 8-membered heterocyclyl group containing 1 to 3 groups selected from N, O, S, SO2, or SONH, a 3- to 8-membered cycloalkyloxy group, a 3- to 8-membered cycloalkylamino group, a 4- to 8-membered heterocyclyloxy group containing 1 to 3 groups selected from N, O, S, SO2, or SONH, a 4- to 8-membered heterocyclylamino group containing 1 to 3 groups selected from N, O, S, SO2, or SONH, or —C(O)(CH2) n R b , -NR a C(O)(CH2) n R b , -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 band optionally, the 3- to 8-membered cycloalkyl group, the 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, S, SO2 or SONH, the 3- to 8-membered cycloalkyloxy group, the 3- to 8-membered cycloalkylamino group, the 4- to 8-membered heterocyclyloxy group containing 1 to 3 atoms selected from N, O, S, SO2 or SONH, or the 4- to 8-membered heterocyclylamino group containing 1 to 3 atoms selected from N, O, S, SO2 or SONH may further include 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 and is substituted with one or more substituents selected from R a or R b are independently hydrogen, deuterium, and C 1-3 and a 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, and optionally the 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or the 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, may further include an oxo group, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 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, 3- to 6-membered cycloalkyl group or -SO2-C 1-3 It is substituted with one or more substituents selected from alkyl groups.

[0020] Or R a or R b are each independently selected from a halogen, a hydroxy group, or a cyano group.

[0021] In a preferred embodiment of the present invention, each R1 is independently selected from a 3- to 8-membered cycloalkyl group, a 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, S, SO2, and SONH, a 3- to 8-membered cycloalkyloxy group, a 4- to 8-membered heterocyclyloxy group containing 1 to 3 atoms selected from N, O, S, SO2, and SONH, -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 and optionally, the 3- to 8-membered cycloalkyl group, the 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, S, SO2 or SONH, the 3- to 8-membered cycloalkyloxy group, and the 4- to 8-membered heterocyclyloxy group containing 1 to 3 atoms selected from N, O, S, SO2 or SONH may further include 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 and is substituted with one or more substituents selected from R a or R bare independently hydrogen, deuterium, and C 1-3 It is selected from an alkyl group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S.

[0022] In a preferred embodiment of the present invention, R2, R3, and R4 are each independently hydrogen, deuterium, halogen, an amino group, a hydroxy group, a cyano group, a nitro group, C 1-6 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- to 8-membered cycloalkyl group, 3- to 8-membered cycloalkyloxy group, 3- to 8-membered cycloalkylamino group, C 6-10 an aryl group, a 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from C(O), N, O, and S; -NR a R b , -NR a C(O)R b or -C(O)NR a R b is selected from.

[0023] In a preferred embodiment of the present invention, R2, R3, and R4 are each independently hydrogen, deuterium, halogen, an amino group, a hydroxy group, a cyano group, a nitro group, C 1-6 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 1-6a hydroxyalkyl group, a 3- to 8-membered cycloalkyl group, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, -NR a C(O)R b or -C(O)NR a R b is selected from R a or R b are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 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 It is selected from a hydroxyalkyl group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 selected from C(O), N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S.

[0024] Or R a or R b are each independently selected from a halogen, a hydroxy group, or a cyano group.

[0025] In a preferred embodiment of the present invention, R2, R3, and R4 are each independently hydrogen, deuterium, halogen, C 1-3 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 cycloalkyloxy groups.

[0026] In a preferred embodiment of the present invention, R2, R3, and R4 are each independently hydrogen, deuterium, halogen, C 1-3 Alkyl group, C 1-3Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 haloalkoxy group or C 1-3 The group is selected from hydroxyalkyl groups.

[0027] In a preferred embodiment of the present invention, any two R2s together with adjacent atoms form a 3- to 8-membered cycloalkyl group, a 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S, or a 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S, and optionally, the 3- to 8-membered cycloalkyl group, the 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S, or the 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S may further include an oxo group, deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 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 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0028] In a preferred embodiment of the present invention, any two R1's together with adjacent atoms form a 3- to 8-membered cycloalkyl group or a 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S, and optionally, the 3- to 8-membered cycloalkyl group or the 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S may further include 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 is replaced with one or more selected from:

[0029] In a preferred embodiment of the present invention, R2 and R3 together with adjacent atoms form a 3- to 8-membered cycloalkyl group, a 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S, or a 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S, and optionally, the 3- to 8-membered cycloalkyl group, the 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S, or the 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S may further contain deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 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 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0030] In a preferred embodiment of the present invention, R2 and R4 together with adjacent atoms form a 6- to 12-membered cycloalkyl group, a 6- to 12-membered heteroaryl group containing 1 to 4 atoms selected from N, O, and S, or a 6- to 12-membered heterocyclyl group containing 1 to 4 atoms selected from N, O, and S, and optionally, the 6- to 12-membered cycloalkyl group, the 6- to 12-membered heteroaryl group containing 1 to 4 atoms selected from N, O, and S, or the 6- to 12-membered heterocyclyl group containing 1 to 4 atoms selected from N, O, and S may further contain deuterium, halogen, amino group, hydroxy group, cyano group, C 1-6 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 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0031] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by general formula (II-a) or (II-c), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] where: Ring A is a 5- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from C(O), N, O, S, SO2, or SONH, or is absent; Ring B is selected from a phenyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S; R2, R3, and R4 are each independently hydrogen, deuterium, halogen, or C 1-3 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 Hydroxyalkyl group, -NR a C(O)R b or -C(O)NR a R b is selected from R a or R b are independently hydrogen, deuterium, and C 1-3 an alkyl group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 atoms selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from C(O), N, O, or S; Alternatively, any two R2 are selected from adjacent atoms and a 3- to 8-membered cycloalkyl group, a 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S, or a 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S, and optionally, the 3- to 8-membered cycloalkyl group, the 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S, or the 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S may further include deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 Alkyl group, C1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 substituted with one or more substituents selected from hydroxyalkyl groups; Alternatively, R2 and R3 together with adjacent atoms form a 3- to 8-membered cycloalkyl group or a 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S, and optionally, the 3- to 8-membered cycloalkyl group or the 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S may further contain deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 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 one or more substituents selected from hydroxyalkyl groups; Alternatively, R2 and R4 together with adjacent atoms form a 6- to 12-membered cycloalkyl group, a 6- to 12-membered heteroaryl group containing 1 to 4 atoms selected from N, O, and S, or a 6- to 12-membered heterocyclyl group containing 1 to 4 atoms selected from N, O, and S, and optionally, the 6- to 12-membered cycloalkyl group, the 6- to 12-membered heteroaryl group containing 1 to 4 atoms selected from N, O, and S, or the 6- to 12-membered heterocyclyl group containing 1 to 4 atoms selected from N, O, and S may further contain deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 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 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0032] In a more preferred embodiment of the present invention, the general formula (II-a) is further represented by the general formula (II-a-1) or (II-a-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0033] In a more preferred embodiment of the present invention, the general formula (II-c) is further represented by general formula (II-c-1) or (II-c-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0034] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by general formula (II-b), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] where: Ring A is absent, a 5- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from C(O), N, O, S, SO2, or SONH, or is absent; Ring B is selected from a phenyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S; R1 is a 3- to 8-membered cycloalkyl group, a 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, S, SO2, or SONH, a 3- to 8-membered cycloalkyloxy group, a 4- to 8-membered heterocyclyloxy group containing 1 to 3 atoms selected from N, O, S, SO2, or SONH, -C(O)(CH2) n R b , -NR a C(O)(CH2) n R b , -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 aS(O)(NH)(CH2) n R b and optionally, the 3- to 8-membered cycloalkyl group, the 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, S, SO2 or SONH, the 3- to 8-membered cycloalkyloxy group, and the 4- to 8-membered heterocyclyloxy group containing 1 to 3 atoms selected from N, O, S, SO2 or SONH may further include 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 and is substituted with one or more substituents selected from R2, R3, and R4 are each independently hydrogen, deuterium, halogen, or C 1-3 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, -NR a C(O)R b or -C(O)NR a R b is selected from R a or R b are independently hydrogen, deuterium, and C 1-3 and a 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, and optionally the 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or the 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, may further include an oxo group, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3Alkyl 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 -SO2-C 1-3 substituted with one or more substituents selected from alkyl groups; Alternatively, any two R2 are selected from adjacent atoms and a 3- to 8-membered cycloalkyl group, a 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S, or a 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S, and optionally, the 3- to 8-membered cycloalkyl group, the 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S, or the 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S may further include deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 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 one or more substituents selected from hydroxyalkyl groups; Alternatively, R2 and R3 together with adjacent atoms form a 3- to 8-membered cycloalkyl group or a 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S, and optionally, the 3- to 8-membered cycloalkyl group or the 4- to 7-membered heterocyclyl group containing 1 to 3 atoms selected from N, O, and S may further contain deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 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 one or more substituents selected from hydroxyalkyl groups; Alternatively, R2 and R4 together with adjacent atoms form a 6- to 12-membered cycloalkyl group, a 6- to 12-membered heteroaryl group containing 1 to 4 atoms selected from N, O, and S, or a 6- to 12-membered heterocyclyl group containing 1 to 4 atoms selected from N, O, and S, and optionally, the 6- to 12-membered cycloalkyl group, the 6- to 12-membered heteroaryl group containing 1 to 4 atoms selected from N, O, and S, or the 6- to 12-membered heterocyclyl group containing 1 to 4 atoms selected from N, O, and S may further contain deuterium, halogen, amino group, hydroxy group, cyano group, C 1-3 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 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0035] In a more preferred embodiment of the present invention, the general formula (I) is further represented by general formula (III-a)-(III-d), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [ka] Ring C is selected from a 5- to 7-membered monocyclic cycloalkyl group, a 6- to 10-membered bicyclic cycloalkyl group, a 5- to 7-membered monocyclic heterocyclyl group containing 1 to 3 groups selected from C(O), N, O, S, SO2 or SONH, and a 7- to 10-membered bicyclic heterocyclyl group containing 1 to 3 groups selected from C(O), N, O, S, SO2 or SONH; Or, ring C is absent, L is a bond, -O-, -R c C(O)-, -R c S(O)NH- or -R c S(O)2, preferably -NHC(O)-; R cis selected from a bond, NH, a 3- to 8-membered cycloalkyl group, a 4- to 8-membered heterocyclyl group containing 1 to 3 groups selected from N, O, S, SO2, or SONH, a 3- to 8-membered cycloalkyloxy group, and a 4- to 8-membered heterocyclyloxy group containing 1 to 3 groups selected from N, O, S, SO2, or SONH; R2, R3, and R4 are each independently hydrogen, deuterium, halogen, or C 1-3 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 cycloalkyl groups, R b represents hydrogen, deuterium, halogen, hydroxyl group, cyano group, C 1-3 an alkyl group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 atoms selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from C(O), N, O, S, SO2, or SONH; y is 1, 2 or 3.

[0036] 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- to 7-membered monocyclic cycloalkyl group, a 6- to 10-membered bicyclic cycloalkyl group, a 5- to 7-membered monocyclic heterocyclyl group containing 1 to 3 groups selected from C(O), N, O, S, SO2 or SONH, and a 7- to 10-membered bicyclic heterocyclyl group containing 1 to 3 groups selected from C(O), N, O, S, SO2 or SONH; Or, ring C is absent, L is a bond, -O-, -R c C(O)-, -R c S(O)NH- or -R cS(O)2, R c is selected from a bond, NH, a 3- to 8-membered cycloalkyl group, a 4- to 8-membered heterocyclyl group containing 1 to 3 groups selected from N, O, S, SO2, or SONH, a 3- to 8-membered cycloalkyloxy group, and a 4- to 8-membered heterocyclyloxy group containing 1 to 3 groups selected from N, O, S, SO2, or SONH; R2 and R4 are each independently hydrogen, deuterium, halogen, or C 1-3 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 hydroxyalkyl groups, R b are hydrogen, deuterium, and C 1-3 an alkyl group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 atoms selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from C(O), N, O, S, SO2, or SONH; y is 1, 2 or 3.

[0037] In a further preferred embodiment of the present invention, [ka] teeth, [ka] is selected from the group:

[0038] In a more preferred embodiment of the present invention, the compound represented by general formula (I) is further represented by general formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] where: M2 is selected from N or CH; Ring C is selected from a 5- to 7-membered monocyclic cycloalkyl group, a 6- to 10-membered bicyclic cycloalkyl group, a 5- to 7-membered monocyclic heterocyclyl group containing 1 to 3 groups selected from C(O), N, O, S, SO2 or SONH, a 7- to 10-membered bicyclic heterocyclyl group containing 1 to 3 groups 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 or a 4- to 8-membered nitrogen-containing heterocyclyl group, said 4- to 8-membered nitrogen-containing heterocyclyl group optionally further comprising —C(O)R b or -S(O)2R b is replaced by R a or R b are each independently hydrogen, deuterium, halogen, hydroxy group, cyano group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 a haloalkoxy group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 atoms selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from C(O), N, O, or S; R2 is hydrogen, deuterium, halogen, C 1-3 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 cycloalkyloxy groups.

[0039] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by general formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [ka] where: L is NR a , O or S; L1 is selected from C(O) or S(O)2; R a are hydrogen, deuterium, halogens, C 1-3 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 cycloalkyloxy groups; M2 is selected from N or CH; M3 is selected from N or CH; R2 is hydrogen, deuterium, halogen, C 1-3 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 cycloalkyloxy groups; or any two R2 together with adjacent atoms form a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 atoms selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from C(O), N, O, or S; R b are independently hydrogen, deuterium, and C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3a haloalkoxy group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, and optionally the 3- to 8-membered cycloalkyl group, the 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or the 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S may further include a halogen, a hydroxy group, an amino group, CN, C 1-3 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; R5 is independently hydrogen, deuterium, halogen, or C 1-3 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 cycloalkyloxy groups; R6 is hydrogen, deuterium, halogen, C 1-3 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 cycloalkyl groups, or any two R5 together with adjacent carbon atoms form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclyl group; 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.

[0040] In a more preferred embodiment of the present invention, R2 is selected from a methyl group or a methoxy group and y is 1.

[0041] In a more preferred embodiment of the invention, M2 is N and M3 is CH.

[0042] In a more preferred embodiment of the present invention, R b is C 1-3 and optionally, the 3- to 6-membered cycloalkyl group or the 5- to 6-membered heteroaryl group containing 1 to 3 selected from N, O, or S may further include a halogen atom, a hydroxy group, CN, or C. 1-3 It is substituted with an alkyl group.

[0043] In a more preferred embodiment of the present invention, q, r, s, and t are all 1.

[0044] In another aspect, the present invention also relates to pharmaceutical compositions, which comprise a therapeutically effective amount of any one of the compounds of the respective general formulas shown, its stereoisomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0045] In some embodiments of the present invention, the weight percentage of the compound, its stereoisomer, or its pharmaceutically acceptable salt in the pharmaceutical composition, based on the free base, 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%.

[0046] In some embodiments of the present invention, the pharmaceutical composition is selected from a tablet, a capsule, a liquid formulation, or an injectable solution, preferably further comprising a filler, and optionally further comprising a disintegrant, or further comprising one or more of a glidant or a lubricant.

[0047] In some embodiments of the invention, the pharmaceutical composition is an immediate release formulation or a sustained release formulation.

[0048] In some embodiments of the present invention, the pharmaceutical composition has a unit dose of the compound, its stereoisomer, or its pharmaceutically acceptable salt, based on the free base, of 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.

[0049] In some embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof may be administered in any convenient manner, for example, orally, parenterally, bucally, sublingually, nasally, rectally, intrathecally or transdermally, and in a pharmaceutical composition adjusted accordingly.

[0050] In some embodiments of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt may be formulated as a liquid or solid preparation, for example, a syrup, suspension, emulsion, tablet, capsule, powder, granule, or lozenge.

[0051] In another aspect, the present invention further relates to the use of any of the compounds of the general formula shown, its stereoisomers or pharmaceutically acceptable salts thereof, or said pharmaceutical compositions in the manufacture of a medicament for treating a CYP11B2-related disease.

[0052] The present invention further relates to the use of a compound represented by the general formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating or preventing chronic kidney disease, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome.

[0053] In a preferred embodiment of the present invention, the hypertension is refractory hypertension.

[0054] In some embodiments, the EC value of the compounds of the present invention for CYP11B2 50 The EC value of the preferred compounds for CYP11B2 is 0.0001 μM to 50 μM. 50 The EC value of the compound is 0.0001 μM to 10 μM. 50 The EC value of the compound is 0.0001 μM to 1 μM. 50 The value is 0.0001 μM to 0.1 μM.

[0055] In addition, the compounds of the present invention have good selectivity for CYP11B1, with the selectivity being greater than 50, with preferred compounds having a selectivity greater than 100, more preferred compounds having a selectivity greater than 200, and even more preferred compounds having a selectivity greater than 500.

[0056] In another aspect, the present invention provides a method for preparing a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising: [ka] The method comprises the steps of reacting compound (Ia) with a boron compound to produce compound (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and then coupling the compound (Ic) with compound (Ic), a stereoisomer thereof or a pharmaceutically acceptable salt thereof to produce a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof; the catalyst for the coupling reaction is a palladium reagent, preferably palladium acetate, tetrakistriphenylphosphinepalladium, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium; X is a halogen, preferably bromine; Z is a boron-containing compound, preferably a dioxaborolanyl group; Ring A, ring B, R1, R2, R3, R4, M1, M2, M3, M4, M5, M6, x, y, z and p are as defined in general formula (I).

[0057] Preferably, the present invention provides a method for preparing a compound represented by general formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [ka] The method comprises the steps of reacting compound (IV-a) with borane to produce compound (IV-b), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and then coupling the compound with compound (IV-c), a stereoisomer thereof or a pharmaceutically acceptable salt thereof to produce a compound represented by general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof; the catalyst for the coupling reaction is a palladium reagent, preferably palladium acetate, tetrakistriphenylphosphinepalladium, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium; X is a halogen, preferably bromine; Z is a boranyl group, preferably dioxaborolane; Ring C, R1, R2, and M2 are as defined in general formula (IV). DETAILED DESCRIPTION OF THE INVENTION

[0058] Unless stated to the contrary, terms used in the specification and claims have the following meanings.

[0059] The term "alkyl group" refers to a saturated aliphatic or hydrocarbon group, which is a straight or branched chain 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, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, and 5-methylhexyl groups. , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available linkage site. 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, hydroxy 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, and carboxylate groups. In the present invention, preferred are 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 hydroxy groups.

[0060] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the ring of the 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, cyclooctyl, etc. Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0061] The term "spirocycloalkyl group" refers to a 5- to 20-membered polycyclic group in which monocyclic rings share one carbon atom (called a spiro atom), which may contain one or more double bonds, but in which none of the rings has a completely conjugated π-electron system. It is preferably 6- to 14-membered, more preferably 7- to 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, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. More preferred 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 include: [ka] Including, Also included are spirocycloalkyl groups in which the monospirocycloalkyl group and the heterocycloalkyl group share a spiro atom, non-limiting examples of which are: [ka] Includes:

[0062] The term "fused cycloalkyl group" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, where one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, it may be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic cycloalkyl groups. Non-limiting examples of fused cycloalkyl groups are: [ka] Includes:

[0063] A "bridged cycloalkyl group" refers to a 5- to 20-membered all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, and it may contain one or more double bonds, but no ring has a completely conjugated π-electron system. It is preferably 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, bridged cycloalkyl groups may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and are preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include the following: [ka]

[0064] The ring of the cycloalkyl group can be fused onto the ring of an aryl group, a heteroaryl group, or a heterocycloalkyl group, where the ring connected to the base skeleton is a cycloalkyl group, non-limiting examples of which include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, etc. The cycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy 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, and carboxylate groups.

[0065] The term "heterocyclyl group" refers to a saturated or partially unsaturated mono- or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more of the ring atoms is nitrogen, oxygen, or S(O). m (where m is an integer of 0 to 2), but does not include the ring moiety -OO-, -OS-, or -SS-, and the other ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 8 ring atoms, most preferably 3 to 8 ring atoms, and even more preferably 3 to 8-membered heterocyclyl groups containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, and includes nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spiroheterocyclyl groups, and nitrogen-containing fused heterocyclyl groups.

[0066] Non-limiting examples of monocyclic heterocyclyl groups include azetidine, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazacycloheptyl, pyranyl, etc., and preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazacycloheptyl, and piperazinyl. Polycyclic heterocyclyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclyl groups, where such spirocyclic, fused-ring, and bridged-ring heterocyclyl groups are optionally linked to other groups via a single bond or further linked in a tandem ring to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups via any two or more atoms on the ring.

[0067] The term "spiroheterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which the monocyclic rings share one atom (called a spiroatom), where one or more of the ring atoms is nitrogen, oxygen, or S(O). m (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 none of the rings has a completely conjugated π-electron system. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of shared spiro atoms between the rings, spiroheterocyclyl groups are divided into monospiroheterocyclyl groups, bisspiroheterocyclyl groups, and polyspiroheterocyclyl groups, and preferred are monospiroheterocyclyl groups and bisspiroheterocyclyl groups. More preferred are 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl groups. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes:

[0068] The term "fused heterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and wherein one or more ring atoms is nitrogen, oxygen, or S(O) m (where m is an integer of 0 to 2), and the other ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings constituting it, it may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably a bicyclic or tricyclic, 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] Includes:

[0069] The term "bridged heterocyclyl group" refers to a 5- to 14-membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, which may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and in which one or more ring atoms is not nitrogen, oxygen, or S(O). m (where m is an integer of 0 to 2), and the other ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings constituting it, it may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclyl groups are: [ka] Includes:

[0070] The ring of the heterocyclyl group may be fused onto the ring of an aryl group, a heteroaryl group, or a cycloalkyl group, where the ring connected to the base skeleton is a heterocyclyl group, non-limiting examples of which are: [ka] This includes, but is not limited to:

[0071] Heterocyclyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy 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.

[0072] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl groups. Phenyle is more preferred. The ring of the aryl group may be fused to a heteroaryl group, heterocyclyl group, or cycloalkyl group, including 5- to 10-membered benzoheteroaryl groups, 3- to 8-membered benzocycloalkyl groups, and 3- to 8-membered benzoheteroalkyl groups, preferably 5- to 6-membered benzoheteroaryl groups, 3- to 6-membered benzocycloalkyl groups, and 3- to 6-membered benzoheteroalkyl groups, where the heterocyclyl group is a heterocyclyl group containing 1 to 3 nitrogen, oxygen, or sulfur atoms, or further containing a 3-membered nitrogen-containing fused ring containing a benzene ring.

[0073] Here, the ring connected to the basic skeleton is an aryl group ring, and non-limiting examples thereof include: [ka] Includes:

[0074] The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy 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.

[0075] 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 examples thereof include imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyridinyl groups, and is preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl, more preferably pyrazolyl, pyrrolyl, and oxazolyl. The ring of the heteroaryl group may be fused to the ring of an aryl group, heterocyclyl group, or cycloalkyl group, where the ring connected to the basic skeleton is the ring of the heteroaryl group, and non-limiting examples thereof include: [ka] Includes:

[0076] Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy 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.

[0077] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. An alkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

[0078] "Haloalkyl group" refers to an alkyl group that is substituted with one or more halogens, where alkyl group is as defined above.

[0079] A "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0080] "Hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, where alkyl group is as defined above.

[0081] The term "alkenyl group" refers to a chain alkenyl group, also known as an olefin group, and refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group, which contains at least one carbon-carbon double bond, and the carbon-carbon double bond may be located at any position within the alkenyl group. The alkenyl group is a group having 2 to 20 carbon atoms (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 to 3 (C 2-3 ) carbon atoms. Non-limiting examples of alkenyl groups are: [ka] Includes.

[0082] wherein 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, hydroxy 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.

[0083] An "alkynyl group" refers to (CH≡C-), which contains at least one carbon-carbon triple bond, and which may be located at any position within the alkynyl group, and which contains at least one carbon-carbon double bond, and which may be located at any position within the alkynyl group, and which has 2 to 20 carbon atoms (C 2-20 ), 2~15(C 2-15 ), 2~12(C2-12 ), 2~10(C 2-10 ), 2~8(C 2-8 ), 2~6(C 2-6 ), 2~4(C 2-4 ) or 2 to 3 (C 2-3 ) carbon atoms. Non-limiting examples of alkynyl groups are: [ka] wherein 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, hydroxy 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.

[0084] The term "alkenylcarbonyl group" refers to -C(O)-(alkenyl group), where the definition of alkenyl group is as defined above. Non-limiting examples of alkenylcarbonyl groups include vinylcarbonyl, propenylcarbonyl, and butenylcarbonyl groups. An alkenylcarbonyl group may be optionally substituted or unsubstituted; if substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

[0085] [ka] refers to a single or double bond.

[0086] "Hydroxy" refers to an -OH group.

[0087] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0088] An "amino group" refers to -NH2.

[0089] A "cyano group" refers to -CN.

[0090] A "nitro group" refers to -NO2.

[0091] A "carbonyl group" refers to -C(O)-.

[0092] A "carboxyl group" refers to -C(O)OH.

[0093] Various terms 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 mean the same thing, i.e., X can be any one or more of A, B, and C.

[0094] Any hydrogen atom described in the present invention may be substituted with its isotope, deuterium, and any hydrogen atom in the compounds of the examples of the present invention may also be substituted with a deuterium atom.

[0095] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes instances where the event or circumstance has occurred or not occurred. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group and instances where the heterocyclyl group is not substituted with an alkyl group.

[0096] "Substituted" refers to the fact that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced with the corresponding number of substituents. Needless to say, substituents are present only at their possible chemical positions, and a person skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable if it is bound to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0097] A "pharmaceutical composition" is meant to contain a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, as well as other components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and promote absorption of the active ingredients, thereby exerting their biological activity.

[0098] "Pharmaceutically acceptable salt" "Pharmaceutically acceptable salt" refers to salts of compounds of the present invention, which are safe and effective when used in a mammalian body and possess the desired biological activity. [Example]

[0099] Example The structure of the compound is confirmed by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR displacements (δ) are 10 -6 The NMR data were measured using a Bruker AVANCE-400 nuclear magnetometer in deuterated dimethyl sulfoxide (DMSO-d), deuterated chloroform (CDCl), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0100] For MS measurements, a FINNIGAN LCQAd(ESI) mass spectrometer (manufacturer: Thermo, model number: Finnigan LCQ advantage MAX) was used.

[0101] For the HPLC measurements, an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm chromatography column) were used.

[0102] Kinase mean inhibition rate and IC 50 The values ​​were measured using a NovoStar plate reader (BMG, Germany).

[0103] Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates were used for thin-layer chromatography (TLC). The silica gel plates used were 0.15mm to 0.2mm in diameter, and 0.4mm to 0.5mm in diameter for product separation and purification by thin-layer chromatography.

[0104] For column chromatography, Yantai Yellow Sea silica gel 200-300 mesh silica gel was generally used as the carrier.

[0105] Known starting materials of the present invention can be synthesized by methods known in the art or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals, etc.

[0106] Unless otherwise specified in the examples, all reactions can be carried out under an argon gas atmosphere or a nitrogen gas atmosphere.

[0107] The argon or nitrogen gas atmosphere means that a balloon of argon or nitrogen gas with a volume of about 1 L is connected to the reaction flask.

[0108] The hydrogen gas atmosphere is defined as a balloon of hydrogen gas with a volume of approximately 1 L connected to the reaction flask.

[0109] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenation apparatus and a Seiran QL-500 hydrogen gas generator or an HC2-SS hydrogenation apparatus were used.

[0110] The hydrogenation reaction was usually carried out by repeating the process of evacuating and filling with hydrogen gas three times.

[0111] For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

[0112] Unless otherwise stated in the examples, the solutions are aqueous solutions.

[0113] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0114] In the examples, thin layer chromatography (TLC) was used to monitor the reaction process. The developer systems used in the reactions were as follows: 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 depending on the polarity of the compounds.

[0115] The eluent systems for column chromatography and the developer systems for thin-layer chromatography used to purify the compounds include the following: A: dichloromethane and methanol system; B: n-hexane and ethyl acetate system; and C: dichloromethane and acetone system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and can also be adjusted by adding small amounts of alkaline or acidic reagents such as triethylamine and acetic acid.

[0116] Intermediates Intermediate Im-1 [ka]

[0117] Step 1. Ethyl 5-bromo-4-methyl-pyridine-3-carboxylate 5-Bromo-4-methyl-pyridine-3-carboxylic acid (20 g, 92.58 mmol) was dissolved in anhydrous N,N-dimethylcarboxamide (200 mL), and absolute 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. The reaction mixture was stirred at room temperature (20 °C) for 16 hours. After completion of the reaction, the reaction was quenched by adding water (50 mL), extracted with ethyl acetate (100 mL × 3), washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude ethyl 5-bromo-4-methyl-pyridine-3-carboxylate (21 g, crude). MSm / z(ESI):244.0, 246.0[M+1].

[0118] Step 2: 4-Bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylate methyl Ethyl 5-bromo-4-methyl-pyridine-3-carboxylate (7 g, 28.68 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL). Lithium diisopropylamide (2 M, 17.21 mL) was added dropwise thereto at -78 °C. Stirring was maintained at -78 °C for 1 hour, and methyl acrylate (6.17 g, 71.70 mmol, 6.46 mL) was then slowly added thereto. The reaction mixture was allowed to warm to room temperature and stirred for 5 hours. After completion of the reaction, water (20 mL) was slowly added dropwise thereto to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column purification (PE / EtOAc=3:1, uv=254 nm), and finally the product methyl 4-bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylate (4 g, 14.0 mmol, yield: 48.8%) was obtained. MSm / z(ESI):284.0, 286.0[M+1].

[0119] Step 3: 4-Bromo-6,7-dihydro-5H-isoquinolin-8-one Methyl 4-bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylate (7 g, 24.64 mmol) was dissolved in 6 M hydrochloric acid (30 mL). The reaction mixture was stirred in an oil bath at 100 °C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and the pH was adjusted to 7-8 with 6 M sodium hydroxide solution. The mixture was washed with ethyl acetate (50 mL x 3) and saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 4-bromo-6,7-dihydro-5H-isoquinolin-8-one (4.8 g, 21.23 mmol, yield: 86.17%). The crude product was used directly in the next step. MSm / z(ESI):226.0, 228.0[M+1].

[0120] Step 4 4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-amine 4-Bromo-6,7-dihydro-5H-isoquinolin-8-one (7 g, 30.96 mmol) was dissolved in ammonia-methanol solution (2 M, 100 mL), and tetraisopropyl titanate (17.60 g, 61.93 mmol, 18.33 mL) was added thereto. The reaction mixture was stirred at 20°C for 16 hours, and then sodium borohydride (1.76 g, 46.45 mmol) was added thereto in an ice-water bath in small portions. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added.

[0121] The reaction was quenched, 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 give the crude product, which was then purified by column chromatography (dichloromethane:methanol = 10:1, UV = 254 nm) to give 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (4.5 g, 19.82 mmol, yield: 63.99%). MSm / z(ESI):227.0, 229.0[M+1].

[0122] Step 5 (R)-4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-amine The following chiral separation was performed on 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (4.5 g, 19.82 mmol) to give the P1 and Im-1 products. [ka]

[0123] [Table 1] MSm / z(ESI):227.0, 229.0[M+1].

[0124] Example 1 N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide [ka]

[0125] 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). Sodium hydride (78.92 mg, 3.29 mmol, 60% purity) was added at 0 °C, and the reaction mixture was stirred at 25 °C for 10 hours. The reaction was stopped, quenched by adding water (5 mL), extracted with ethyl acetate (5 mL × 2), the combined organic phases were 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 give the title product, 6-bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (410 mg, yellow solid). The yield was 77.2%. MSm / z(ESI):242.0, 244.0[M+1].

[0126] 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)diboron (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 atmosphere was purged with nitrogen gas three times, and the reaction solution was stirred at 90°C for 10 hours. The reaction was stopped, cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using 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). The yield was 61.2%. MS m / z(ESI):290.1[M+1].

[0127] Step 3 N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide In a 25 mL reaction flask, 4-bromo-5,6,7,8-tetrahydroisoquinolin-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, quenched by adding water (5 mL), extracted with dichloromethane (5 mL × 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 give the title product, N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (500 mg). The yield was 80.2%. MSm / z(ESI):283.0, 285.0[M+1].

[0128] Step 4 N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide N-(4-Bromo-5,6,7,8-tetrahydroisoquinolin-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 atmosphere was purged with nitrogen gas three times, 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 extracted with ethyl acetate (5 mL × 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 give the title product N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (75 mg). The yield was 58.2%. MS m / z(ESI):366.2[M+1]. 1 H NMR(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).

[0129] Example 1 was divided to obtain 1-A and 1-B.

[0130] [Table 2]

[0131] Example 2 N-(4-(4-methyl-3-carbonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide [ka]

[0132] Referring to the synthetic route of Example 1, 6-bromo-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was replaced with 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one to obtain the title product N-(4-(4-methyl-3-carbonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide. MS m / z(ESI):366.2[M+1]. 1 H NMR(400MHz,DMSO) δ8.33(s,1H),8.27(d,1H),8.20(s,1H),7.25(d,1H),7.05(dd,1H),7.01(d,1H),5.09(q,1H ),4.71(s,2H),3.32(s,3H),2.60(t,2H),2.23-2.08(m,2H),1.95-1.60(m,4H),1.05(t,3H).

[0133] Example 2 was split to give 2-A and 2-B.

[0134] [Table 3]

[0135] Examples 3-56 were obtained by referring to the similar preparation method of Example 1.

[0136] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6]

[0137] Example 4 [ka]

[0138] Step 1, Step 2 1-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one. Using 7-bromo-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one as a starting material, 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one was obtained in the same manner as in Steps 1 and 2 of Example 1. MS m / z(ESI):302.2[M+1].

[0139] Step 3 N-(4-(1-methyl-2-carbonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide In a similar manner to Step 4 of Example 1, 7-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one was obtained. MS m / z(ESI):322.2[M+1].

[0140] Step 4 N-(4-(1-methyl-2-carbonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide In a similar manner to Step 3 of Example 1, N-(4-(1-methyl-2-carbonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide was obtained. MS m / z(ESI):378.2[M+1].

[0141] Example 10 N-(4-(8-methyl-7-carbonyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide [ka]

[0142] Step 1 6-Bromo-1-methyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one 6-Bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one (5 g, 22.02 mmol) was dissolved in N,N-dimethylcarboxamide (100 mL). Potassium tert-butoxide (4.94 g, 44.04 mmol) was slowly added to the solution in an ice-water bath. After stirring for 0.5 hours, iodomethane (4.69 g, 33.03 mmol, 2.06 mL) was added dropwise. The reaction mixture was stirred at room temperature (20 °C) for 5.5 hours. After completion of the reaction, the reaction was quenched by slowly adding water (10 mL) in an ice-water bath. The mixture was extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was subjected to column purification (PE / EtOAc=3:1, uv=254 nm), and finally a pale yellow solid 6-bromo-1-methyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one (4 g, yield 75.3%) was obtained. MSm / z(ESI):241.0, 243.0[M+1].

[0143] Step 2 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one 6-Bromo-1-methyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one (2.5 g, 10.37 mmol) was dissolved in dioxane (50 mL), and bis(pinacolato)diboron (3.16 g, 12.44 mmol), potassium acetate (2.04 g, 20.74 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (752.49 mg, 1.04 mmol) were added in small portions. The reaction mixture was purged with nitrogen gas multiple times and then stirred in an oil bath at 100 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, diluted with water (10 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was then purified by column chromatography (PE / EtOAc = 5:1, UV = 254 nm) to give a white solid, 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (2.4 g, 8.33 mmol, yield: 80.32%). MS m / z(ESI):289.1[M+1].

[0144] Step 3 N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide In a 25 mL reaction flask, 4-bromo-5,6,7,8-tetrahydroisoquinolin-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, quenched by adding water (5 mL), extracted with dichloromethane (5 mL × 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 give the title product, N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (500 mg, yellow solid). The yield was 80.2%. MS m / z(ESI):283.0[M+1].

[0145] Step 4 N-(4-(8-methyl-7-carbonyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (333.06 mg, 1.16 mmol) and N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (328 mg, 1.16 mmol) were dissolved in a mixture of HO (5 mL) and EtOH (25 mL), followed by the addition of sodium carbonate (246 mg, 2.32 mmol) and tetrakis(triphenylphosphine)palladium (127.21 mg, 110.08 μmol). The reaction mixture was purged with nitrogen gas multiple times and then stirred in an oil bath at 100°C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was then purified by column chromatography (DCM / MeOH = 10:1, UV = 254 nm) to finally give N-(4-(8-methyl-7-carbonyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (200 mg, yield: 58.92%). MS m / z(ESI):365.1[M+1]. 1 H NMR(400MHz,DMSO) δ8.36(s,1H),8.29(d,1H),8.25(s,1H),8.22(d,1H),7.72(d,1H),5.10(q,1H),3.36( s,3H),2.95(dd,2H),2.73-2.59(m,4H),2.15(qd,2H),1.96-1.60(m,4H),1.05(t,3H).

[0146] Example 10 was split to give 10-A and 10-B.

[0147] [Table 5]

[0148] Example 37 (R)-2-(Dicyclo[1.1.1]pentan-1-yl)-N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide [ka]

[0149] Using Intermediate Im-1 as the starting material, the product (R)-2-(dicyclo[1.1.1]pentan-1-yl)-N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide was obtained by referring to Example 1. MS m / z(ESI):416.2[M+1].

[0150] Example 48 [ka]

[0151] Step 1 4-Bromo-7,7-dimethoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-6-ol Potassium hydroxide (5.29 g, 94.32 mmol) was dissolved in methanol (50 mL) and, under cooling in an ice-water bath and nitrogen gas protection, 4-bromo-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one was added. The mixture was stirred at 0 °C for 5 minutes. Iodobenzene diacetate (6.08 g, 18.86 mmol) was then added. The mixture was stirred at 18 °C for 4 hours. The reaction mixture was evaporated to dryness at low temperature, and the crude product was quenched with saturated brine (100 mL) and extracted with ethyl acetate (50 mL × 3). The mixture was separated, and the organic phases were combined and washed with saturated brine (100 mL × 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 (eluting with dichloromethane:methanol = 100:0 to 95:5) to obtain the desired product, 4-bromo-7,7-dimethoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-6-ol (1.5 g, brown oil) in 58.02% yield. MSm / z(ESI):274.0, 276.0[M+1].

[0152] Step 2 4-Bromo-7,7-dimethoxy-7H-cyclopenta[c]pyridine 4-Bromo-7,7-dimethoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-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). Trifluoroacetic anhydride (2.30 g, 10.94 mmol, 1.52 mL) was added under nitrogen gas protection and ice-water bath cooling. The mixture was stirred at 20 °C for 12 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (150 mL). The organic phase was separated, washed sequentially with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 80:20) to obtain the desired product, 4-bromo-7,7-dimethoxy-7H-cyclopenta[c]pyridine (1.3 g), in a yield of 92.76%. MSm / z(ESI):256.0, 258.0[M+1].

[0153] Step 3 4-Bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridine Trimethylsulfoxonium iodide (3.35 g, 15.23 mmol) was dissolved in dimethyl sulfoxide (20 mL), and sodium hydride (609.09 mg, 15.23 mmol, 60% w / w) was added under nitrogen gas protection. The mixture was stirred at 18 °C for 3 hours. Under nitrogen gas protection, 4-bromo-7,7-dimethoxy-7H-cyclopenta[c]pyridine (1.30 g, 5.08 mmol) was added. The mixture was stirred at 18 °C for 12 hours. The reaction mixture was quenched with saturated brine (130 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was separated, washed with saturated brine (50 mL × 5), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 4-bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridine (1.1 g), which was used directly in the next step. MSm / z(ESI):270.0, 272.0[M+1].

[0154] Step 4 4-Bromo-5,5a-dihydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6(4bH)-one 4-Bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[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 for 2 hours. The mixture was evaporated to dryness at low temperature, quenched by the addition of saturated brine (50 mL), extracted with dichloromethane (50 mL × 2), and the combined organic phase was washed sequentially with saturated brine (50 mL × 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 desired product, 4-bromo-5,5a-dihydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6(4bH)-one (0.55 g, light brown solid) in 60.28% yield. MSm / z(ESI):224.0, 226.0[M+1].

[0155] Step 5 4-Bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6-amine 4-Bromo-5,5a-dihydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-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 for 3 hours. The reaction mixture 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 3 hours. The reaction mixture was evaporated to dryness, and the crude product was dissolved in dichloromethane (60 mL) and washed with saturated brine (30 mL × 2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6-amine (0.44 g). The crude product was used directly in the next step. MSm / z(ESI):225.0, 227.0[M+1].

[0156] Step 6 N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide was synthesized using 4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6-amine and propionyl chloride as starting materials, following Step 3 of Example 1. MSm / z(ESI):281.0, 283.0[M+1].

[0157] Step 7 N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide was synthesized using N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one as starting materials, following Step 4 of Example 1. MS m / z(ESI):362.2[M+1].

[0158] The sample was subjected to chiral separation as follows to give the P1 and P2 products.

[0159] [Table 6]

[0160] The product P1 was subjected to chiral resolution as follows to give P1A and P1B.

[0161] [Table 7]

[0162] The product P2 was subjected to chiral resolution as follows to give P2A and P2B.

[0163] [Table 8]

[0164] The LCMS and HNMR of sample P2B are as follows: 1 H 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,1H),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].

[0165] Example 57 1-Methyl-N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-1H-pyrazole-4-carboxamide [ka]

[0166] Referring to the synthetic route in Example 1, propionyl chloride was replaced with 1-methyl-1H-pyrazole-4-carbonyl chloride to give the title product 1-methyl-N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-1H-pyrazole-4-carboxamide 57. MS m / z(ESI):418.2[M+1].

[0167] Example 58 6-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridin-3-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one [ka]

[0168] Step 1 tert-Butyl 3-((5-bromopyridin-3-yl)oxo)azetidine-1-carboxylate To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate 58b (2 g, 11.56 mmol) in tetrahydrofuran (25 mL), sodium hydride (693 mg, 17.34 mmol, 60%) was added and stirred at room temperature for 30 min. A solution of 3-bromo-5-fluoropyridine 58a (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). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary evaporated, and purified by column chromatography to give the title product tert-butyl 3-((5-bromopyridin-3-yl)oxo)azetidine-1-carboxylate 58c (1 g, pale yellow solid). The yield was 33%. MS m / z(ESI):329.0[M+1].

[0169] Step 2 3-(azetidin-3-oxy)-5-bromopyridine To a solution of tert-butyl 3-((5-bromopyridin-3-yl)oxo)azetidine-1-carboxylate 58c (1 g, 3.04 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL) dropwise, stirred at room temperature for 1 h, concentrated under reduced pressure, and dried to give the title product 3-(azetidin-3-oxy)-5-bromopyridine 58d (1.1 g, crude). MS m / z(ESI):229.0[M+1].

[0170] Step 3 3-Bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridine Referring to step 3 of the synthetic route in Example 1, propionyl chloride was replaced with ethanesulfonyl chloride to give the title product, 3-bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridine 58e. MS m / z(ESI):321.0[M+1].

[0171] Step 4 6-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridin-3-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one Referring to step 4 of the synthetic route in Example 1, N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide was replaced with 3-bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridine to give the title product 6-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridin-3-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one 58. MS m / z(ESI):404.1[M+1].

[0172] Example 59 N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide [ka]

[0173] Referring to the synthetic route in Example 1, propionyl chloride was replaced with acetyl chloride to give the title product N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide 59. MS m / z(ESI):352.2[M+1].

[0174] Example 60 1-methyl-6-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one [ka]

[0175] Step 1 tert-Butyl 6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate 3,5-Dibromopyridine 60a (3 g, 12.66 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate 60b (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. The reaction mixture was purged with nitrogen gas three times and then stirred in an oil bath at 100 °C for 16 h. After the reaction was completed, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain the title product tert-butyl 6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate 60c (2 g, beige solid) in a yield of 44.6%. MS m / z(ESI):354.1[M+1].

[0176] Step 2 2-(5-Bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane Referring to Step 2 of the synthetic route in Example 58, the title product 2-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane 60d was obtained. MS m / z(ESI):254.1[M+1].

[0177] Step 3 (6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazol-4-yl)methanone Referring to Step 3 of the synthetic route in Example 1, the title product 2-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane 60f was obtained. MS m / z(ESI):362.1[M+1].

[0178] Step 4 1-methyl-6-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one Referring to step 4 of the synthetic route in Example 1, the title product 1-methyl-6-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one 60 was obtained. MS m / z(ESI):445.2[M+1].

[0179] Example 61 1-Methyl-N-(4-(4-methyl-3-carbonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-1H-pyrazole-4-carboxamide [ka]

[0180] Step 1 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (5 g, 21.93 mmol) was dissolved in N,N-dimethylcarboxamide (50 mL). Potassium tert-butoxide (4.92 g, 43.85 mmol) was slowly added to the solution in an ice-water bath. After stirring for 0.5 h, iodomethane (4.67 g, 32.89 mmol, 2.05 mL) was added dropwise. The reaction mixture was stirred at room temperature (20 °C) for 5.5 h. After completion of the reaction, the mixture was quenched by slowly adding HO (20 mL) in an ice-water bath. The mixture was extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (PE / EtOAc=3:1, uv=254 nm) to finally obtain a pale yellow solid 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (4.5 g, yield 84.7%). MS m / z(ESI):241.9[M+1].

[0181] Step 2 4-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (4.5 g, 18.59 mmol) was dissolved in dioxane (50 mL) and bis(pinacolato)diboron (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 added portionwise. The reaction mixture was purged with nitrogen gas multiple times and then stirred in an oil bath at 100 °C for 16 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, slowly added with HO (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5:1, uv = 254 nm) to finally obtain a white solid 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5 g, 17.29 mmol, yield: 93.02%). MS m / z(ESI):290.1[M+1].

[0182] Step 3 N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)-1-methyl-1H-pyrazole-4-carboxamide 4-Bromo-5,6,7,8-tetrahydroisoquinolin-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. The reaction mixture was stirred at 25 °C for 4 hours. The reaction was stopped and quenched with water (10 mL). The mixture was extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude was purified by column chromatography (PE / EtOAc=1:1, UV=254 nm) to give the desired product N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)-1-methyl-1H-pyrazole-4-carboxamide (400 mg, yield: 52.1%). MS m / z(ESI):335.0[M+1].

[0183] Step 4 1-Methyl-N-(4-(4-methyl-3-carbonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-1H-pyrazole-4-carboxamide N-(4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 285.6 μmol), 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (99.6 mg, 342.7 μmol), and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (99.6 mg, 342.7 μmol) were dissolved in a mixture of HO (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. The reaction mixture was purged with nitrogen gas multiple times and then stirred in an oil bath at 100 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by column chromatography (DCM / MeOH = 10:1, UV = 254 nm) to finally give 1-methyl-N-(4-(4-methyl-3-carbonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-1H-pyrazole-4-carboxamide (50 mg, yield: 41.7%). MS m / z(ESI):418.1[M+1].

[0184] Example 62 7-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridin-3-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one [ka]

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

[0186] Step 2 4-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (4.5 g, 18.59 mmol) was dissolved in dioxane (50 mL) and bis(pinacolato)diboron (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 added portionwise. The reaction mixture was purged with nitrogen gas multiple times and then stirred in an oil bath at 100 °C for 16 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, slowly added with HO (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude was purified by column chromatography (PE / EtOAc = 5:1, uv = 254 nm) to finally obtain a white solid 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5 g, 17.29 mmol, 93.02% yield). MS m / z(ESI):290.1[M+1].

[0187] Step 3 tert-Butyl 3-((5-bromopyridin-3-yl)oxo)azetidine-1-carboxylate 3,5-Dibromopyridine (3 g, 12.8 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.66 g, 15.36 mmol) were dissolved in toluene (30 mL) and then cuprous iodide (244 mg, 1.28 mmol), cesium carbonate (12.6 g, 38.4 mmol), and 1,10-phenanthroline (460 mg, 2.56 mmol) were added. The reaction mixture was purged with nitrogen gas multiple times and then stirred in an oil bath at 100 °C for 16 h. After completion of the reaction, the mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude was purified by column chromatography (PE / EtOAc=5:1, uv=254 nm) to finally obtain the desired product tert-butyl 3-((5-bromopyridin-3-yl)oxo)azetidine-1-carboxylate (3.0 g, yield: 71.4%). MS m / z(ESI):329.0[M+1].

[0188] Step 4 3-(azetidin-3-oxy)-5-bromopyridine tert-Butyl 3-((5-bromopyridin-3-yl)oxo)azetidine-1-carboxylate (500 mg, 1.52 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was added thereto. The reaction mixture was stirred at room temperature for 4 hours. After the reaction of the raw material was completed, the excess solvent was directly concentrated to give crude 3-(azetidin-3-oxy)-5-bromopyridine (350 mg, crude). The crude product was used directly in the next step. MS m / z(ESI):228.9[M+1].

[0189] Step 5 3-Bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridine 3-(azetidin-3-oxy)-5-bromopyridine (350 mg, crude) was dissolved in tetrahydrofuran (10 mL), and triethylamine (462 mg, 4.56 mmol) and ethanesulfonyl chloride (292 mg, 2.28 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 2), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (PE / EtOAc = 3:1, UV = 254 nm) to finally give the desired product, 3-bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridine (300 mg, yield: 61.7%). MS m / z(ESI):320.9[M+1].

[0190] Step 6 7-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridin-3-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 3-Bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridine (100 mg, 311.6 μmol) and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (109.1 mg, 374.0 μmol) were dissolved in a mixture of HO (2 mL) and EtOH (10 mL), followed by the addition of sodium carbonate (99 mg, 935.1 μmol) and tetrakis(triphenylphosphine)palladium (36.0 mg, 31.2 μmol). The reaction mixture was purged with nitrogen gas multiple times and then stirred in an oil bath at 100 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by column chromatography (DCM / MeOH = 10:1, UV = 254 nm) to finally give 7-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridin-3-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (55 mg, yield: 43.7%). MS m / z(ESI):404.1[M+1].

[0191] Example 63 N-(4-(4-methyl-3-carbonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide [ka]

[0192] Using 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one, 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine as starting materials, referring to Example 10, the target product N-(4-(4-methyl-3-carbonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide was finally obtained. MS m / z(ESI):352.1[M+1].

[0193] Example 64 4-Methyl-7-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one [ka]

[0194] Step 1 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (5 g, 21.93 mmol) was dissolved in N,N-dimethylcarboxamide (50 mL). Potassium tert-butoxide (4.92 g, 43.85 mmol) was slowly added to the solution in an ice-water bath. After stirring for 0.5 h, iodomethane (4.67 g, 32.89 mmol, 2.05 mL) was added dropwise. The reaction mixture was stirred at room temperature (20 °C) for 5.5 h. After completion of the reaction, the mixture was quenched by slowly adding HO (20 mL) in an ice-water bath. The mixture was extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (PE / EtOAc=3:1, uv=254 nm) to finally obtain a pale yellow solid 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (4.5 g, yield 84.7%). MS m / z(ESI):241.9[M+1].

[0195] Step 2 4-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (4.5 g, 18.59 mmol) was dissolved in dioxane (50 mL) and bis(pinacolato)diboron (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 added portionwise. The reaction mixture was purged with nitrogen gas multiple times and then stirred in an oil bath at 100 °C for 16 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, slowly added with HO (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude was purified by column chromatography (PE / EtOAc = 5:1, uv = 254 nm) to finally obtain a white solid 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5 g, 17.29 mmol, yield: 93.02%). MS m / z(ESI):290.1[M+1].

[0196] Step 3 tert-Butyl 6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-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. The reaction mixture was purged with nitrogen gas multiple times and then stirred in an oil bath at 100 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by column chromatography (PE / EtOAc = 5:1, UV = 254 nm) to finally give a beige solid, tert-butyl 6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (2 g, 5.65 mmol, yield: 44.58%). MS m / z(ESI):354.0[M+1].

[0197] Step 4 2-(5-Bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane tert-Butyl 6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (500 mg, 1.41 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. After the reaction of the raw material was completed, the excess solvent was directly concentrated to give 2-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane (360 mg, crude). The crude product was used directly in the next step. MS m / z(ESI):254.0[M+1].

[0198] Step 5 (6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazol-4-yl)methanone 2-(5-Bromopyridin-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, respectively, and the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction was quenched by adding water (5 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (PE / EtOAc = 3:1, uv = 254 nm) to finally obtain the desired product (6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazol-4-yl)methanone (350 mg, yield: 68.7%). MS m / z(ESI):362.1[M+1].

[0199] Step 6 4-Methyl-7-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (6-(5-Bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazol-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]oxazin-3(4H)-one (96.5 mg, 331.4 μmol) were dissolved in a mixture of HO (2 mL) and EtOH (10 mL), followed by the addition of sodium carbonate (88.0 mg, 828.6 μmol) and tetrakis(triphenylphosphine)palladium (32.0 mg, 27.6 μmol). The reaction mixture was purged with nitrogen gas multiple times and then stirred in an oil bath at 100 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (DCM / MeOH = 10:1, UV = 254 nm) to finally give a pale yellow solid, 4-methyl-7-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (45 mg, yield: 36.7%). MS m / z(ESI):445.1[M+1]. MS m / z(ESI):444.2[M+1].

[0200] Example 65 5-Methyl-N-(4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)isoxazole-4-carboxamide [ka]

[0201] Referring to Example 57, the product 5-methyl-N-(4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)isoxazole-4-carboxamide was obtained. MS m / z(ESI):419.2[M+1].

[0202] Example 66 N-(4-(7-fluoro-1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide [ka]

[0203] Referring to Example 1, the product N-(4-(7-fluoro-1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide was obtained. MS m / z(ESI):384.1[M+1].

[0204] Example 67 N-((4bR,5aS)-4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide [ka]

[0205] 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 N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide as starting materials, N-((4bR,5aS)-4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide was synthesized by referring to Step 7 of Example 48. MS m / z(ESI):364.2[M+1].

[0206] [Table 9]

[0207] After the sample was subjected to chiral resolution, P1 and P2 were obtained. The chiral resolution conditions were as follows:

[0208] [Table 10]

[0209] Example 68 6-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-5-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one [ka]

[0210] Step 1 tert-Butyl 5-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate 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 at 90 °C for 5 hours. The reaction was quenched by adding saturated brine (50 mL) to the mixture, which was then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed sequentially with saturated brine (50 mL × 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 desired product, tert-butyl 5-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (0.32 g, white solid) in 58.81% yield. MSm / z(ESI):339.1, 341.1[M+1].

[0211] Step 2 5-Bromo-1',2',3',6'-tetrahydro-3,4'-bipyridine hydrochloride tert-Butyl 5-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (0.2 g, 589.58 μmol) was dissolved in 4 M dioxane hydrochloride (10 mL), and the mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give crude 5-bromo-1',2',3',6'-tetrahydro-3,4'-bipyridine hydrochloride (0.16 g). The crude product was used directly in the next step. MSm / z(ESI):239.0, 241.0[M+1].

[0212] Step 3 5-Bromo-1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine 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 for 1 hour. The reaction mixture was washed with saturated brine (30 mL × 2), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 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. MSm / z(ESI):343.0, 345.0[M+1].

[0213] Step 4 6-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-5-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one 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 starting materials, 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 by referring to Step 4 of Example 1. MS m / z(ESI):426.1[M+1]. 1H NMR(400MHz, CDCl3) δ8.73(d,J=2.1Hz,1H),8.64(d,J=2.1Hz,1H),7.87(s,1H),7.64-7.56(m,1H),7.42-7.31(m,1H),7.11-7.03(m,1H),6.32-6.19(m,1H),5. 29(s,2H),4.17-4.02(m,2H),3.70-3.55(m,2H),3.44(s,3H),2.79-2 .63(m,2H),2.42-2.26(m,1H),1.31-1.17(m,2H),1.10-0.97(m,2H).

[0214] Example 69 6-(5-(1-(cyclopropylsulfonyl)piperidin-4-yl)pyridin-3-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one [ka]

[0215] 6-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-5-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (16 mg, 37.6 μmol) was dissolved in ethanol (5 mL) and palladium carbon (10% w / w, 50% water) (4.0 mg) was added under nitrogen gas protection. The mixture was stirred at 20 °C under a hydrogen gas atmosphere (1 atm) for 12 hours. The catalyst was removed by filtration, and the liquid phase was evaporated to dryness to obtain the crude product. The crude product was purified by prep-HPLC to obtain the desired product, 6-(5-(1-(cyclopropylsulfonyl)piperidin-4-yl)pyridin-3-yl)-2-methoxyoxazin-2-one (1 mg). MS m / z(ESI):428.1[M+1].

[0216] Example 70 6-(1'-(cyclopropylcarbonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-5-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one [ka]

[0217] Referring to Example 68, the product 6-(1′-(cyclopropylcarbonyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridin]-5-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was obtained. MS m / z(ESI):390.1[M+1].

[0218] Example 71 7-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-5-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one [ka]

[0219] Referring to Example 68, the product 7-(1′-(cyclopropylsulfonyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridin]-5-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one was obtained. MS m / z(ESI):426.1[M+1].

[0220] Example 72 (R)-2,2,2-trifluoro-N-(4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide [ka]

[0221] The synthetic route of Example 1 was followed to obtain the title product (R)-2,2,2-trifluoro-N-(4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide 130. MS m / z(ESI):406.1[M+1].

[0222] Example 73 (R)-N-(4-(1-(methyl-d3)-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide [ka]

[0223] Using deuterated iodomethane as a raw material, the product (R)—N-(4-(1-(methyl-d3)-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide was obtained by referring to Example 1. MS m / z(ESI):369.2[M+1].

[0224] Example 74 ((R)-N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide-d5 [ka]

[0225] Using deuterated propanoic acid as a raw material, the product ((R)-N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide-d5 was obtained in accordance with Example 1. MS m / z(ESI):371.2[M+1].

[0226] Example 75 (R) —N-(8-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-3,4-dihydro-2H-pyran[3,2-c]pyridin-4-yl)propanamide [ka]

[0227] Step 1 (R)—N-(8-bromo-3,4-dihydro-2H-pyran[3,2-c]pyridin-4-yl)propanamide Using 8-bromo-2,3-dihydro-4H-pyran[3,2-c]pyridin-4-one as a starting material, the title product (R)—N-(8-bromo-3,4-dihydro-2H-pyran[3,2-c]pyridin-4-yl)propanamide was obtained by following the synthesis of steps 4 and 5 of intermediate Im-1 and step 3 of Example 1. MSm / z(ESI):285.0, 287.0[M+1].

[0228] Step 2 (R)—N-(8-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-3,4-dihydro-2H-pyran[3,2-c]pyridin-4-yl)propanamide Using (R)—N-(8-bromo-3,4-dihydro-2H-pyran[3,2-c]pyridin-4-yl)propanamide as the raw material, the target product (R)—N-(8-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-3,4-dihydro-2H-pyran[3,2-c]pyridin-4-yl)propanamide was obtained by referring to Step 4 of Example 1. MS m / z(ESI):368.1[M+1].

[0229] Example 76 (S)—N-(7-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2,3-dihydrofuran[3,2-c]pyridin-3-yl)propanamide [ka]

[0230] Step 1 2-[(3,5-dibromo-4-pyridine)oxy]-N-methoxy-N-methyl-acetamide 3,5-Dibromopyridin-4-ol (0.5 g, 1.98 mmol) and 2-bromo-N-methoxy-N-methylacetamide (359.87 mg, 1.98 mmol) were dissolved in N,N-dimethylcarboxamide (5 mL). Under nitrogen gas protection, potassium carbonate (819.75 mg, 5.93 mmol) was added. The mixture was stirred at 25 °C for 12 h. The reaction was quenched by adding saturated brine (50 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed sequentially with saturated brine (30 mL × 5), 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 60:40) to obtain the desired product (0.58 g, 83% yield). MS m / z(ESI):352.9[M+1].

[0231] Step 2 7-Bromofuran[3,2-c]pyridin-3-one 2-[(3,5-dibromo-4-pyridine)oxy]-N-methoxy-N-methylacetamide (0.58 g, 1.64 mmol) was dissolved in THF (10 mL) and cooled in a dry ice ethanol bath under nitrogen gas protection. The mixture was stirred at -78 °C for 1 h. The reaction mixture was slowly warmed to 0 °C, and then saturated aqueous ammonium chloride (1 mL) was added to quench the reaction. Saturated brine (50 mL) was added to the mixture, which was then extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed sequentially with saturated brine (30 mL × 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) to obtain the desired product, 7-bromofuran[3,2-c]pyridin-3-one (0.15 g, 42.78% yield). MSm / z(ESI):213.9, 215.9[M+1].

[0232] Step 3 (S)-7-Bromo-2,3-dihydrofuran[3,2-c]pyridin-3-amine The product (S)-7-bromo-2,3-dihydrofuran[3,2-c]pyridin-3-amine was obtained by referring to Step 4 and Step 5 of Intermediate Im-1. MSm / z(ESI):215.0, 217.0[M+1].

[0233] Step 4 (S)—N-(7-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2,3-dihydrofuran[3,2-c]pyridin-3-yl)propanamide The product (S)—N-(7-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2,3-dihydrofuran[3,2-c]pyridin-3-yl)propanamide was obtained by synthesis with reference to Example 1. MS m / z(ESI):354.1[M+1].

[0234] Example 77 1-Methyl-N-(1-(6-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)pyrazin-2-yl)piperidin-4-yl)-1H-pyrazole-4-carboxamide [ka]

[0235] Starting from 3,5-dibromopyrazine and tert-butyl piperidin-4-ylaminocarbamate, the title product 1-methyl-N-(1-(6-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)pyrazin-2-yl)piperidin-4-yl)-1H-pyrazole-4-carboxamide was obtained by referring to Example 60. MS m / z(ESI):448.2[M+1].

[0236] Biological Test Evaluation The present invention will be further explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0237] Test Example 1 The G-402 cell line was used as a host cell to express (transiently express or stably transfect) human CYP11 family enzymes. Specifically, G-402 cell lines stably expressing human CYP11B1 and human CYP11B2 were established. The G-402 cell line expressed cofactors (adrenodoxin and adrenodoxin reductase) that are crucial for the activity of the CYP11 family, and it was demonstrated that the cell line itself does not possess CYP11 family-related enzyme activity (compared to H295R cells). Therefore, the G-402 cell line is highly suitable as a host cell for ectopically expressing CYP11 family enzymes.

[0238] The G-402 cell line, originally derived from a renal myoblastoma, is available from the American Type Culture Collection (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 the cells were screened by administering specific antibiotics. The activity of the enzymes expressed by the screened monoclonal cells was assessed using 11-desoxycorticosterone (a substrate for CYP11B2) and 11-desoxycortisol (a substrate for CYP11B1).

[0239] G-402 cells expressing the CYP11 plasmid established by 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. Cellular enzyme assays were performed using DMEM / F12 medium containing 2.5% charcoal-stripped FBS and appropriate concentrations of substrate (1 μM 11-desoxycorticosterone or 1 μM 11-desoxycortisol). To detect cellular enzyme activity, cells were seeded into 96-well plates and incubated for 16 h. The supernatant was then transferred and analyzed for the concentration of the desired product (CYP11B2 product: aldosterone; CYP11B1 product: cortisol). The concentrations of these products were measured by HTRF experiments at CisBio.

[0240] In cellular enzyme experiments, the inhibitory effect of a test compound on the product produced can indicate its inhibitory effect on the enzyme. The dose-dependent inhibition of the compound on enzyme activity was calculated by plotting the concentration of the test compound (x-axis) versus the measured product level (y-axis). The raw data were then fitted to a four-parameter s-type function (Morgan-Mercer-Flodin, MMF model) using the least squares method: y = (AB + Cx D ) / (B+x D ) where 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 inhibitor, and C corresponds to the amount of product detected from G402 cells expressing the empty vector plasmid.

[0241] EC of the compounds of this patent 50 The values ​​were measured using the G-402 experimental system described above. CYP11B2 enzyme activity was measured under the conditions of 1 μM 11-desoxycorticosterone and varying amounts of inhibitor, and CYP11B1 enzyme activity was measured under the conditions of 1 μM 11-desoxycortisol and varying amounts of inhibitor.

[0242] [Table 11]

[0243] [Table 12] Note: hSF is an abbreviation for human selective factor, which refers to the selectivity of a compound for CYP11B2 over CYP11B1, and the hSF value is the ratio of CYP11B1 EC50 to CYP11B2 EC50.

[0244] The above data demonstrate that the compounds of the present invention have good CYP11B2 activity and high selectivity over the CYP11B1 enzyme.

[0245] Test Example 2: Pharmacokinetics measurement in rats 1. Research purpose: Using SD rats as test animals, the pharmacokinetic behavior of the compound of the present invention in vivo (plasma) after oral administration was investigated in rats.

[0246] 2. Test Scheme 2.1 Test Drugs: The compounds of the present invention are prepared in-house.

[0247] 2.2 Test animals: SD rats, 3 males per group, were used. 2.3 Drug Combinations: Preparation of oral medication: 0.5% CMC-Na (1% Tween 80) 5 g of carboxymethylcellulose sodium (CMC-Na, viscosity: 800 to 1200 Cps) was weighed and dissolved in 1000 mL of purified water, and 10 g of Tween 80 was added. The mixture was mixed uniformly to form a clear solution.

[0248] The compound of the example was weighed and dissolved in the solution, shaken well to homogenize, and then ultrasonicated for 15 minutes to obtain a clear, colorless solution with a concentration of 0.5 mg / mL.

[0249] Preparation of intravenous drugs: 5% DMSO + 10% Solutol HS15 + 85% PBS Weigh out the compound of example, and in proportion to the total volume of administration, first add 5% DMSO, vortex, and ultrasonicate for 2 minutes, and then completely dissolve it; then add 10% Solutol HS15, vortex, and ultrasonicate for 2 minutes, and then completely dissolve it; finally add 85% PBS, vortex, and ultrasonicate for 5 minutes, and then pass through a 0.22 μM filter membrane to obtain a colorless and clear solution.The concentration is 0.2 mg / mL.

[0250] 2.4 Administration: Three male SD rats per group were used. After an overnight fast, each was administered PO at a dose of 5 mg / kg in a volume of 10 mL / kg.

[0251] Three male SD rats per group were used. After an overnight fast, each rat was administered IV at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0252] 2.5 Sampling: 0.2 mL of blood was collected from the jugular vein of the 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, placed in EDTA-2K test tubes, and centrifuged at 4°C and 8000 rpm for 6 minutes to separate the plasma, which was then stored at -80°C and served 4 hours after administration.

[0253] 3 Experimental results: The final measurement results were obtained using the LC-MS / MS method. [Table 13]

[0254] The experimental results show that the compounds of the present invention have very good exposure in vivo in rats.

[0255] Test Example 3: Pharmacokinetics measurement in mice 1. Research purpose: Balb / c mice were used as test animals to examine the pharmacokinetic behavior of the compound of the present invention in vivo (plasma) in mice after oral administration.

[0256] 2. Test Scheme 2.1 Test Drugs: The compounds of the present invention are prepared in-house.

[0257] 2.2 Test animals: Male Balb / c mice (3 mice per group) were used. Shanghai Bikai Laboratory Animal Co., Ltd., Animal Production Permit Number (SCXK (Shanghai) 2013-0006 No. 0.311620400001794).

[0258] 2.3 Drug Combinations: Preparation of oral medication: 0.5% CMC-Na (1% Tween 80) 0.5 g of carboxymethylcellulose sodium (CMC-Na, viscosity: 800 to 1200 Cps) was weighed and dissolved in 99 mL of purified water, and 1 ml of Tween 80 was added. The mixture was mixed uniformly to form a clear solution.

[0259] The compounds of Example 1 and Example 2 were weighed and dissolved in the solution, shaken well, and sonicated for 15 minutes to obtain a clear, colorless solution with a concentration of 0.5 mg / mL.

[0260] Preparation of intravenous drugs: 5% DMSO + 10% Solutol HS15 + 85% PBS The compounds of Example 1 and Example 2 were weighed, and in proportion to the total volume administered, 5% DMSO was first added, vortexed, and sonicated for 2 minutes until completely dissolved; then 10% Solutol HS15 was added, vortexed, and sonicated for 2 minutes until completely dissolved; finally, 85% PBS was added, vortexed, and sonicated for 5 minutes, and passed through a 0.22 μM filter membrane to obtain a colorless, transparent, and clear solution. The concentration was 0.2 mg / mL.

[0261] 2.4 Administration: Male Balb / c mice (3 mice per group) were administered PO after overnight fasting at a dose of 5 mg / kg in a volume of 10 mL / kg. Male Balb / c mice (3 per group) were administered IV after overnight fasting at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0262] 2.5 Sampling: 0.04 mL of blood was collected from the orbit of the 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, placed in EDTA-2K test tubes, centrifuged at 4°C and 8000 rpm for 6 minutes to separate the plasma, stored at -80°C, and fed 4 hours after administration.

[0263] 3 Experimental results: The final measurement results were obtained using the LC-MS / MS method. [Table 14]

[0264] The experimental results show that the compounds of the present invention have very good exposure in vivo in mice.

[0265] Test Example 4: In vivo drug efficacy measurement Male cynomolgus monkeys were orally administered the test compound (PO) at doses of 0 mpk (vehicle group), 0.1 mpk, 0.3 mpk, 1 mpk, and 3 mpk. Each group received 5 μg / kg ACTH intravenously (IV) at 1 hour. Approximately 0.5 mL of blood samples were collected at -1 hour, 0 hours, 0.5 hours, 1.0 hours, 1.5 hours, 2 hours, and 3 hours after ACTH IV injection. The samples were centrifuged (3200 g, 2-8°C for 10 minutes) within one hour of collection, and the plasma aldosterone, cortisol, corticosterone, 11-desoxycortisol, and 11-desoxycorticosterone contents at each time point were analyzed by LC / MS-MS. Experimental Results:

[0266] [Table 15]

[0267] The experimental results show that the compounds of the present invention can effectively reduce the content of aldosterone without causing significant changes in hormones such as cortisol.

Claims

1. A compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 where: 【Chemistry 2】 is a single or double bond, Ring A is a 5- to 7-membered heterocyclyl group containing 2 to 3 heteroatoms selected from N, O, or S, and Ring A contains at least one oxygen atom; Ring B is a 5- to 6-membered heteroaryl group or a phenyl group; Ring C is a cycloalkyl group, a heteroaryl group, a heterocyclyl group, or is absent; M １ , M ２ , M ４ , M ５ , M ６ are each independently selected from N, C, NH, or CH; M ３ is a bond, N or CH; R １ are each 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)(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 and optionally the cycloalkyl group, heterocyclyl group, cycloalkyloxy group, heterocyclyloxy group, cycloalkylamino group, heterocyclylamino group, cycloalkylthio group or heterocyclylthio group can further be 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, 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 and is substituted with one or more substituents selected from Or, any two R １ form a 3- to 8-membered cycloalkyl group or a 4- to 7-membered heterocyclyl group together with adjacent carbon atoms, and optionally, the 3- to 8-membered cycloalkyl group or the 4- to 7-membered heterocyclyl group may further comprise 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 is replaced by R ａ or R ｂ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups, and optionally the cycloalkyl, aryl, heteroaryl, or heterocyclyl groups are further selected from oxo, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or -S(O) ２ substituted with one or more substituents selected from alkyl groups; R ２ , R ３ or R ４ are each independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, and are each independently selected from the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, and ａ C(O)(CH ２ ) ｎ R ｂ or -C(O)NR ａ (CH ２ ) ｎ R ｂ is optionally further substituted; Or, R ２ and R ３ form a 3- to 8-membered cycloalkyl group, a 5- to 6-membered heteroaryl group, or a 4- to 7-membered heterocyclyl group together with adjacent atoms, and optionally the 3- to 8-membered cycloalkyl group, the 5- to 6-membered heteroaryl group, or the 4- to 7-membered heterocyclyl group is further substituted with one or more substituents selected from 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, or a hydroxyalkyl group; Or, any two R ２ form a 3- to 8-membered cycloalkyl group, a 5- to 6-membered heteroaryl group, or a 4- to 7-membered heterocyclyl group together with adjacent atoms, and optionally the 3- to 8-membered cycloalkyl group, the 5- to 6-membered heteroaryl group, or the 4- to 7-membered heterocyclyl group is further substituted with one or more substituents selected from 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, or a hydroxyalkyl group; Or, R ２ and R ４ form a 5- to 14-membered cycloalkyl group, a 5- to 14-membered heteroaryl group, or a 5- to 14-membered heterocyclyl group together with adjacent atoms, and optionally the 5- to 14-membered cycloalkyl group, the 5- to 14-membered heteroaryl group, or the 5- to 14-membered 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; p, x, y, and z are each independently selected from 1, 2, 3, or 4; n is selected from 0, 1, 2 or 3, a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 【Request Item 2】 【Chemistry 3】 but, 【Chemistry 4】 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from:

3. Ring C is absent or a 3- to 10-membered cycloalkyl group or C(O), N, O, S, SO ２ or SONH; Preferably, ring C is a 5- to 7-membered monocyclic cycloalkyl group, a 6- to 10-membered bicyclic cycloalkyl group, C(O), N, O, S, SO ２ or SONH; a 5- to 7-membered monocyclic heterocyclyl group containing 1 to 3 selected from C(O), N, O, S, SO ２ or SONH; More preferably, ring C is 【Transformation 5】 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

4. R １ each independently represents a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocyclyl group, a 3- to 8-membered cycloalkyloxy group, a 4- to 8-membered heterocyclyloxy group, a 3- to 8-membered cycloalkylamino group, a 4- to 8-membered heterocyclylamino group, a 3- to 8-membered cycloalkylthio group, a 4- to 8-membered 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 or -NR ａ S(O)(NH)(CH ２ ) ｎ R ｂ and optionally, the 3- to 10-membered cycloalkyl group, 4- to 10-membered heterocyclyl group, 3- to 8-membered cycloalkyloxy group, 4- to 8-membered heterocyclyloxy group, 3- to 8-membered cycloalkylamino group, 4- to 8-membered heterocyclylamino group, 3- to 8-membered cycloalkylthio group, and 4- to 8-membered heterocyclylthio group may further be selected from the group consisting of an oxo group, a deuterium atom, a halogen atom, an amino group, a hydroxy group, a cyano group, a nitro group, a C １－６ 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, —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 and is substituted with one or more substituents selected from R ａ or R ｂ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ 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 and a hydroxyalkyl group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 selected from C(O), N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, and optionally the 3- to 8-membered cycloalkyl group, the 5- to 8-membered heteroaryl group containing 1 to 3 selected from C(O), N, O, or S, or the 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, may further include an oxo group, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ 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, 3- to 6-membered cycloalkyl group or —SO ２ -C １－６ substituted with one or more substituents selected from alkyl groups; Preferably, R １ are each independently a 3- to 10-membered cycloalkyl group, N, O, S, SO ２ a 4- to 10-membered heterocyclyl group containing 1 to 3 selected from SONH, a 3- to 8-membered cycloalkyloxy group, a 3- to 8-membered cycloalkylamino group, N, O, S, SO ２ or a 4- to 8-membered heterocyclyloxy group containing 1 to 3 selected from SONH, N, O, S, SO ２ or a 4- to 8-membered heterocyclylamino group containing 1 to 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 and optionally selected from the 3- to 10-membered cycloalkyl groups, N, O, S, SO ２ a 4- to 10-membered heterocyclyl group containing 1 to 3 selected from SONH, a 3- to 8-membered cycloalkyloxy group, a 3- to 8-membered cycloalkylamino group, N, O, S, SO ２ or a 4- to 8-membered heterocyclyloxy group containing 1 to 3 selected from N, O, S, SO ２ or SONH, and the 4- to 8-membered heterocyclylamino group containing 1 to 3 selected from the group consisting of 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 and is substituted with one or more substituents selected from R ａ or R ｂ are each independently hydrogen, deuterium, halogen, a hydroxy group, a cyano group, C １－３ and optionally, the 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or the 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S, may further include an oxo group, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ 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, 3- to 6-membered cycloalkyl group or —SO ２ -C １－３ 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, which is substituted with one or more substituents selected from alkyl groups.

5. R ２ , R ３ or R ４ are each independently hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ 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- to 8-membered cycloalkyl group, 3- to 8-membered cycloalkyloxy group, 3- to 8-membered cycloalkylamino group, C ６－１０ an aryl group, a 5- to 6-membered heteroaryl group containing 1 to 3 atoms selected from N, O, and S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 atoms selected from C(O), N, O, and S; -NR ａ R ｂ , -NR ａ C(O)R ｂ or -C(O)NR ａ R ｂ is selected from Preferably, R ２ , R ３ or R ４ are each independently hydrogen, deuterium, halogen, or C １－３ 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 5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the aryl group is selected from the group consisting of cycloalkyloxy groups.

6. Furthermore, a compound represented by general formula (II-a), (II-b) or (II-c), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, 【Transformation 6】 where: Ring A is a 6-membered heterocyclyl group; Ring B is selected from a phenyl group or a 5-6 membered heteroaryl group containing 1-3 atoms selected from N, O or S; R ２ , R ３ or R ４ are each independently hydrogen, deuterium, halogen, or C １－３ 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, —NR ａ C(O)R ｂ or -C(O)NR ａ R ｂ is selected from R ａ or R ｂ are each independently hydrogen, deuterium, halogen, a hydroxy group, a cyano group, C １－３ The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from an alkyl group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O or S.

7. Further, a compound represented by general formula (III-b)-(III-c), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Transformation 7】 Ring C is a 5- to 7-membered monocyclic cycloalkyl group, a 6- to 10-membered bicyclic cycloalkyl group, C(O), N, O, S, SO ２ or SONH; a 5- to 7-membered monocyclic heterocyclyl group containing 1 to 3 selected from C(O), N, O, S, SO ２ or SONH; Or, ring C is absent, L is a bond, —O—, or —R ｃ C(O)-, -R ｃ S(O)NH- or -R ｃ S (O) ２ is selected from, preferably —NHC(O)—; R ｃ represents a bond, NH, a 3- to 8-membered cycloalkyl group, N, O, S, or SO ２ or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from SONH, a 3- to 8-membered cycloalkyloxy group, N, O, S, SO ２ or SONH; R ２ , R ３ or R ４ are each independently hydrogen, deuterium, halogen, or C １－３ 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 cycloalkyl groups, R ｂ is hydrogen, deuterium, C １－３ an alkyl group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or C(O), N, O, S, SO ２ or SONH; The compound, its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein y is 1, 2 or 3. 【Request Item 8】 【Transformation 8】 teeth, 【Chemistry 9】 and preferably selected from the group 【Chemistry 10】 8. The compound according to claim 1 or 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

9. Further, a compound represented by general formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 11】 where: M ２ is selected from N or CH; Ring C is a 5- to 7-membered monocyclic cycloalkyl group, a 6- to 10-membered bicyclic cycloalkyl group, C(O), N, O, S, SO ２ or SONH; a 5- to 7-membered monocyclic heterocyclyl group containing 1 to 3 selected from C(O), N, O, S, SO ２ or SONH, or absent, and preferably ring C is selected from a 6-membered monocyclic cycloalkyl group; 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 or a 4- to 8-membered nitrogen-containing heterocyclyl group, said 4- to 8-membered nitrogen-containing heterocyclyl group optionally further comprising —C(O)R ｂ or -S(O) ２ R ｂ is replaced by R ａ or R ｂ are each independently hydrogen, deuterium, halogen, a hydroxy group, a cyano group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ a haloalkoxy group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1 to 3 selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1 to 3 selected from C(O), N, O, or S; R ２ is hydrogen, deuterium, halogen, C １－３ 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 6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the aryl group is selected from the group consisting of cycloalkyloxy groups. 【Request Item 10】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 1. The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 in the manufacture of a drug for treating or preventing kidney disease, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, aldosteronism and Cushing's syndrome, preferably wherein the hypertension is refractory hypertension, the kidney disease is chronic kidney disease and the aldosteronism is primary aldosteronism.

13. Use of a compound of the general formula shown in any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a drug for treating a CYP11B2-related disease.

14. A method for producing a compound represented by general formula (I) according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising: 【Chemistry 16】 The method comprises the steps of reacting compound (I-a) with a boron compound to produce compound (I-b), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and then subjecting the compound (I-b), a stereoisomer thereof or a pharmaceutically acceptable salt thereof to a coupling reaction with compound (I-c), a stereoisomer thereof or a pharmaceutically acceptable salt thereof to produce a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof; the catalyst for the coupling reaction is a palladium reagent, preferably palladium acetate, tetrakistriphenylphosphinepalladium, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium; X is a halogen, preferably bromine; Z is a boron-containing compound, preferably a dioxaborolanyl group; Ring A, Ring B, Ring C, R １ , R ２ , R ３ , R ４ , M １ , M ２ , M ３ , M ４ , M ５ , M ６ , x, y, z and p are defined as in claim 1.

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