Pyridine polycyclic compound inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a pyridine polycyclic compound inhibitor as well as a preparation method and application thereof. Particularly, the invention relates to a compound shown in a general formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound in medicines for treating chronic kidney diseases, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome, wherein each substituent in the general formula (I) is as defined in the specification. # imgabs0 #

Description

Pyridine polycyclic compound inhibitor, preparation method and application thereof

[0001] This application claims the benefit of Chinese patent application No. 2022114779612, filed on November 23, 2022. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of biomedicine, and specifically relates to a pyridine polycyclic compound inhibitor, a preparation method and an application thereof. Background Art

[0003] Aldosterone is a steroid hormone secreted from the adrenal glands that binds to and activates the mineralocorticoid receptor (MR). In primary cells of the distal renal tubules and collecting ducts, MR activation leads to sodium and water retention accompanied by potassium excretion, causing plasma volume expansion and elevated blood pressure (BP). The renin-angiotensin-aldosterone system (RAAS), an endocrine system, regulates blood pressure and fluid balance. Current antihypertensive medications—angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs)—regulate blood pressure by inhibiting this pathway. Long-term use of ACEi or ARBs can cause an "aldosterone breakthrough," in which aldosterone levels rise after a brief decrease, leading to target organ damage. Currently, the only marketed aldosterone inhibitor, spironolactone, can cause hyperkalemia. Excess aldosterone measured in the circulation is called primary aldosteronism (PA) and occurs when aldosterone production is dysregulated by the renin-angiotensin-aldosterone system (RAAS). PA was originally identified in patients with adrenal adenomas, and recent evidence suggests an increased prevalence associated with obesity. PA is a common cause of secondary hypertension, with a prevalence of 14% to 21% in patients with resistant hypertension (RHTN), defined as blood pressure that remains above the target blood pressure of 140 / 90 mm Hg despite the use of three antihypertensive medications (calcium channel blockers, angiotensin inhibitors, angiotensin receptor blockers, and diuretics). Refractory hypertension is a high-risk condition with a high rate of comorbidities including diabetes, chronic kidney disease, ischemic heart disease, and cerebrovascular disease.

[0004] CYP11B2 is the gene encoding aldosterone synthase, which is highly homologous to the gene sequence encoding cortisol synthase CYP11B1. Developing highly selective CYP11B2 inhibitors to inhibit the synthesis of aldosterone is the main direction for the treatment of refractory hypertension and primary aldosteronism.

[0005] Summary of the Invention

[0006] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:

[0007] in:

[0008] is a single bond or a double bond;

[0009] Ring A is phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or absent;

[0010] Ring B is a 4-7 membered heterocyclyl, a 5-6 membered heteroaryl or a phenyl group;

[0011] Ring C is cycloalkyl, heteroaryl, heterocyclyl or absent;

[0012] M1, M2, M4, M5, and M6 are each independently selected from N, NH, or CH;

[0013] M3 is a bond, N or CH;

[0014] R1 is independently selected from cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio, heterocyclylthio, -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 a S(O)(NH)(CH2) n R b or -NS(O)(CH2) n R a R b Optionally, the cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio or heterocyclylthio is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)(CH2) n R b、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0015] Alternatively, any two R1s form a 3-8 membered cycloalkyl or 4-7 membered heterocyclic group with adjacent carbon atoms, and optionally, the 3-8 membered cycloalkyl or 4-7 membered heterocyclic group is further substituted with an oxo group, -C(O)R b 、-NR a C(O)R b 、-S(O)2R b 、-S(O)(NH)R b 、-NR a S(O)2R b or -NR a S(O)(NH)R b replaced by;

[0016] R a or R b each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally, the cycloalkyl, aryl, heteroaryl or heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl or -S(O)2alkyl;

[0017] R2, R3 or R4 are each independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a C(O)(CH2) n R b or -C(O)NR a (CH2) n R b , which may optionally be further substituted;

[0018] Alternatively, R2 and R3 together with adjacent atoms form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclyl, optionally wherein the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl;

[0019] Alternatively, any two R2 form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclyl with adjacent atoms, and the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclyl is optionally further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl;

[0020] Alternatively, R2 and R4 form a 5-14 membered cycloalkyl, a 5-14 membered heteroaryl or a 5-14 membered heterocyclyl with adjacent atoms, optionally wherein the 5-14 membered cycloalkyl, the 5-14 membered heteroaryl or the 5-14 membered heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl;

[0021] p, x, y and z are each independently selected from 1, 2, 3 or 4;

[0022] n is selected from 0, 1, 2 or 3;

[0023] when for M1 is N, and ring C is When R1 is not -NR a C(O)R b and -NR a S(O)2R b ;

[0024] When M1 is N, ring C does not exist or is hour, Not for

[0025] In certain embodiments of the present invention, a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[0026] in:

[0027] is a single bond or a double bond;

[0028] Ring A is phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or absent; when ring A is absent, R2 is connected to ring B;

[0029] Ring B is a 4-7 membered heterocyclyl, a 5-6 membered heteroaryl or a phenyl group;

[0030] Ring C is a cycloalkyl, heteroaryl, heterocyclyl or does not exist; when ring C does not exist, R1 is connected to superior;

[0031] M1, M2, M4, M5, and M6 are each independently selected from N, NH, or CH;

[0032] M3 is a bond, N or CH;

[0033] R1 is independently selected from cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio, heterocyclylthio, -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 Optionally, the cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio or heterocyclylthio is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0034] Alternatively, any two R1s form a 3-8 membered cycloalkyl or 4-7 membered heterocyclic group with adjacent carbon atoms, and optionally, the 3-8 membered cycloalkyl or 4-7 membered heterocyclic group is further replaced by -C(O)R b 、-NR a C(O)R b 、-S(O)2R b 、-S(O)(NH)R b 、-NR a S(O)2R b or -NR a S(O)(NH)R b replaced by;

[0035] 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;

[0036] R2, R3 or R4 are each independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a C(O)(CH2) n R b or -C(O)NR a (CH2) n R b , which may optionally be further substituted;

[0037] Alternatively, R2 and R3 together with adjacent atoms form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclyl, optionally wherein the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl;

[0038] Alternatively, any two R2 form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclyl with adjacent atoms, and the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclyl is optionally further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl;

[0039] p, x, y and z are each independently selected from 1, 2, 3 or 4;

[0040] n is selected from 0, 1, 2 or 3.

[0041] In a preferred embodiment of the present invention, Ring A is not selected from a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group containing 1-3 groups selected from C(O), N, O, S, SO2 or SONH.

[0042] In a preferred embodiment of the present invention, ring A is selected from a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group containing 1-3 atoms selected from C(O), N, O, S, SO2 or SONH, preferably a 5-7 membered heterocyclic group containing 2-3 atoms selected from N, O or S and ring A contains at least one oxygen atom.

[0043] In a preferred embodiment of the present invention, ring A is absent.

[0044] In a preferred embodiment of the present invention, ring B is selected from phenyl, containing 1-3 5-7 membered heterocyclic groups or 5-6 membered heteroaryl groups selected from C(O), N, O or S.

[0045] In a preferred embodiment of the present invention, Selected from

[0046] In a preferred embodiment of the present invention, ring C is selected from a 3-10 membered cycloalkyl group or a 4-10 membered heterocyclic group containing 1-3 groups selected from C(O), N, O, S, SO2 or SONH;

[0047] In a preferred embodiment of the present invention, ring C is selected from a 5-7 membered monocyclic cycloalkyl, a 6-10 membered bicyclic cycloalkyl, a 5-7 membered monocyclic heterocyclic group containing 1-3 groups selected from C(O), N, O, S, SO2 or SONH, and a 7-10 membered bicyclic heterocyclic group containing 1-3 groups selected from C(O), N, O, S, SO2 or SONH.

[0048] In a preferred embodiment of the present invention, ring C is selected from the following groups:

[0049] In a preferred embodiment of the present invention, ring C is absent.

[0050] In a preferred embodiment of the present invention, R1 is independently selected from 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio, -C(O)(CH2) n Rb 、-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 Optionally, the 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0051] R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C (O), N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, optionally, the 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C (O), N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl or -SO2-C 1-6 substituted by a substituent in the alkyl group.

[0052] In a preferred embodiment of the present invention, R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C (O), N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, optionally, the 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C (O), N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 3-6 membered cycloalkyl or -SO2-C 1-6 substituted by a substituent in the alkyl group.

[0053] In a preferred embodiment of the present invention, R1 is independently selected from 3-10 membered cycloalkyl, 4-10 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy containing 1-3 selected 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 a S(O)(NH)(CH2) n R b Optionally, the 3-10 membered cycloalkyl, the 4-10 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, the 3-8 membered cycloalkyloxy, the 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH is further substituted by one or more selected oxo groups, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0054] R a or R b are each independently selected from hydrogen, deuterium, C 1-3 alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, optionally, the 5-8 membered heteroaryl containing 1-3 selected from N, O or S or the 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or -SO2-C 1-3 substituted by a substituent in the alkyl group.

[0055] In a preferred embodiment of the present invention, R1 is independently selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio, -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 Optionally, the 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -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 -NRa S(O)(NH)(CH2) n R b substituted by a substituent in;

[0056] R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 hydroxyalkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C(O), N, O or S, or 4-8 membered heterocyclyl containing 1-3 selected from C(O), N, O or S.

[0057] In a preferred embodiment of the present invention, R1 is independently selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH, 4-8 membered heterocyclylamino containing 1-3 selected 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 a S(O)(NH)(CH2) n R b , optionally, the 3-8 membered cycloalkyl, the 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, the 3-8 membered cycloalkyloxy, the 3-8 membered cycloalkylamino, the 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH or the 4-8 membered heterocyclylamino containing 1-3 selected N, O, S, SO2 or SONH are further substituted by one or more selected oxo groups, -C(O)(CH2) nR b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0058] R a or R b are each independently selected from hydrogen, deuterium, C 1-3 alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, optionally, the 5-8 membered heteroaryl containing 1-3 selected from N, O or S or the 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, 3-6 membered cycloalkyl or -SO2-C 1-3 substituted by a substituent in the alkyl group.

[0059] Or, R a or R b are each independently selected from halogen, hydroxy or cyano.

[0060] In a preferred embodiment of the present invention, R1 is independently selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or 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 aS(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Optionally, the 3-8 membered cycloalkyl, the 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, the 3-8 membered cycloalkyloxy, the 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH is further substituted by one or more selected oxo groups, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0061] R a or R b are each independently selected from hydrogen, deuterium, C 1-3 alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 groups selected from N, O or S, or 4-8 membered heterocyclic group containing 1-3 groups selected from C(O), N, O or S.

[0062] In a preferred embodiment of the present invention, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkylamino, C 6-10 Aryl, 5-6 membered heteroaryl containing 1-3 selected from N, O, S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, -NR a R b 、-NR a C(O)R b or -C(O)NR a R b .

[0063] In a preferred embodiment of the present invention, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, -NR a C(O)R b or -C(O)NR a R b ;

[0064] R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 hydroxyalkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C(O), N, O or S, or 4-8 membered heterocyclyl containing 1-3 selected from C(O), N, O or S.

[0065] Or, R a or R b are each independently selected from halogen, hydroxy or cyano.

[0066] In a preferred embodiment of the present invention, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyloxy.

[0067] In a preferred embodiment of the present invention, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 Hydroxyalkyl.

[0068] In a preferred embodiment of the present invention, any two R2 form a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 selected from N, O, and S, or a 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S with adjacent atoms; optionally, the 3-8 membered cycloalkyl group, the 5-6 membered heteroaryl group containing 1-3 selected from N, O, and S, or the 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S are further substituted by one or more oxo groups, deuterium groups, halogen groups, amino groups, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 The alkyl group is substituted with a hydroxyalkyl substituent.

[0069] In a preferred embodiment of the present invention, any two R1s form a 3-8 membered cycloalkyl group or a 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S with adjacent atoms; optionally, the 3-8 membered cycloalkyl group or the 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S is further substituted by one or more selected from oxo, -C(O)R b 、-NR a C(O)R b 、-S(O)2R b 、-S(O)(NH)R b 、-NR a S(O)2R b or -NR a S(O)(NH)R b replaced.

[0070] In a preferred embodiment of the present invention, R2 and R3 form a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 selected from N, O, and S, or a 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S with adjacent atoms; optionally, the 3-8 membered cycloalkyl group, the 5-6 membered heteroaryl group containing 1-3 selected from N, O, and S, or the 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S are further substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 The alkyl group is substituted with a hydroxyalkyl substituent.

[0071] In a preferred embodiment of the present invention, R2 and R4 form a 6-12 membered cycloalkyl group, a 6-12 membered heteroaryl group containing 1-4 selected from N, O, and S, or a 6-12 membered heterocyclic group containing 1-4 selected from N, O, and S with adjacent atoms; optionally, the 6-12 membered cycloalkyl group, the 6-12 membered heteroaryl group containing 1-4 selected from N, O, and S, or the 6-12 membered heterocyclic group containing 1-4 selected from N, O, and S are further substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 The alkyl group is substituted with a hydroxyalkyl substituent.

[0072] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by the general formula (II-a) or (II-c), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0073] in,

[0074] Ring A is a 5-7 membered heterocyclic group containing 1-3 groups selected from C(O), N, O, S, SO2 or SONH or is absent;

[0075] Ring B is selected from phenyl or a 5-6 membered heteroaryl group containing 1-3 groups selected from N, O or S;

[0076] R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 Hydroxyalkyl, -NR a C(O)R b or -C(O)NR a R b ;

[0077] R a or R b are each independently selected from hydrogen, deuterium, C 1-3Alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S, or 4-8 membered heterocyclyl containing 1-3 selected from C(O), N, O or S;

[0078] Alternatively, any two R2 form a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 selected from N, O, and S, or a 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S, with adjacent atoms, and optionally, the 3-8 membered cycloalkyl group, the 5-6 membered heteroaryl group containing 1-3 selected from N, O, and S, or the 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S is further substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 substituted with a hydroxyalkyl substituent;

[0079] Alternatively, R2 and R3 form a 3-8 membered cycloalkyl group or a 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S with adjacent atoms; optionally, the 3-8 membered cycloalkyl group or the 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S is further substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1- substituted with a 3-hydroxyalkyl substituent;

[0080] Alternatively, R2 and R4 form a 6-12 membered cycloalkyl group, a 6-12 membered heteroaryl group containing 1-4 selected from N, O, and S, or a 6-12 membered heterocyclic group containing 1-4 selected from N, O, and S with adjacent atoms; optionally, the 6-12 membered cycloalkyl group, the 6-12 membered heteroaryl group containing 1-4 selected from N, O, and S, or the 6-12 membered heterocyclic group containing 1-4 selected from N, O, and S are further substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 The alkyl group is substituted with a hydroxyalkyl substituent.

[0081] In a more preferred embodiment of the present invention, the general formula (II-a) is further a compound represented by the general formula (II-a-1) or (II-a-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0082] In a more preferred embodiment of the present invention, the general formula (II-c) is further a compound represented by the general formula (II-c-1) or (II-c-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0083] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by the general formula (II-b), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0084] in,

[0085] Ring A is absent or contains 1-3 5-7 membered heterocyclic groups selected from C(O), N, O, S, SO2 or SONH, or is absent;

[0086] Ring B is selected from phenyl or a 5-6 membered heteroaryl group containing 1-3 groups selected from N, O or S;

[0087] R1 is selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy containing 1-3 selected 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 a S(O)(NH)(CH2) n R b Optionally, the 3-8 membered cycloalkyl, the 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, the 3-8 membered cycloalkyloxy, the 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH is further substituted by one or more selected oxo groups, -C(O)(CH2) n Rb 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0088] R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, -NR a C(O)R b or -C(O)NR a R b ;

[0089] R a or R b are each independently selected from hydrogen, deuterium, C 1-3 alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, optionally, the 5-8 membered heteroaryl containing 1-3 selected from N, O or S or the 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or -SO2-C 1-3 Substituted by a substituent in the alkyl group;

[0090] Alternatively, any two R2 form a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 selected from N, O, and S, or a 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S, with adjacent atoms, and optionally, the 3-8 membered cycloalkyl group, the 5-6 membered heteroaryl group containing 1-3 selected from N, O, and S, or the 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S is further substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 substituted with a hydroxyalkyl substituent;

[0091] Alternatively, R2 and R3 form a 3-8 membered cycloalkyl group or a 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S with adjacent atoms; optionally, the 3-8 membered cycloalkyl group or the 4-7 membered heterocyclic group containing 1-3 selected from N, O, and S is further substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1- substituted with a 3-hydroxyalkyl substituent;

[0092] Alternatively, R2 and R4 form a 6-12 membered cycloalkyl group, a 6-12 membered heteroaryl group containing 1-4 selected from N, O, and S, or a 6-12 membered heterocyclic group containing 1-4 selected from N, O, and S with adjacent atoms; optionally, the 6-12 membered cycloalkyl group, the 6-12 membered heteroaryl group containing 1-4 selected from N, O, and S, or the 6-12 membered heterocyclic group containing 1-4 selected from N, O, and S are further substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 The alkyl group is substituted with a hydroxyalkyl substituent.

[0093] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by the general formula (III-a)-(III-d), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0094] Ring C is selected from 5-7 membered monocyclic cycloalkyl, 6-10 membered bicyclic cycloalkyl, 5-7 membered monocyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH, and 7-10 membered bicyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH;

[0095] Alternatively, ring C is absent;

[0096] L is selected from a bond, -O-, -R c C(O)-、-R c S(O)NH- or -R c S(O)2, preferably -NHC(O)-;

[0097] R c Selected from a bond, NH, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 selected from N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy containing 1-3 selected from N, O, S, SO2 or SONH;

[0098] R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl;

[0099] R b Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S, or 4-8 membered heterocyclyl containing 1-3 selected from C(O), N, O, S, SO2 or SONH;

[0100] y is 1, 2, or 3.

[0101] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by the general formula (III') or the general formula (IV'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0102] Ring C is selected from 5-7 membered monocyclic cycloalkyl, 6-10 membered bicyclic cycloalkyl, 5-7 membered monocyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH, and 7-10 membered bicyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH;

[0103] Alternatively, ring C is absent;

[0104] L is selected from a bond, -O-, -R c C(O)-、-R c S(O)NH- or -R c S(O)2;

[0105] R c Selected from a bond, NH, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 selected from N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy containing 1-3 selected from N, O, S, SO2 or SONH;

[0106] R2 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 hydroxyalkyl;

[0107] R b Selected from hydrogen, deuterium, C 1-3 Alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S, or 4-8 membered heterocyclyl containing 1-3 selected from C(O), N, O, S, SO2 or SONH;

[0108] y is 1, 2, or 3.

[0109] In a further preferred embodiment of the present invention, Selected from the following groups:

[0110] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by the general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0111] in:

[0112] M2 is selected from N or CH;

[0113] Ring C is selected from 5-7 membered monocyclic cycloalkyl, 6-10 membered bicyclic cycloalkyl, 5-7 membered monocyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH, 7-10 membered bicyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH, or is absent;

[0114] R1 is selected from -C(O)R b 、-NR a C(O)R b 、-ORb 、-S(O)2R b 、-S(O)(NH)R b 、-NR a S(O)2R b 、-NR a S(O)(NH)R b or a 4-8 membered heterocyclic group, wherein the 4-8 membered nitrogen-containing heterocyclic group is optionally further -C(O)R b or -S(O)2R b replaced by;

[0115] R a or R b are independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 a haloalkoxy group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1-3 groups selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1-3 groups selected from C(O), N, O, or S;

[0116] R2 is selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyloxy.

[0117] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by the general formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0118] in:

[0119] L is selected from NR a , O or S;

[0120] L1 is selected from C(O) or S(O)2;

[0121] R a Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 cycloalkyloxy;

[0122] M2 is selected from N or CH;

[0123] M3 is selected from N or CH;

[0124] R2 is selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 cycloalkyloxy;

[0125] Alternatively, any two R2 together with adjacent atoms form a 3-8 membered cycloalkyl group, a 5-8 membered heteroaryl group containing 1-3 selected from N, O or S, or a 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S;

[0126] R b are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S, or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, optionally, the 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S, or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S is further substituted by halogen, hydroxyl, amino, CN, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Substituted by hydroxyalkyl or 3-6 membered cycloalkyl;

[0127] R5 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 cycloalkyloxy;

[0128] R6 is selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl;

[0129] Or any two R5 form a 3-8 membered cycloalkyl or 3-8 membered heterocyclic group with adjacent carbon atoms;

[0130] Ring D is selected from 3-8 membered cycloalkyl or 4-8 membered heterocyclic group, preferably 4-6 membered nitrogen-containing heterocyclic group;

[0131] q, r, s, t are each independently selected from 1 or 2;

[0132] and k is independently selected from 1, 2 or 3.

[0133] In a more preferred embodiment of the present invention, R2 is selected from methyl or methoxy, and y is 1.

[0134] In a more preferred embodiment of the present invention, M2 is N and M3 is CH.

[0135] In a more preferred embodiment of the present invention, R b Selected from C 1-3 alkyl, 3-6 membered cycloalkyl or 5-6 membered heteroaryl containing 1-3 selected from N, O or S, optionally, the 3-6 membered cycloalkyl or 5-6 membered heteroaryl containing 1-3 selected from N, O or S is further substituted with halogen, hydroxyl, CN or C 1-3 Alkyl substituted.

[0136] In a more preferred embodiment of the present invention, q, r, s, and t are all 1.

[0137] On the other hand, the present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0138] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, has a weight percentage of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof of 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%.

[0139] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, and preferably further comprises a filler, optionally a disintegrant, or further comprises one or more of a glidant or a lubricant.

[0140] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0141] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, the unit dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is 1-1000 mg, preferably 1-500 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.

[0142] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

[0143] In certain embodiments of the present invention, the compound, its stereoisomers or pharmaceutically acceptable salts thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0144] On the other hand, the present invention further relates to the use of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of drugs for treating diseases related to CYP11B2.

[0145] The present invention further relates to the use of the compound represented by the general formula, its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in the preparation of drugs for treating or preventing chronic kidney disease, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome.

[0146] In a preferred embodiment of the present invention, the hypertension is refractory hypertension.

[0147] In some embodiments, the compounds of the present invention have an EC of 0. 50 The values ​​range from 0.0001 μM to 50 μM; the EC values ​​of the preferred compounds for CYP11B2 50 The values ​​are between 0.0001 μM and 10 μM; more preferred compounds have an EC value for CYP11B2 50 The value is between 0.0001 μM and 1 μM; further preferred compounds have an EC value of 50 The values ​​ranged from 0.0001 μM to 0.1 μM.

[0148] At the same time, the compounds of the present invention have good selectivity for CYP11B1, with a selectivity greater than 50, preferably the selectivity of the compounds greater than 100, more preferably the selectivity of the compounds greater than 200, and further preferably the selectivity of the compounds greater than 500.

[0149] 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 the following steps:

[0150] Compound (Ia) reacts with a boron compound to prepare compound (Ib), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and then reacts with compound (Ic), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, through a coupling reaction to prepare the compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

[0151] The catalyst for the coupling reaction is a palladium reagent, preferably palladium acetate, tetrakistriphenylphosphine palladium, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0152] X is halogen, preferably bromine;

[0153] Z is a boron-containing compound, preferably a dioxaboryl group;

[0154] Ring A, Ring B, R1, R2, R3, R4, M1, M2, M3, M4, M5, M6, x, y, z and p are as defined in the general formula (I).

[0155] 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, comprising the following steps:

[0156] Compound (IV-a) reacts with borane to prepare compound (IV-b), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and reacts with compound (IV-c), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, through a coupling reaction to prepare a compound represented by formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

[0157] The catalyst for the coupling reaction is a palladium reagent, preferably palladium acetate, tetrakistriphenylphosphine palladium, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0158] X is halogen, preferably bromine;

[0159] Z is a boryl group, preferably dioxaborane;

[0160] Ring C, R1, R2, and M2 are as defined in the general formula (IV).

[0161] Detailed Description of the Invention

[0162] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0163] The term "alkyl" refers to a saturated aliphatic 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, 5-methylhexyl, 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 point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0164] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring 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 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0165] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiral atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl. More preferably, it is 3 yuan / 6 yuan, 3 yuan / 5 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0166] wait;

[0167] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0168] wait.

[0169] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can 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 alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0170] wait.

[0171] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0172] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0173] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it is a 3-8 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0174] Non-limiting examples of monocyclic heterocyclic groups include azetidine, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0175] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between the rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiral heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0176] wait.

[0177] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0178] wait.

[0179] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0180] wait.

[0181] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0182] wait.

[0183] The heterocyclyl group may be optionally substituted or unsubstituted. When 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, oxo, carboxyl or carboxylate.

[0184] The term "aryl" 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. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl, and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl, and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

[0185] Wherein the ring connecting to the parent structure is an aryl ring, non-limiting examples of which include:

[0186] wait.

[0187] The aryl group may be substituted or unsubstituted. When 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.

[0188] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0189] wait.

[0190] The heteroaryl group may be optionally substituted or unsubstituted, and when 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.

[0191] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0192] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0193] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0194] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0195] "Alkenyl" refers to an alkenyl group, also known as an alkene group, which refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond and the carbon-carbon double bond can be located at any position within the alkenyl group. The alkenyl group is a group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2-3 ) carbon atoms. Non-limiting examples of alkenyl groups include: The alkenyl group can be further substituted by other related groups, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0196] "Alkynyl" refers to (CH≡C-), which contains at least one carbon-carbon triple bond and the carbon-carbon triple bond can be located at any position within the alkynyl group, which contains at least one carbon-carbon double bond and the carbon-carbon double bond can be located at any position within the alkenyl group, and the alkynyl group is a group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2-3 ) carbon atoms. Non-limiting examples of alkynyl groups include: The alkynyl group can be further substituted by other related groups, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0197] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein the definition of alkenyl is as described above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0198] Refers to a single bond or a double bond.

[0199] "Hydroxy" refers to an -OH group.

[0200] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0201] "Amino" refers to -NH2.

[0202] "Cyano" refers to -CN.

[0203] "Nitro" refers to -NO2.

[0204] "Carbonyl" refers to -C(O)-.

[0205] "Carboxyl" refers to -C(O)OH.

[0206] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0207] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0208] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0209] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0210] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together 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, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0211] "Pharmaceutically acceptable salt" and "pharmaceutically usable salt" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0212] Example

[0213] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0214] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0215] HPLC analysis was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0216] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0217] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0218] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0219] The 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, and other companies.

[0220] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0221] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0222] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0223] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0224] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0225] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0226] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0227] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0228] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0229] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0230] intermediates

[0231] Intermediate Im-1

[0232] Step 1: 5-Bromo-4-methyl-pyridine-3-carboxylic acid ethyl ester

[0233] 5-Bromo-4-methyl-pyridine-3-carboxylic acid (20 g, 92.58 mmol) was dissolved in anhydrous N,N-dimethylformamide (200 mL). Anhydrous ethanol (42.65 g, 925.79 mmol, 54.06 mL), HATU (52.39 g, 138.87 mmol), and TEA (28.10 g, 277.74 mmol, 38.74 mL) were added. The reaction system was stirred at room temperature (20°C) for 16 hours. After completion, the reaction was quenched with water (50 mL), extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain crude 5-bromo-4-methyl-pyridine-3-carboxylic acid ethyl ester (21 g, crude).

[0234] MS m / z(ESI):244.0, 246.0[M+1].

[0235] Step 2: 4-Bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylic acid methyl ester

[0236] Dissolve ethyl 5-bromo-4-methyl-pyridine-3-carboxylate (7 g, 28.68 mmol) in anhydrous tetrahydrofuran (200 mL). Add lithium diisopropylamide (2 M, 17.21 mL) dropwise at -78°C and maintain stirring at -78°C for 1 hour. Then, slowly add methyl acrylate (6.17 g, 71.70 mmol, 6.46 mL). Allow the reaction system to warm to room temperature and continue stirring for 5 hours. After completion, slowly add water (20 mL) dropwise to quench the reaction. Extract with ethyl acetate (50 mL x 3), wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, and filter and concentrate to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc=3:1, uv=254 nm) to obtain methyl 4-bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylate (4 g, 14.0 mmol, 48.8% yield).

[0237] MS m / z(ESI):284.0, 286.0[M+1].

[0238] Step 3 4-Bromo-6,7-dihydro-5H-isoquinolin-8-one

[0239] Dissolve methyl 4-bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylate (7 g, 24.64 mmol) in 6 M hydrochloric acid (30 mL). Stir the reaction system in an oil bath at 100°C for 2 hours. After completion, cool to room temperature and adjust the pH to 7-8 with 6 M sodium hydroxide solution. Wash with ethyl acetate (50 mL x 3) and saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, and filter and concentrate to obtain crude 4-bromo-6,7-dihydro-5H-isoquinolin-8-one (4.8 g, 21.23 mmol, 86.17% yield). This crude product was used directly in the next reaction.

[0240] MS m / z(ESI):226.0, 228.0[M+1].

[0241] Step 4: 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine

[0242] Dissolve 4-bromo-6,7-dihydro-5H-isoquinolin-8-one (7 g, 30.96 mmol) in ammonia-methanol solution (2 M, 100 mL) and add tetraisopropyl titanate (17.60 g, 61.93 mmol, 18.33 mL). Stir the reaction system at 20 ° C for 16 hours. Then, add sodium borohydride (1.76 g, 46.45 mmol) in batches in an ice-water bath. Continue stirring the reaction system at room temperature for 2 hours. After the reaction is complete, add water (20 mL).

[0243] The reaction was quenched, filtered through celite, extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (Dichloromethane:Methanol = 10:1, UV = 254 nm) to afford 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (4.5 g, 19.82 mmol, 63.99% yield).

[0244] MS m / z(ESI):227.0, 229.0[M+1].

[0245] Step 5 (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine

[0246] 4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (4.5 g, 19.82 mmol) was subjected to the following chiral separation to obtain P1 and Im-1 products, respectively.

[0247] MS m / z(ESI):227.0, 229.0[M+1].

[0248] Example 1

[0249] 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

[0250] first step

[0251] 6-Bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0252] 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 then added at 0°C. The reaction was stirred at 25°C for 10 hours. The reaction was stopped and quenched with water (5 mL). The mixture was extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 6-bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (410 mg, yellow solid), in a yield of 77.2%.

[0253] MS m / z(ESI):242.0, 244.0[M+1].

[0254] Step 2

[0255] 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

[0256] 6-Bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (410 mg, 1.69 mmol), pinacol 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 replaced with nitrogen three times, and the reaction solution was stirred at 90°C for 10 hours. The reaction was stopped and cooled to room temperature. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product, 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (300 mg, yellow solid) in a yield of 61.2%.

[0257] MS m / z(ESI):290.1[M+1].

[0258] Step 3

[0259] N-(4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0260] 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). Propionyl chloride (224.07 mg, 2.42 mmol) was then added dropwise. The reaction mixture was stirred at 25°C for 3 hours. The reaction was stopped and quenched with water (5 mL). The mixture was extracted with dichloromethane (5 mL x 2). The combined organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (500 mg) in an 80.2% yield.

[0261] MS m / z(ESI):283.0, 285.0[M+1].

[0262] Step 4

[0263] 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

[0264] N-(4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (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 replaced with nitrogen three times and the reaction solution was stirred at 90°C for 10 hours. The reaction was stopped and quenched by adding water (5 mL). The mixture was 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 residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate 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) in a yield of 58.2%.

[0265] MS m / z(ESI):366.2[M+1].

[0266] 1HNMR(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).

[0267] Example 1 was split to obtain 1-A and 1-B

[0268] Example 2

[0269] 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

[0270] 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 give 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.

[0271] MS m / z(ESI):366.2[M+1].

[0272] 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).

[0273] Example 2 was separated to obtain 2-A and 2-B.

[0274] The similar preparation method of reference example 1 was used to obtain examples 3-56

[0275] Example 4

[0276] Step one, step two

[0277] 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.

[0278] Using 7-bromo-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one as the starting material, the same method as in the first step of Example 1 was used to obtain 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 in the second step.

[0279] MS m / z(ESI):302.2[M+1].

[0280] Step 3

[0281] 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

[0282] The same method as in the fourth step of Example 1 was used to obtain 7-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one.

[0283] MS m / z(ESI):322.2[M+1].

[0284] Step 4

[0285] 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

[0286] The same method as in the third step of Example 1 was used to obtain 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.

[0287] MS m / z(ESI):378.2[M+1].

[0288] Example 10

[0289] N-(4-(8-methyl-7-carbonyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0290] first step

[0291] 6-Bromo-1-methyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one

[0292] Dissolve 6-bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one (5 g, 22.02 mmol) in N,N-dimethylformamide (100 mL). Slowly add potassium tert-butoxide (4.94 g, 44.04 mmol) in an ice-water bath. After stirring for 0.5 hour, add iodomethane (4.69 g, 33.03 mmol, 2.06 mL) dropwise. Stir the reaction system at room temperature (20°C) for 5.5 hours. After completion, slowly add water (10 mL) in an ice-water bath to quench the reaction. Extract with ethyl acetate (20 mL x 2), wash with saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, and filter and concentrate to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 3:1, uv = 254 nm) to obtain 6-bromo-1-methyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one (4 g, yield 75.3%) as a light yellow solid.

[0293] MS m / z(ESI):241.0, 243.0[M+1].

[0294] Step 2

[0295] 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

[0296] Dissolve 6-bromo-1-methyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one (2.5 g, 10.37 mmol) in dioxane (50 mL). Add pinacol diboronate (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). The reaction system was purged with nitrogen several times and stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, cool to room temperature, filter through celite, dilute with water (10 mL), extract with ethyl acetate (20 mL x 2), wash with saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5:1, uv = 254 nm) to give 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, 80.32% yield) as a white solid.

[0297] MS m / z(ESI):289.1[M+1].

[0298] Step 3

[0299] N-(4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0300] 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). Propionyl chloride (224.07 mg, 2.42 mmol) was then added dropwise. The reaction mixture was stirred at 25°C for 3 hours. The reaction was stopped and quenched with water (5 mL). The mixture was extracted with dichloromethane (5 mL x 2). The combined organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (500 mg, yellow solid) in an 80.2% yield.

[0301] MS m / z(ESI):283.0[M+1].

[0302] Step 4

[0303] N-(4-(8-methyl-7-carbonyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0304] 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)propionamide (328 mg, 1.16 mmol) were dissolved in a mixed solvent of H₂O (5 mL) and EtOH (25 mL). Sodium carbonate (246 mg, 2.32 mmol) and tetrakis(triphenylphosphine)palladium (127.21 mg, 110.08 μmol) were added sequentially. The reaction system was purged with nitrogen several times and then stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, 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 obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 10:1, UV = 254 nm) to obtain 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, 58.92% yield).

[0305] MS m / z(ESI):365.1[M+1].

[0306] 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,1 H),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).

[0307] Example 10 was split to obtain 10-A and 10-B

[0308] Example 37

[0309] (R)-2-(Bicyclo[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

[0310] Using intermediate Im-1 as raw material, refer to Example 1 to obtain the product (R)-2-(bicyclo[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.

[0311] MS m / z(ESI):416.2[M+1].

[0312] Example 48

[0313] first step

[0314] 4-Bromo-7,7-dimethoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-6-ol

[0315] Potassium hydroxide (5.29 g, 94.32 mmol) was dissolved in methanol (50 mL). 4-Bromo-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one was added under nitrogen protection while cooling in an ice-water bath. The mixture was stirred at 0°C for 5 minutes. Iodobenzene acetate (6.08 g, 18.86 mmol) was then added. The mixture was stirred at 18°C ​​for 4 hours. The reaction solution was evaporated to dryness at low temperature. The crude product was quenched with saturated brine (100 mL) and extracted with ethyl acetate (50 mL x 3). The mixture was separated, and the organic phases were combined and washed with saturated brine (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with dichloromethane:methanol=100:0 to 95:5) to give the target product 4-bromo-7,7-dimethoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-6-ol (1.5 g, brown oil) in a yield of 58.02%.

[0316] MS m / z(ESI):274.0, 276.0[M+1].

[0317] Step 2

[0318] 4-Bromo-7,7-dimethoxy-7H-cyclopenta[c]pyridine

[0319] Dissolve 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) in dichloromethane (60 mL). Add trifluoroacetic anhydride (2.30 g, 10.94 mmol, 1.52 mL) under nitrogen and ice-water cooling. Stir the mixture at 20°C for 12 hours. Quench the reaction by adding saturated aqueous sodium bicarbonate (150 mL). Separate the organic phase, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 80:20) to give the target product 4-bromo-7,7-dimethoxy-7H-cyclopenta[c]pyridine (1.3 g) in a yield of 92.76%.

[0320] MS m / z(ESI):256.0, 258.0[M+1].

[0321] Step 3

[0322] 4-Bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridine

[0323] Trimethylsulfoxide iodide (3.35 g, 15.23 mmol) was dissolved in dimethylsulfoxide (20 mL). Sodium hydroxide (609.09 mg, 15.23 mmol, 60% w / w) was added under nitrogen. The mixture was stirred at 18°C ​​for 3 hours. 4-Bromo-7,7-dimethoxy-7H-cyclopenta[c]pyridine (1.30 g, 5.08 mmol) was added under nitrogen. 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 yield crude 4-bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridine (1.1 g). The crude product was used directly in the next step.

[0324] MS m / z(ESI):270.0, 272.0[M+1].

[0325] Step 4

[0326] 4-Bromo-5,5a-dihydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6(4bH)-one

[0327] Dissolve 4-bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridine (1.1 g, 4.07 mmol) in acetone (30 mL). Add p-toluenesulfonic acid monohydrate (774.61 mg, 4.07 mmol) under nitrogen. Stir the mixture at 18°C ​​for 2 hours. Evaporate the mixture to dryness at low temperature, quench the reaction with saturated brine (50 mL), and extract with dichloromethane (50 mL x 2). Combine the organic phases, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 75:25) to give the target product 4-bromo-5,5a-dihydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6(4bH)-one (0.55 g, light brown solid) in a yield of 60.28%.

[0328] MS m / z(ESI):224.0, 226.0[M+1].

[0329] Step 5

[0330] 4-Bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-amine

[0331] 4-Bromo-5,5a-dihydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6(4bH)-one (0.55 g, 2.45 mmol) was dissolved in a 2M methanolic ammonia solution (20 mL). Tetraisopropyloxytitanium (2.16 g, 4.91 mmol) was added under nitrogen. The mixture was stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature, and sodium borohydride (185.74 mg, 4.91 mmol) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was evaporated to dryness, and the crude product was dissolved in dichloromethane (60 mL) and washed with saturated brine (30 mL x 2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude 4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-amine (0.44 g). The crude product was used directly in the next step.

[0332] MS m / z(ESI):225.0, 227.0[M+1].

[0333] Step 6

[0334] N-(4-Bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide

[0335] N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propionamide was synthesized by using 4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-amine and propionyl chloride as raw materials, referring to the third step of Example 1.

[0336] MS m / z(ESI):281.0, 283.0[M+1].

[0337] Step 7

[0338] N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide

[0339] N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[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 were used as raw materials and N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide was synthesized by referring to the fourth step of Example 1.

[0340] MS m / z(ESI):362.2[M+1].

[0341] The sample was chirally separated to obtain products P1 and P2.

[0342] The product P1 was chirally resolved under the following conditions to obtain P1A and P1B

[0343] The product P2 was chirally resolved under the following conditions to obtain P2A and P2B

[0344] The LCMS and HNMR of sample P2B are as follows,

[0345] 1H NMR (400MHz, CDCl3) δ8.48(s,1H),8.40(s,1H),7.50(dd,J=8.4,2.0Hz,1H),7.44–7.34(m,1H),7.11(d,J=8.4Hz,1H),6.04–5.88(m,1 H),5.77–5.58(m,1H),3.41(s,3H),3.00(t,J=7.4Hz,2H),2.79–2.64(m,2H),2.60–2.48(m,1H),2.40–2.21(m,3H),1.37–1.15(m,5H).

[0346] MS m / z(ESI):362.2[M+1].

[0347] Example 57

[0348] 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

[0349] Referring to the synthetic route of Example 1, propionyl chloride was replaced with 1-methyl-1H-pyrazole-4-carbonyl chloride to obtain the title product 1-methyl-N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-1H-pyrazole-4-carboxamide 57.

[0350] MS m / z(ESI):418.2[M+1].

[0351] Example 58

[0352] 6-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxy)pyridin-3-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0353] first step

[0354] tert-Butyl 3-((5-bromopyridin-3-yl)oxy)azetidine-1-carboxylate

[0355] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate 58b (2 g, 11.56 mmol) in tetrahydrofuran (25 mL) was added sodium hydroxide (693 mg, 17.34 mmol, 60%), and the mixture was stirred at room temperature for 30 minutes. Then, a solution of 3-bromo-5-fluoropyridine 58a (1.6 g, 9.25 mmol) in tetrahydrofuran (10 mL) was added dropwise. The mixture was stirred at room temperature overnight, and water was added. The mixture was extracted with dichloromethane (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The title product, tert-butyl 3-((5-bromopyridin-3-yl)oxy)azetidine-1-carboxylate 58c, was obtained as a light yellow solid in a yield of 33%.

[0356] MS m / z(ESI):329.0[M+1].

[0357] Step 2

[0358] 3-(azetidine-3-oxy)-5-bromopyridine

[0359] To a solution of tert-butyl 3-((5-bromopyridin-3-yl)oxy)azetidine-1-carboxylate 58c (1 g, 3.04 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL) dropwise. The mixture was stirred at room temperature for 1 hour and concentrated to dryness under reduced pressure to give the title product 3-(azetidine-3-oxy)-5-bromopyridine 58d (1.1 g, crude).

[0360] MS m / z(ESI):229.0[M+1].

[0361] Step 3

[0362] 3-Bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxy)pyridine

[0363] Referring to the third step of the synthetic route of Example 1, propionyl chloride was replaced with ethanesulfonyl chloride to obtain the title product 3-bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxy)pyridine 58e

[0364] MS m / z(ESI):321.0[M+1].

[0365] Step 4

[0366] 6-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxy)pyridin-3-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0367] Referring to the fourth step of the synthetic route of Example 1, N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide was replaced with 3-bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxy)pyridine to obtain the title product 6-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxy)pyridin-3-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one 58.

[0368] MS m / z(ESI):404.1[M+1].

[0369] Example 59

[0370] 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

[0371] Referring to the synthetic route of Example 1, propionyl chloride was replaced with acetyl chloride to obtain 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

[0372] MS m / z(ESI):352.2[M+1].

[0373] Example 60

[0374] 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

[0375] first step

[0376] tert-Butyl 6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0377] 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). Sodium tert-butoxide (2.43 g, 25.33 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (733 mg, 1.27 mmol), and tris(dibenzylideneacetone)palladium (580 mg, 633 μmol) were added. The reaction system was purged with nitrogen three 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, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and 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), yield: 44.6%

[0378] MS m / z(ESI):354.1[M+1].

[0379] Step 2

[0380] 2-(5-Bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0381] Referring to the second step of the synthetic route of Example 58, the title product 2-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane 60d was obtained.

[0382] MS m / z(ESI):254.1[M+1].

[0383] Step 3

[0384] (6-(5-Bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazol-4-yl)methanone

[0385] Referring to the third step of the synthetic route of Example 1, the title product 2-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane 60f was obtained.

[0386] MS m / z(ESI):362.1[M+1].

[0387] Step 4

[0388] 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

[0389] Referring to the fourth step of the synthetic route of Example 1, the title product 1-methyl-6-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one 60 was obtained.

[0390] MS m / z(ESI):445.2[M+1].

[0391] Example 61

[0392] 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

[0393] first step

[0394] 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0395] Dissolve 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (5 g, 21.93 mmol) in N,N-dimethylformamide (50 mL). Slowly add potassium tert-butoxide (4.92 g, 43.85 mmol) in an ice-water bath. After stirring for 0.5 hour, iodomethane (4.67 g, 32.89 mmol, 2.05 mL) is added dropwise. The reaction system is stirred at room temperature (20°C) for 5.5 hours. After completion, slowly add H2O (20 mL) in an ice-water bath to quench the reaction. The product is extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 3:1, uv = 254 nm) to give 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (4.5 g, yield 84.7%) as a light yellow solid.

[0396] MS m / z(ESI):241.9[M+1].

[0397] Step 2

[0398] 4-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0399] 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). 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. The reaction system was purged with nitrogen several times and stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and H2O (20 mL) was slowly added. The mixture was extracted with ethyl acetate (20 mL x 2). The mixture was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5:1, uv = 254 nm) to obtain 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) as a white solid.

[0400] MS m / z(ESI):290.1[M+1].

[0401] Step 3

[0402] N-(4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0403] 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-dimethylformamide (20 mL). 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 quenched by the addition of water (10 mL). The mixture was extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 1:1, UV = 254 nm) to give the target product N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)-1-methyl-1H-pyrazole-4-carboxamide (400 mg, yield: 52.1%).

[0404] MS m / z(ESI):335.0[M+1].

[0405] Step 4

[0406] 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

[0407] N-(4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 285.6 μmol) and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (99.6 mg, 342.7 μmol) were dissolved in a mixed solvent of H2O (2 mL) and EtOH (10 mL). Sodium carbonate (91 mg, 857.0 μmol) and tetrakis(triphenylphosphine)palladium (33.0 mg, 28.6 μmol) were added sequentially. The reaction system was purged with nitrogen several times and then stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, 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 obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 10:1, UV = 254 nm) to afford 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, 41.7% yield).

[0408] MS m / z(ESI):418.1[M+1].

[0409] Example 62

[0410] 7-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxy)pyridin-3-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0411] first step

[0412] 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0413] Dissolve 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (5 g, 21.93 mmol) in N,N-dimethylformamide (50 mL). Slowly add potassium tert-butoxide (4.92 g, 43.85 mmol) in an ice-water bath. After stirring for 0.5 hour, iodomethane (4.67 g, 32.89 mmol, 2.05 mL) is added dropwise. The reaction system is stirred at room temperature (20°C) for 5.5 hours. After completion, slowly add H2O (20 mL) in an ice-water bath to quench the reaction. The product is extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 3:1, uv = 254 nm) to give 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (4.5 g, yield 84.7%) as a light yellow solid.

[0414] MS m / z(ESI):241.9[M+1].

[0415] Step 2

[0416] 4-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0417] 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). 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. The reaction system was purged with nitrogen several times and stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and H2O (20 mL) was slowly added. The mixture was extracted with ethyl acetate (20 mL x 2). The mixture was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5:1, uv = 254 nm) to obtain 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) as a white solid.

[0418] MS m / z(ESI):290.1[M+1].

[0419] Step 3

[0420] tert-Butyl 3-((5-bromopyridin-3-yl)oxy)azetidine-1-carboxylate

[0421] 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 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 system was purged with nitrogen several times and stirred in an oil bath at 100°C for 16 hours. After the reaction was completed, 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 obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5:1, uv = 254 nm) to obtain the target product tert-butyl 3-((5-bromopyridin-3-yl)oxy)azetidine-1-carboxylate (3.0 g, yield: 71.4%).

[0422] MS m / z(ESI):329.0[M+1].

[0423] Step 4

[0424] 3-(azetidine-3-oxy)-5-bromopyridine

[0425] Dissolve tert-butyl 3-((5-bromopyridin-3-yl)oxy)azetidine-1-carboxylate (500 mg, 1.52 mmol) in dichloromethane (10 mL) and add trifluoroacetic acid (1 mL). Stir the reaction at room temperature for 4 hours. After the reaction is complete, concentrate the excess solvent to obtain crude 3-(azetidine-3-oxy)-5-bromopyridine (350 mg, crude). This crude product is directly used in the next reaction.

[0426] MS m / z(ESI):228.9[M+1].

[0427] Step 5

[0428] 3-Bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxy)pyridine

[0429] 3-(Azetidine-3-oxy)-5-bromopyridine (350 mg, crude) was dissolved in tetrahydrofuran (10 mL). Triethylamine (462 mg, 4.56 mmol) and ethylsulfonyl chloride (292 mg, 2.28 mmol) were added, respectively, and the reaction system was stirred at room temperature for 4 hours. After completion, the reaction was quenched by the addition of water (5 mL). The mixture was extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 3:1, UV = 254 nm) to obtain the target product, 3-bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxy)pyridine (300 mg, yield: 61.7%).

[0430] MS m / z(ESI):320.9[M+1].

[0431] Step 6

[0432] 7-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxy)pyridin-3-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0433] 3-Bromo-5-((1-(ethylsulfonyl)azetidin-3-yl)oxy)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 mixed solvent of H2O (2 mL) and EtOH (10 mL). Sodium carbonate (99 mg, 935.1 μmol) and tetrakis(triphenylphosphine)palladium (36.0 mg, 31.2 μmol) were added sequentially. The reaction system was purged with nitrogen several times and then stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, 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 obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 10:1, UV = 254 nm) to obtain 7-(5-((1-(ethylsulfonyl)azetidin-3-yl)oxo)pyridin-3-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (55 mg, 43.7% yield).

[0434] MS m / z(ESI):404.1[M+1].

[0435] Example 63

[0436] 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

[0437] Using 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one and 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 obtained.

[0438] MS m / z(ESI):352.1[M+1].

[0439] Example 64

[0440] 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

[0441] first step

[0442] 7-Bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0443] Dissolve 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (5 g, 21.93 mmol) in N,N-dimethylformamide (50 mL). Slowly add potassium tert-butoxide (4.92 g, 43.85 mmol) in an ice-water bath. After stirring for 0.5 hour, iodomethane (4.67 g, 32.89 mmol, 2.05 mL) is added dropwise. The reaction system is stirred at room temperature (20°C) for 5.5 hours. After completion, slowly add H2O (20 mL) in an ice-water bath to quench the reaction. The product is extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 3:1, uv = 254 nm) to give 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (4.5 g, yield 84.7%) as a light yellow solid.

[0444] MS m / z(ESI):241.9[M+1].

[0445] Step 2

[0446] 4-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0447] 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). Diboronic acid pinacol ester (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. The reaction system was purged with nitrogen several times and stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and H2O (20 mL) was slowly added. The mixture was extracted with ethyl acetate (20 mL x 2). The mixture was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5:1, uv = 254 nm) to obtain 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) as a white solid.

[0448] MS m / z(ESI):290.1[M+1].

[0449] Step 3

[0450] tert-Butyl 6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0451] 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). 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 system was purged with nitrogen several times and stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched with water (10 mL). The mixture was extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5:1, uv = 254 nm) to obtain beige solid tert-butyl 6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (2 g, 5.65 mmol, 44.58% yield).

[0452] MS m / z(ESI):354.0[M+1].

[0453] Step 4

[0454] 2-(5-Bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0455] Dissolve tert-butyl 6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (500 mg, 1.41 mmol) in dichloromethane (10 mL) and add trifluoroacetic acid (1 mL). Stir the reaction at room temperature for 4 hours. After the reaction is complete, concentrate the excess solvent to obtain crude 2-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane (360 mg, crude). This crude product is directly used in the next reaction.

[0456] MS m / z(ESI):254.0[M+1].

[0457] Step 5

[0458] (6-(5-Bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-1H-pyrazol-4-yl)methanone

[0459] 2-(5-Bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane (360 mg, crude) was dissolved in tetrahydrofuran (10 mL). Triethylamine (430 mg, 4.23 mmol) and 1-methyl-1H-pyrazole-4-carboxylic acid (270 mg, 2.12 mmol) were added, respectively. The reaction system 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 × 2), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 3:1, uv = 254 nm) to obtain the target product (6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)(1-methyl-1H-pyrazol-4-yl)methanone (350 mg, yield: 68.7%).

[0460] MS m / z(ESI):362.1[M+1].

[0461] Step 6

[0462] 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

[0463] (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 mixed solvent of H2O (2 mL) and EtOH (10 mL). Sodium carbonate (88.0 mg, 828.6 μmol) and tetrakis(triphenylphosphine)palladium (32.0 mg, 27.6 μmol) were added sequentially. The reaction system was purged with nitrogen several times and then stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, 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 obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 10:1, UV = 254 nm) to obtain 4-methyl-7-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (45 mg, 36.7% yield) as a pale yellow solid.

[0464] MS m / z(ESI):445.1[M+1].

[0465] MS m / z(ESI):444.2[M+1].

[0466] Example 65

[0467] 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

[0468] Reference Example 57 was used to obtain 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.

[0469] MS m / z(ESI):419.2[M+1].

[0470] Example 66

[0471] 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

[0472] Refer to Example 1 to obtain 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)propionamide

[0473] MS m / z(ESI):384.1[M+1].

[0474] Example 67

[0475] N-((4bR,5aS)-4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide

[0476] 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-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide as raw materials, N-((4bR,5aS)-4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide was synthesized according to the seventh step of Example 48.

[0477] MS m / z(ESI):364.2[M+1].

[0478] The sample was subjected to chiral separation to obtain P1 and P2. The chiral separation conditions were as follows:

[0479] Example 68

[0480] 6-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridinyl]-5-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0481] first step

[0482] tert-Butyl 5-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0483] 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, ditriphenylpalladium dichloride (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) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 70:30) to give the target product tert-butyl 5-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (0.32 g, white solid) in a yield of 58.81%.

[0484] MS m / z(ESI):339.1, 341.1[M+1].

[0485] Step 2

[0486] 5-Bromo-1',2',3',6'-tetrahydro-3,4'-bipyridine hydrochloride

[0487] Tert-butyl 5-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (0.2 g, 589.58 μmol) was dissolved in dioxane hydrochloride (4 M, 10 mL). The mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to afford crude 5-bromo-1',2',3',6'-tetrahydro-3,4'-bipyridine hydrochloride (0.16 g). This crude product was used directly in the next step.

[0488] MS m / z(ESI):239.0, 241.0[M+1].

[0489] Step 3

[0490] 5-Bromo-1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine

[0491] 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). Cyclopropylsulfonyl chloride (106.12 mg, 754.79 μmol) was added under nitrogen. The mixture was stirred at 20°C for 1 hour. The reaction mixture was washed with saturated brine (30 mL x 2), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 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.

[0492] MS m / z(ESI):343.0, 345.0[M+1].

[0493] Step 4

[0494] 6-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridinyl]-5-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0495] 6-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-5-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was synthesized by referring to the fourth step of Example 1 using 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one and 5-bromo-1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine as raw materials.

[0496] MS m / z(ESI):426.1[M+1].

[0497] 1 H 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).

[0498] Example 69

[0499] 6-(5-(1-(cyclopropylsulfonyl)piperidin-4-yl)pyridin-3-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0500] 6-(1'-(Cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridinyl]-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). Palladium on carbon (w / w 10% containing 50% water) (4.0 mg) was added under nitrogen. The mixture was stirred at 20°C under a hydrogen atmosphere (1 atm) for 12 hours. The catalyst was removed by filtration, and the liquid phase was evaporated to dryness to obtain a crude product. The crude product was separated by Prep-HPLC to yield the desired product, 6-(5-(1-(cyclopropylsulfonyl)piperidin-4-yl)pyridin-3-yl)-2-methoxyoxazin-2-one (1 mg).

[0501] MS m / z(ESI):428.1[M+1].

[0502] Example 70

[0503] 6-(1'-(cyclopropylcarbonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-5-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0504] Refer to Example 68 to obtain the product 6-(1'-(cyclopropylcarbonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-5-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one.

[0505] MS m / z(ESI):390.1[M+1].

[0506] Example 71

[0507] 7-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridinyl]-5-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0508] Refer to Example 68 to obtain the product 7-(1'-(cyclopropylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridinyl]-5-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one.

[0509] MS m / z(ESI):426.1[M+1].

[0510] Example 72

[0511] (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

[0512] Referring to the synthetic route of Example 1, 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 was obtained.

[0513] MS m / z(ESI):406.1[M+1].

[0514] Example 73

[0515] (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

[0516] Using deuterated iodomethane as a raw material, refer to Example 1 to obtain 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.

[0517] MS m / z(ESI):369.2[M+1].

[0518] Example 74

[0519] ((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

[0520] Using deuterated propionic acid as a raw material, refer to Example 1 to obtain 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.

[0521] MS m / z(ESI):371.2[M+1].

[0522] Example 75

[0523] (R)-N-(8-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propanamide

[0524] first step

[0525] (R)-N-(8-Bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propanamide

[0526] Using 8-bromo-2,3-dihydro-4H-pyrano[3,2-c]pyridin-4-one as the raw material, the synthesis of the intermediate Im-1 in the fourth and fifth steps and the third step of Example 1 was referred to obtain the title product (R)-N-(8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propanamide.

[0527] MS m / z(ESI):285.0, 287.0[M+1].

[0528] Step 2

[0529] (R)-N-(8-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propanamide

[0530] Using (R)-N-(8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propionamide as raw material, refer to the fourth step of Example 1 to obtain 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-pyrano[3,2-c]pyridin-4-yl)propionamide.

[0531] MS m / z(ESI):368.1[M+1].

[0532] Example 76

[0533] (S)-N-(7-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2,3-dihydrofuro[3,2-c]pyridin-3-yl)propanamide

[0534] first step

[0535] 2-[(3,5-Dibromo-4-pyridyl)oxy]-N-methoxy-N-methyl-acetamide

[0536] 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-dimethylformamide (5 mL). Potassium carbonate (819.75 mg, 5.93 mmol) was added under nitrogen. The mixture was stirred at 25°C for 12 hours. The reaction was quenched by adding saturated brine (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed sequentially with saturated brine (30 mL x 5), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 60:40) to obtain the desired product (0.58 g, 83% yield).

[0537] MS m / z(ESI):352.9[M+1].

[0538] Step 2

[0539] 7-Bromofuro[3,2-c]pyridin-3-one

[0540] 2-[(3,5-Dibromo-4-pyridyl)oxy]-N-methoxy-N-methyl-acetamide (0.58 g, 1.64 mmol) was dissolved in THF (10 mL). Under nitrogen, n-butyllithium (1 M, 1.64 mL) was added under a dry ice-ethanol bath. The mixture was stirred at -78°C for 1 hour. The reaction solution was slowly warmed to 0°C and quenched by the addition of saturated aqueous ammonium chloride (1 mL). The mixture was then added to saturated brine (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed sequentially with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 70:30) to obtain the desired product, 7-bromofuro[3,2-c]pyridin-3-one (0.15 g, 42.78% yield).

[0541] MS m / z(ESI):213.9,215.9[M+1].

[0542] Step 3

[0543] (S)-7-Bromo-2,3-dihydrofluoro[3,2-c]pyridin-3-amine

[0544] Referring to the fourth and fifth steps of intermediate Im-1, the product (S)-7-bromo-2,3-dihydrofluoro[3,2-c]pyridin-3-amine was obtained.

[0545] MS m / z(ESI):215.0, 217.0[M+1].

[0546] Step 4

[0547] (S)-N-(7-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2,3-dihydrofuro[3,2-c]pyridin-3-yl)propanamide

[0548] The product (S)-N-(7-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2,3-dihydrofuro[3,2-c]pyridin-3-yl)propanamide was obtained by referring to Example 1.

[0549] MS m / z(ESI):354.1[M+1].

[0550] Example 77

[0551] 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

[0552] Using 3,5-dibromopyrazine and tert-butyl piperidin-4-ylcarbamate as raw materials, reference was made to Example 60 to obtain 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.

[0553] MS m / z(ESI):448.2[M+1].

[0554] Biological test evaluation

[0555] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0556] Test Example 1

[0557] The G-402 cell line is used as a host cell to express (transiently or stably) enzymes of the human CYP11 family. Specifically, G-402 cell lines stably expressing human CYP11B1 and human CYP11B2 were established. It has been confirmed that the G-402 cell line expresses cofactors (cortical ferredoxin and cortical ferredoxin reductase) that are important for the activity of the CYP11 family, and (compared to H295R cells) the cell line itself does not have CYP11 family-related enzyme activity. Therefore, the G-402 cell line is very suitable as a host cell for ectopic expression of CYP11 family enzymes.

[0558] The G-402 cell line was originally derived from renal myoblastoma and can be obtained from ATCC (CRL-1440). The main components of the expression plasmid include the ORF of human CYP11B1 or human CYP11B2, a suitable promoter (CMV promoter), and a suitable resistance marker (neomycin). The expression plasmid is transfected into G-402 cells using standard techniques and then screened with specific antibiotics. The activity of the enzyme expressed by the screened monoclonal cells is evaluated using 11-deoxycorticosterone (a substrate for CYP11B2) and 11-deoxycortisol (a substrate for CYP11B1).

[0559] G-402 cells expressing the CYP11 plasmid established with the above protocol 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. Enzyme assays were performed using DMEM / F12 medium containing 2.5% charcoal-stripped FBS and the appropriate concentration of substrate (1 μM 11-deoxycorticosterone or 1 μM 11-deoxycortisol). To measure enzyme activity, cells were plated in 96-well plates and incubated for 16 hours. The supernatant was then transferred and analyzed for the concentration of the expected product (aldosterone for CYP11B2 and cortisol for CYP11B1). The concentrations of these products were determined using CisBio's HTRF assay.

[0560] In cell enzyme experiments, the inhibitory effect of the test compound on the generated product can reflect its inhibitory effect on the enzyme. The dose-dependent inhibition of the compound on the enzyme activity is calculated by plotting the test compound concentration (x-axis) against the measured product level (y-axis). The raw data are then fitted to a 4-parameter sigmoid function (Morgan-Mercer-Flodin, MMF model) using the least squares method: y = (AB + Cx D ) / (B+x D )

[0561] 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. 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 in G402 cells expressing an empty plasmid.

[0562] The EC of this patented compound 50 The values ​​were determined using the G-402 assay system described above. CYP11B2 enzyme activity was determined in the presence of 1 μM 11-deoxycorticosterone and variable amounts of inhibitors, and CYP11B1 enzyme activity was determined in the presence of 1 μM 11-deoxycortisol and variable amounts of inhibitors. Note: hSF is the abbreviation of human selective factor, which refers to the selectivity of compound CYP11B2 for CYP11B1. The value of hSF is the ratio of CYP11B1 EC50 to CYP11B2 EC50.

[0563] It can be seen from the above data that the compounds of the present invention have good CYP11B2 activity and higher selectivity compared to CYP11B1 enzyme.

[0564] Test Example 2 Pharmacokinetic Determination in Rats

[0565] 1. Research objectives:

[0566] SD rats were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in rats (plasma) after oral administration.

[0567] 2. Experimental Plan

[0568] 2.1 Investigational Drugs:

[0569] The compound of the present invention is homemade.

[0570] 2.2 Experimental Animals

[0571] There were 3 male SD rats in each group.

[0572] 2.3 Drug preparation:

[0573] Oral administration drug preparation: 0.5% CMC-Na (1% Tween 80)

[0574] Weigh 5g of sodium carboxymethylcellulose (CMC-Na, viscosity: 800-1200 cps), dissolve it in 1000mL of purified water, and add 10g of Tween 80. Mix well to form a clear solution.

[0575] The example compound was weighed and dissolved in the solution, shaken and sonicated for 15 minutes to obtain a colorless clear solution with a concentration of 0.5 mg / mL.

[0576] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0577] The example compound was weighed and first added with 5% DMSO in proportion to the total volume of the compound to be administered. The mixture was vortexed and sonicated for 2 minutes to completely dissolve. Then, 10% Solutol HS15 was added and vortexed and sonicated for 2 minutes to completely dissolve the compound. Finally, 85% PBS was added and vortexed and sonicated for 5 minutes. The solution was filtered through a 0.22 μM filter to obtain a colorless, transparent, clear solution with a concentration of 0.2 mg / mL.

[0578] 2.4 Administration:

[0579] Three male SD rats were administered PO after overnight fasting at a dose of 5 mg / kg in a dosing volume of 10 mL / kg.

[0580] Three male SD rats were administered IV after overnight fasting at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0581] 2.5 Sample collection:

[0582] Before administration and at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, and 24.0 h after administration, 0.2 mL of blood was collected from the jugular vein of the experimental animals. The blood was placed in an EDTA-2K tube and centrifuged at 8000 rpm for 6 min at 4°C to separate the plasma, which was then stored at -80°C. The animals were fed 4 h after administration.

[0583] 3 Experimental results: The final determination results were obtained using the LCMS / MS method

[0584] The experimental results show that the compound of the present invention has a very good exposure amount in rats.

[0585] Test Example 3 Pharmacokinetic Determination in Mice

[0586] 1. Research objectives:

[0587] Balb / c mice were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in mice (plasma) after oral administration.

[0588] 2. Experimental Plan

[0589] 2.1 Investigational Drugs:

[0590] The compound of the present invention is homemade.

[0591] 2.2 Experimental Animals

[0592] Balb / c mice (3 males per group) were obtained from Shanghai Bikai Laboratory Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 No. 311620400001794).

[0593] 2.3 Drug preparation:

[0594] Oral administration drug preparation: 0.5% CMC-Na (1% Tween 80)

[0595] Weigh 0.5 g of sodium carboxymethylcellulose (CMC-Na, viscosity: 800-1200 cps), dissolve it in 99 mL of purified water, and add 1 mL of Tween 80. Mix well to form a clear solution.

[0596] Example 1 and Example 2 were weighed and dissolved in the solution, shaken and ultrasonicated for 15 minutes to obtain a colorless clear solution with a concentration of 0.5 mg / mL.

[0597] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0598] Example 1 and Example 2 were weighed, and 5% DMSO was first added according to the total volume ratio of the dosage, and the mixture was vortexed and sonicated for 2 minutes to completely dissolve. Then, 10% Solutol HS15 was added, and the mixture was vortexed and sonicated for 2 minutes to completely dissolve. Finally, 85% PBS was added, and the mixture was vortexed and sonicated for 5 minutes. The mixture was filtered through a 0.22 μM filter to obtain a colorless, transparent, clear solution with a concentration of 0.2 mg / mL.

[0599] 2.4 Administration:

[0600] Balb / c mice (3 males per group) were fasted overnight and PO-administered at a dose of 5 mg / kg in a volume of 10 mL / kg.

[0601] Balb / c mice (3 males per group) were fasted overnight and administered IV at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0602] 2.5 Sample collection:

[0603] Before administration and at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, and 24.0 h after administration, 0.04 mL of blood was collected from the experimental animals' orbits, placed in EDTA-2K tubes, and centrifuged at 8000 rpm for 6 min at 4°C to separate the plasma, which was then stored at -80°C. The animals were fed 4 h after administration.

[0604] 3 Experimental results: The final determination results were obtained using the LCMS / MS method

[0605] The experimental results show that the compound of the present invention has a very good exposure amount in mice.

[0606] Test Example 4 In vivo efficacy determination

[0607] Male cynomolgus monkeys were gavaged (PO) with the test compound and divided into 0 mpk (vehicle group), 0.1 mpk, 0.3 mpk, 1 mpk, and 3 mpk dose groups. Each group received an intravenous (IV) injection of 5 μg / kg ACTH one hour later. Blood samples were collected at -1 hour, 0 hour, 0.5 hour, 1.0 hour, 1.5 hour, 2 hours, and 3 hours after the intravenous injection of ACTH, with approximately 0.5 mL of blood collected at each time point. The samples were centrifuged within one hour of collection (3200 g, 10 minutes at 2 to 8°C), and then the plasma levels of aldosterone, cortisol, corticosterone, 11-deoxycortisol, and 11-deoxycorticosterone at each time point were analyzed by LC / MS-MS. The experimental results are as follows:

[0608] The experimental results show that the compound 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: in: is a single bond or a double bond; Ring A is a 5-7 membered heterocyclic group containing 2-3 heteroatoms selected from N, O or S, and Ring A contains at least one oxygen atom; Ring B is a 5-6 membered heteroaryl group or a phenyl group; Ring C is cycloalkyl, heteroaryl, heterocyclyl or absent; M1, M2, M4, M5, and M6 are each independently selected from N, C, NH, or CH; M3 is a bond, N or CH; R1 is independently selected from cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio, heterocyclylthio, -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 a S(O)(NH)(CH2) n R b or -NS(O)(CH2) n R a R b Optionally, the cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio or heterocyclylthio is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in; Alternatively, any two R1s form a 3-8 membered cycloalkyl or 4-7 membered heterocyclic group with adjacent carbon atoms, and optionally, the 3-8 membered cycloalkyl or 4-7 membered heterocyclic group is further substituted with an oxo group, -C(O)R b 、-NR a C(O)R b 、-S(O)2R b 、-S(O)(NH)R b 、-NR a S(O)2R b or -NR a S(O)(NH)R b replaced by; R a or R b each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally, the cycloalkyl, aryl, heteroaryl or heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl or -S(O)2alkyl; R2, R3 or R4 are each independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a C(O)(CH2) n R b or -C(O)NR a (CH2) n R b , which may optionally be further substituted; Alternatively, R2 and R3 form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclic group with adjacent atoms, and optionally the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclic group is further replaced by one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl. generation; Alternatively, any two R2 form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclyl with adjacent atoms, and the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclyl is optionally further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl; Alternatively, R2 and R4 form a 5-14 membered cycloalkyl, a 5-14 membered heteroaryl or a 5-14 membered heterocyclyl with adjacent atoms, optionally wherein the 5-14 membered cycloalkyl, the 5-14 membered heteroaryl or the 5-14 membered heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl; p, x, y and z are each independently selected from 1, 2, 3 or 4; n is selected from 0, 1, 2 or 3.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Selected from 3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring C is absent or selected from 3-10 membered cycloalkyl or 4-10 membered heterocyclic group containing 1-3 groups selected from C(O), N, O, S, SO2 or SONH; Preferably, ring C is selected from 5-7 membered monocyclic cycloalkyl, 6-10 membered bicyclic cycloalkyl, 5-7 membered monocyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH, 7-10 membered bicyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH; More preferably, ring C is selected from the following groups:

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is independently selected from 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio, -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 Optionally, the 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in; R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C(O), N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, any Preferably, the 3-8 membered cycloalkyl, the 5-8 membered heteroaryl containing 1-3 selected from C(O), N, O or S, or the 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, is further substituted with one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 3-6 membered cycloalkyl or -SO2-C 1-6 Substituted by a substituent in the alkyl group; Preferably, R1 is independently selected from 3-10 membered cycloalkyl, 4-10 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH, 4-8 membered heterocyclylamino containing 1-3 selected 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 a S(O)(NH)(CH2) n R b Optionally, the 3-10 membered cycloalkyl, the 4-10 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, the 3-8 membered cycloalkyloxy, the 3-8 membered cycloalkylamino, the 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH or the 4-8 membered heterocyclylamino containing 1-3 selected N, O, S, SO2 or SONH, is further substituted by one or more selected from oxo, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in; R a or R b are independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, optionally, the 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, 3-6 membered cycloalkyl or -SO2-C 1-3 substituted by a substituent in the alkyl group.

5. The compound according to claim 1 or 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkylamino, C 6-10 Aryl, 5-6 membered heteroaryl containing 1-3 selected from N, O, S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, -NR a R b 、-NR a C(O)R b or -C(O)NR a R b ; Preferably, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyloxy.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, further being a compound represented by general formula (II-a), (II-b) or (II-c), its stereoisomer or a pharmaceutically acceptable salt thereof: in, Ring A is a 6-membered heterocyclic group; Ring B is selected from phenyl or a 5-6 membered heteroaryl group containing 1-3 groups selected from N, O or S; R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, -NR a C(O)R b or -C(O)NR a R b ; R a or R b are independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 groups selected from N, O or S, or 4-8 membered heterocyclic group containing 1-3 groups selected from C(O), N, O or S.

7. The compound according to any one of claims 1 to 5, its stereoisomers or pharmaceutically acceptable salts thereof, further being a compound represented by general formula (III-b) to (III-c), its stereoisomers or pharmaceutically acceptable salts thereof: Ring C is selected from 5-7 membered monocyclic cycloalkyl, 6-10 membered bicyclic cycloalkyl, 5-7 membered monocyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH, and 7-10 membered bicyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH; Alternatively, ring C is absent; L is selected from a bond, -O-, -R c C(O)-、-R c S(O)NH- or -R c S(O)2, preferably -NHC(O)-; R c Selected from a bond, NH, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 selected from N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy containing 1-3 selected from N, O, S, SO2 or SONH; R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl; R b Selected from hydrogen, deuterium, C 1-3 Alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S, or 4-8 membered heterocyclyl containing 1-3 selected from C(O), N, O, S, SO2 or SONH; y is 1, 2, or 3.

8. The compound according to claim 1 or 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following groups: Preferred 9. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, further being a compound represented by general formula (IV), its stereoisomer or a pharmaceutically acceptable salt thereof: in: M2 is selected from N or CH; Ring C is selected from 5-7 membered monocyclic cycloalkyl, 6-10 membered bicyclic cycloalkyl, 5-7 membered monocyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH, 7-10 membered bicyclic heterocyclic group containing 1-3 members selected from C(O), N, O, S, SO2 or SONH or is absent; preferably, ring C is selected from 6 membered monocyclic cycloalkyl; R1 is selected from -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 4-8 membered heterocyclic group, wherein the 4-8 membered nitrogen-containing heterocyclic group is optionally further -C(O)R b or -S(O)2R b replaced by; R a or R b are independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 a haloalkoxy group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1-3 groups selected from N, O, or S, or a 4- to 8-membered heterocyclyl group containing 1-3 groups selected from C(O), N, O, or S; R2 is selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyloxy.

10. The compound described below, its stereoisomer or a pharmaceutically acceptable salt thereof:

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

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

13. Use of the compound of any one of claims 1 to 10, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating diseases associated with CYP11B2.

14. A method for preparing the compound of general formula (I) as claimed in claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, comprising the following steps: Compound (Ia) reacts with a boron compound to prepare compound (Ib), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and then reacts with compound (Ic), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, through a coupling reaction to prepare the 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, tetrakistriphenylphosphine palladium, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; X is halogen, preferably bromine; Z is a boron-containing compound, preferably a dioxaboryl group; Ring A, Ring B, Ring C, R1, R2, R3, R4, M1, M2, M3, M4, M5, M6, x, y, z and p are as defined in claim 1.

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