Bis(fused ring) compounds, preparation method therefor and use thereof

Abstract

The present invention relates to a bis(fused ring) compound inhibitor, a preparation method therefor and the use thereof. In particular, the present invention relates to compounds represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compounds, and the use thereof in the preparation of drugs used for treating chronic kidney disease, renal or cardiac fibrosis, diabetic kidney disease, congestive heart failure, hypertension, primary aldosterone hyperplasia, and Cushing's syndrome.

Description

Bifused ring compounds, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a bifused ring compound inhibitor, its preparation method, and its application. Background Technology

[0002] Aldosterone is a steroid hormone secreted by 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 resulting in elevated blood pressure (BP). The renin-angiotensin-aldosterone system (RAAS), as an endocrine system, regulates blood pressure and fluid balance in the human body. Current antihypertensive drugs—angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor antagonists (ARBs), and mineralocorticoid receptor antagonists (MRAs)—regulate blood pressure by inhibiting this pathway. Patients taking ACEi or ARBs long-term may experience "aldosterone breakthrough," where aldosterone levels temporarily decrease and then rise, damaging target organs. Currently, the only marketed aldosterone inhibitor is spironolactone, which can cause hyperkalemia. Excess aldosterone measured in circulation is called primary aldosteronism (PA), and it occurs when the renin-angiotensin-aldosterone system (RAAS) dysregulates aldosterone production. PA was initially found 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 refractory hypertension (RHTN), defined as blood pressure remaining above the target level of 140 / 90 mmHg even with the use of three antihypertensive medications (calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics). Refractory hypertension is a high-risk condition with a high comorbidity rate, including diabetes, chronic kidney disease, ischemic heart disease, and cerebrovascular disease.

[0003] CYP11B2 is the gene encoding aldosterone synthase, and its sequence is highly homologous to that of CYP11B1, which encodes cortisol synthase. Developing highly selective CYP11B2 inhibitors to inhibit aldosterone synthesis is a major direction for the treatment of refractory hypertension and essential aldosteronism. Summary of the Invention

[0004] The object of this invention is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0005] in:

[0006] It can be a single bond or a double bond;

[0007] The ring C is cycloalkyl, heteroaryl, heterocyclic, or absent;

[0008] Z is selected from CR a Or N;

[0009] M1, M3, M4, M5, and M6 are selected independently from N and NR in different regions. a C or CR a ;

[0010] M2 is a bond, N, or CH;

[0011] R1 is independently selected from alkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, cycloalkyloxy, heterocyclicoxy, cycloalkylamino, heterocyclicamino, cycloalkylthio, heterocyclicthio, and -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 alkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, cycloalkyloxy, heterocyclic oxy, cycloalkylamino, heterocyclic amino, cycloalkylthio, or heterocyclic thio group is further selected from one or more groups chosen from R. c Substituents;

[0012] R c Each group is independently selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -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 The alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further converted to -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 The substituents in it are replaced;

[0013] Alternatively, any two R1 atoms can form C with adjacent carbon atoms. 3-8 Cycloalkyl or 4-7 membered heterocyclic group, optionally, the C 3- 8-cyclic alkyl or 4-7-membered heterocyclic groups are further converted to oxo groups, alkyl groups, or -C(O)R groups. 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;

[0014] R a or R b Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclic, optionally, the cycloalkyl, aryl, heteroaryl or heterocyclic group is further substituted by one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, heteroaryl or -S(O)2alkyl;

[0015] R2 or R3 is independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR a C(O)(CH2) n R b or -C(O)NR a (CH2) n R b The optional ones can be further replaced;

[0016] p, x, or y are independently selected from 1, 2, 3, or 4 in each location;

[0017] n is selected from 0, 1, 2 or 3.

[0018] This invention provides a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0019] in:

[0020] It can be a single bond or a double bond;

[0021] The ring C is cycloalkyl, heteroaryl, heterocyclic, or absent;

[0022] Z is selected from CR a Or N;

[0023] M1, M3, and M4 are independently selected from N and NR in different regions. a , or CR a ;

[0024] M5 and M6 are selected independently from N, C, or CR in different regions. a ;

[0025] M2 is a bond, N, or CH;

[0026] R1 is independently selected from alkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, cycloalkyloxy, heterocyclicoxy, cycloalkylamino, heterocyclicamino, cycloalkylthio, heterocyclicthio, and -(CH2). n C(O)R b -(CH2) n NR a C(O)R b -(CH2) n OR b -(CH2) n NHR b -(CH2)n SR b -(CH2) n S(O)2R b -(CH2) n S(O)(NH)R b -(CH2) n NR a S(O)2R b -(CH2) n NR a S(O)(NH)R b Or -(CH2) n NS(O)R a R b Optionally, the alkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, cycloalkyloxy, heterocyclic oxy, cycloalkylamino, heterocyclic amino, cycloalkylthio, or heterocyclic thio group is further selected from one or more groups chosen from R. c Substituents;

[0027] R c Each group is independently selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -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 The alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further converted to -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 The substituents in it are replaced;

[0028] Alternatively, any two R1 atoms can form C with adjacent carbon atoms. 3-8 Cycloalkyl or 4-7 membered heterocyclic group, optionally, the C 3- 8-cyclic alkyl or 4-7-membered heterocyclic groups are further converted to oxo groups, alkyl groups, or -C(O)R groups. 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;

[0029] R a or R b Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclic, optionally, the cycloalkyl, aryl, heteroaryl or heterocyclic group is further substituted by one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, heteroaryl or -S(O)2alkyl;

[0030] R2 or R3 is independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR a C(O)(CH2) n R b or -C(O)NR a (CH2) n R b The optional ones can be further replaced;

[0031] p, x, or y are independently selected from 1, 2, 3, or 4 in each location;

[0032] n is selected from 0, 1, 2 or 3.

[0033] In a preferred embodiment of the present invention, ring C is selected from C. 3-10 Cycloalkyl or containing 1-3 4-10 membered heterocyclic groups selected from C(O), N, O, S, SO2 or SONH; preferably C 3-6Cycloalkyl or containing 1-3 4-6 membered heterocyclic groups selected from C(O), N, O, S, SO2 or SONH.

[0034] In a preferred embodiment of the present invention, R1 is selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from C(O), N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, or containing 1-3 4-8 membered heterocyclic amino groups selected from N, O, S, SO2 or SONH -(CH2). n C(O)R b -(CH2) n NR a C(O)R b -(CH2) n OR b -(CH2) n NR a R b -(CH2) n SR b -(CH2) n S(O)2R b -(CH2) n S(O)(NH)R b -(CH2) n NR a S(O)2R b -(CH2) n NR a S(O)(NH)R b Or -(CH2) n NS(O)R a R b Optionally, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from C(O), N, O, S, SO2 or SONH, optionally further containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from C(O), N, O, S, SO2 or SONH, and optionally further containing one or more groups selected from R cSubstituents;

[0035] R c Each is independently selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, -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 Optionally, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, optionally further modified by -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 The substituents in it are replaced;

[0036] R a or Rb Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, optionally, the C 3-8 Cycloalkyl, containing 1-3 5-8-membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O or S, further by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 heterocyclic or -SO2-C 1-6 Substituents in alkyl groups.

[0037] In a preferred embodiment of the present invention, R1 is independently selected from C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3- 10 Cycloalkyl, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C3-8 cycloalkyloxy groups, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, -C(O)(CH2) n R b -NR a C(O)(CH2) n R b -O(CH2) n R b -NH(CH2) n R b -S(CH2) nR 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 C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, optionally further further containing one or more groups selected from R c Substituents;

[0038] R c Each is independently selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, -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 bOptionally, the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, optionally further modified by -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 The substituents in it are replaced.

[0039] In a preferred embodiment of the present invention, R1 is independently selected from C. 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, -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 or -NR a S(O)(NH)R b Optionally, the C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, or containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, further surrounded by one or more 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 The substituents in it are replaced;

[0040] R a or R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-3 Alkyl, C 3-8 The cycloalkyl group, containing 1-3 5-8-membered heteroaryl groups selected from N, O, or S, or containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O, or S, optionally, the 5-8-membered heteroaryl group containing 1-3 5-8-membered heteroaryl groups selected from N, O, or S, or the 4-8-membered heterocyclic group containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O, or S, is further surrounded by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups or -SO2-C 1-3 Substituents in alkyl groups.

[0041] In a preferred embodiment of the present invention, R2 or R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, C3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, C 6-10 aryl, containing 1-3 5-6 membered heteroaryl groups selected from N, O, S, or containing 1-3 4-8 membered heterocyclic groups 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 .

[0042] In a preferred embodiment of the present invention, R2 or R3 is independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyloxy groups.

[0043] In a preferred embodiment of the invention, a compound of general formula (I) or a pharmaceutically acceptable salt thereof is provided:

[0044] in:

[0045] It can be a single bond or a double bond;

[0046] The ring C is cycloalkyl, heteroaryl, heterocyclic, or absent;

[0047] Z is selected from CR a Or N;

[0048] M1, M3, M4, M5, and M6 are independently selected from N, NH, C, or CH in each region;

[0049] M2 is a bond, N, or CH;

[0050] R1 is independently selected from cycloalkyl, heterocyclic, cycloalkyloxy, heterocyclic oxy, cycloalkylamino, heterocyclic amino, cycloalkylthio, heterocyclic thio, and -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, heterocyclic, cycloalkyloxy, heterocyclic oxy, cycloalkylamino, heterocyclic amino, cycloalkylthio, or heterocyclic thio group is further selected from one or more groups 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 The substituents in it are replaced;

[0051] Alternatively, any two R1 atoms can form C with adjacent carbon atoms. 3-8 Cycloalkyl or 4-7 membered heterocyclic group, optionally, the C 3- 8-cyclic alkyl or 4-7-membered heterocyclic groups are further oxidized by oxo groups, -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;

[0052] R a or R bEach group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclic, optionally, the cycloalkyl, aryl, heteroaryl or heterocyclic group is further substituted by one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, heteroaryl or -S(O)2alkyl;

[0053] R2 or R3 is independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR a C(O)(CH2) n R b or -C(O)NR a (CH2) n R b The optional ones can be further replaced;

[0054] Alternatively, R2 and R3 form C with adjacent atoms. 3-8 Cycloalkyl, 5-6-membered heteroaryl, or 4-7-membered heterocyclic, optionally C 3-8 The cycloalkyl, 5-6-membered heteroaryl or 4-7-membered heterocyclic group is further substituted by one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl.

[0055] p, x, or y are independently selected from 1, 2, 3, or 4 in each location;

[0056] n is selected from 0, 1, 2, or 3;

[0057] In a preferred embodiment of the invention, general formula (I) is further a compound of general formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof:

[0058] in,

[0059] The ring C is a cycloalkyl, heteroaryl, or heterocyclic group;

[0060] Z is selected from CR a Or N;

[0061] M1, M2, and M3 are each independently selected from N or CR. a;

[0062] M5 is independently selected from N, C, or CH;

[0063] R1, R2, R a x is defined as in general formula (I).

[0064] In a preferred embodiment of the invention, general formula (I) is further a compound of general formula (I-2-a), (I-2-b), (I-2-c) or (I-2-d) or a pharmaceutically acceptable salt thereof:

[0065] in,

[0066] Z is selected from CH or N;

[0067] Ring E is independently selected from C. 3-8 Cycloalkyl, containing 1-3 5-6 heteroaryl groups selected from N, O, S, or containing 1-3 4-8 heterocyclic groups selected from C(O), N, O, or S;

[0068] M1, M2, or M3 are each independently selected from N or CR a ;

[0069] M7 or M8 are each independently selected from N, C or CH;

[0070] M9 or M 10 Each is independently selected from O, S, NH or CH2;

[0071] R1, R2, R a As defined by general formula (I).

[0072] In a preferred embodiment of the invention, general formula (I) is further a compound of general formula (I-2a) or (I-2b) or a pharmaceutically acceptable salt thereof:

[0073] in,

[0074] Z is independently selected from CH or N;

[0075] The ring C is a cycloalkyl, heteroaryl, or heterocyclic group;

[0076] L stands for bond, C 1-3 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, NR a , O or S;

[0077] M1, M2, or M3 are each independently selected from N or CR a ;

[0078] M5 is selected from N or CRa ;

[0079] Ring D is selected from 3-12 membered heterocyclic groups containing 1-3 nitrogen atoms or C. 3-10 cycloalkyl;

[0080] R a Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S;

[0081] R1, R2, and x are defined as in general formula (I).

[0082] In a preferred embodiment of the invention, general formula (I) is further a compound represented by general formulas (I-3) to (I-10) or a pharmaceutically acceptable salt thereof:

[0083] in,

[0084] Z or M2 are each independently selected from N or CH;

[0085] R1, R2, and x are defined as in general formula (I).

[0086] In a preferred embodiment of the present invention, L is a bond, CH2, NH, O, or S;

[0087] M1, M2, or M3 are each independently selected from N or CR a ;

[0088] M5 is selected from N or CR a ;

[0089] Ring D is selected from 5-6 membered monocyclic heterocyclic groups containing 1-3 nitrogen atoms, 6-10 membered bridged ring heterocyclic groups containing 1-3 nitrogen atoms, or 6-10 membered fused ring heterocyclic groups containing 1-3 nitrogen atoms;

[0090] R a Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl.

[0091] In a preferred embodiment of the present invention, each of R1 is independently selected from -(CH2). n C(O)R b-(CH2) n OR b -(CH2) n S(O)2R b -(CH2) n NR a C(O)R b Or -(CH2) n NR a R b ;

[0092] R a or R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-3 Alkyl, C 3-6 Cycloalkyl, containing 1-3 4-6 membered heterocyclic groups selected from N, O, S, SO2 or SONH, containing 1-3 5-6 membered heteroaryl groups selected from C(O), N, O or S; optionally, the C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups containing 1-3 C(O), N, O, S, SO2 or SONH, or 5-6 membered heteroaryl groups containing 1-3 C(O), N, O or S, further surrounded by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl or C 3-6 Substituents in cycloalkyl groups;

[0093] R2 is independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl.

[0094] In a preferred embodiment of the invention, general formula (I) is further a compound of general formula (I-3a) to general formula (I-10a) or a pharmaceutically acceptable salt thereof:

[0095] In a preferred embodiment of the present invention, ring C is selected from C. 3-10 Cycloalkyl or containing 1-3 4-10 membered heterocyclic groups selected from C(O), N, O, S, SO2 or SONH.

[0096] In a preferred embodiment of the present invention, the ring C is selected from 5-7 member monocyclic cycloalkyl, 6-10 member bicyclic cycloalkyl, containing 1-3 5-7 member monocyclic heterocyclic groups selected from C(O), N, O, S, SO2 or SONH, or containing 1-3 7-10 member bicyclic heterocyclic groups selected from C(O), N, O, S, SO2 or SONH.

[0097] In a preferred embodiment of the present invention, the ring C is selected from 5-7 member monocyclic cycloalkyl, 5-10 member fused cycloalkyl, 5-10 member spirocycloalkyl, 6-10 member bridged cycloalkyl, containing 1-3 5-7 member monoheterocyclic groups selected from C(O), N, O, S, SO2 or SONH, containing 1-3 5-10 member fused heterocyclic groups selected from C(O), N, O, S, SO2 or SONH, containing 1-3 5-10 member spirocyclic groups selected from C(O), N, O, S, SO2 or SONH, or containing 1-3 6-10 member bridged heterocyclic groups selected from C(O), N, O, S, SO2 or SONH;

[0098] In a preferred embodiment of the present invention, the ring C is selected from the following groups:

[0099] In a preferred embodiment of the present invention, R1 is independently selected from C. 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 3-8 Cycloalkyloxy, 4-8 membered heterocyclic alkyloxy, C 3-8 Cycloalkylamino, 4-8 membered heterocyclic amino, C 3-8 Cycloalkyl thiogroup, 4-8 membered heterocyclic thiogroup, -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 C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C3-8 Cycloalkyloxy, 4-8 membered heterocyclic alkyloxy, C 3-8 Cycloalkylamino, 4-8 membered heterocyclic amino, C 3-8 The cycloalkyl thio group and the 4-8 membered heterocyclic thio group are further divided by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 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 The substituents in it are replaced;

[0100] R a or R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, optionally, the C 3-8 Cycloalkyl, containing 1-3 5-8-membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O or S, further by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 heterocyclic or -SO2-C 1-6 Substituents in alkyl groups.

[0101] In a preferred embodiment of the present invention, R a or R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, optionally, the C 3-8 Cycloalkyl, containing 1-3 5-8-membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O or S, further by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 3-6 membered cycloalkyl or -SO2-C 1-6 Substituents in alkyl groups.

[0102] In a preferred embodiment of the present invention, R1 is independently selected from C. 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy groups, 4-8 membered heterocyclic alkyl groups containing 1-3 N, O, S, SO2 or SONH, or -C(O)(CH2) n R b -NR a C(O)(CH2) n R b -O(CH2) n R b -S(O)2(CH2) nR 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 C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 The cycloalkyloxy group, or a 4-8 membered heterocyclic alkyloxy group containing 1-3 N, O, S, SO2, or SONH groups, is further surrounded by one or more 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 The substituents in it are replaced;

[0103] R a or R b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 3-8 The cycloalkyl group, containing 1-3 5-8-membered heteroaryl groups selected from N, O, or S, or containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O, or S, optionally, the 5-8-membered heteroaryl group containing 1-3 5-8-membered heteroaryl groups selected from N, O, or S, or the 4-8-membered heterocyclic group containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O, or S, is further surrounded by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups or -SO2-C 1-3 Substituents in alkyl groups.

[0104] In a preferred embodiment of the present invention, R1 is independently selected from C.3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 3-8 Cycloalkyloxy, 4-8 membered heterocyclic alkyloxy, C 3-8 Cycloalkylamino, 4-8 membered heterocyclic amino, C 3-8 Cycloalkyl thiogroup, 4-8 membered heterocyclic thiogroup, -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 C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C3-8 cycloalkyloxy group, 4-8 membered heterocyclic oxy group, C 3-8 Cycloalkylamino, 4-8 membered heterocyclic amino, C 3-8 The cycloalkyl thio group and the 4-8 membered heterocyclic thio group are further divided by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 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 The substituents in it are replaced;

[0105] R a or R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S.

[0106] In a preferred embodiment of the present invention, R1 is independently selected from C. 3-8 Cycloalkyl groups, containing 1-3 4-8 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, -C(O)(CH2) n R b -NR a C(O)(CH2) n R b -O(CH2) n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n R b -NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Optionally, the C 3-8 Cycloalkyl groups, containing 1-3 4-8 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, or a 4-8 membered heterocyclic amino group containing 1-3 N, O, S, SO2 or SONH, or a 4-8 membered heterocyclic amino group containing 1-3 N, O, S, SO2 or SONH, further by one or more oxo groups, -C(O)(CH2). n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n Rb -S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b The substituents in it are replaced;

[0107] R a or R b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 3-8 The cycloalkyl group, containing 1-3 5-8-membered heteroaryl groups selected from N, O, or S, or containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O, or S, optionally, the 5-8-membered heteroaryl group containing 1-3 5-8-membered heteroaryl groups selected from N, O, or S, or the 4-8-membered heterocyclic group containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O, or S, is further surrounded by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups or -SO2-C 1-3 Substituents in alkyl groups.

[0108] In a preferred embodiment of the present invention, R1 is independently selected from C. 3-8 Cycloalkyl groups, containing 1-3 4-8 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy groups, 4-8 membered heterocyclic alkyl groups containing 1-3 N, O, S, SO2 or SONH, or -C(O)(CH2) n R b -NR a C(O)(CH2) n R b -S(O)2(CH2) n R b -S(O)(NH)(CH2) n R b -NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Optionally, the C3-8 Cycloalkyl groups, containing 1-3 4-8 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 The cycloalkyloxy group, or a 4-8 membered heterocyclic alkyloxy group containing 1-3 N, O, S, SO2, or SONH groups, is further surrounded by one or more 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 The substituents in it are replaced;

[0109] In a preferred embodiment of the present invention, R2 or R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C3-8 cycloalkyloxy, C 3-8 Cycloalkylamino, C 6-10 aryl, containing 1-3 5-6 membered heteroaryl groups selected from N, O, S, or containing 1-3 4-8 membered heterocyclic groups 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 .

[0110] In a preferred embodiment of the present invention, R2 or R3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6Hydroxyalkyl, C 3-8 Cycloalkyl groups or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, -NR a C(O)R b or -C(O)NR a R b ;

[0111] R a or R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S.

[0112] In a preferred embodiment of the present invention, R2 or R3 is independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyloxy groups.

[0113] In a preferred embodiment of the present invention, R2 or R3 is independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Hydroxyalkyl.

[0114] In a more preferred embodiment of the invention, the general formula (I) is further a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof:

[0115] The ring C is selected from 5-7 membered cycloalkyl, 6-10 membered cycloalkyl, containing 1-3 5-7 membered heterocyclic groups selected from C(O), N, O, S, SO2 or SONH, or containing 1-3 7-10 membered heterocyclic groups selected from C(O), N, O, S, SO2 or SONH;

[0116] Z is selected from CR a Or N;

[0117] M2 and M5 are selected from N, C, or CH;

[0118] R1 is independently selected from cycloalkyl, heterocyclic, cycloalkyloxy, heterocyclic oxy, cycloalkylamino, heterocyclic amino, cycloalkylthio, heterocyclic thio, and -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, heterocyclic, cycloalkyloxy, heterocyclic oxy, cycloalkylamino, heterocyclic amino, cycloalkylthio, or heterocyclic thio group is further selected from one or more groups 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 The substituents in it are replaced;

[0119] Alternatively, any two R1 atoms can form C with adjacent carbon atoms. 3-8Cycloalkyl or 4-7 membered heterocyclic group, optionally, the C 3- 8-cyclic alkyl or 4-7-membered heterocyclic groups are further converted to oxo groups, alkyl groups, or -C(O)R groups. 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;

[0120] R a or R b Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclic groups. Optionally, the cycloalkyl, aryl, heteroaryl or heterocyclic group is further substituted by 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.

[0121] R2 is selected from hydrogen, deuterium, oxo group, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR a C(O)(CH2) n R b or -C(O)NR a (CH2) n R b The optional ones can be further replaced;

[0122] x is selected from 1, 2, 3, or 4;

[0123] n is selected from 0, 1, 2 or 3.

[0124] In a more preferred embodiment of the invention, the general formula (I) is further a compound represented by general formula (I-2) or a pharmaceutically acceptable salt thereof:

[0125] In a more preferred embodiment of the invention, the general formula (I-2) is further a compound represented by general formula (I-2a) or a pharmaceutically acceptable salt thereof:

[0126] The ring C is a cycloalkyl, heteroaryl, or heterocyclic group;

[0127] M2 and M5 are selected from N, C, or CH;

[0128] Ring D is selected from 3-15 membered heterocyclic groups containing 1-3 nitrogen atoms or C. 3-10 Cycloalkyl.

[0129] In a more preferred embodiment of the present invention, ring D is selected from the following groups:

[0130] In a more preferred embodiment of the invention, the general formula (I) is further a compound represented by general formula (I-3) or general formula (I-4) or a pharmaceutically acceptable salt thereof:

[0131] In a more preferred embodiment of the invention, the general formula (I) is further a compound represented by general formula (I-1-a), (I-1-b) or (I-1-c) or a pharmaceutically acceptable salt thereof:

[0132] in,

[0133] Ring E is independently selected from C. 3-8 Cycloalkyl, containing 1-3 5-6 heteroaryl groups selected from N, O, S, or containing 1-3 4-8 heterocyclic groups selected from C(O), N, O, or S;

[0134] M2, M7, or M8 are each independently selected from N, C, or CH;

[0135] R1, R2, and x are defined as in general formula (I).

[0136] In certain embodiments of the invention, a compound of general formula (VII) or a pharmaceutically acceptable salt thereof is provided:

[0137] in,

[0138] Ring A is selected from 1-3 5-6 membered heteroaryl groups selected from N, O, and S, or 1-3 4-6 membered heterocyclic groups selected from C(O), N, O, or S;

[0139] Ring B is selected from C 3-6 Cycloalkyl, phenyl, containing 1-3 5-6 heteroaryl groups selected from N, O, S or containing 1-3 4-6 heterocyclic groups selected from C(O), N, O or S;

[0140] Ring E is selected from C 3-8Cycloalkyl, containing 1-3 5-6 heteroaryl groups selected from N, O, S, or containing 1-3 4-8 heterocyclic groups selected from C(O), N, O, or S;

[0141] M1, M2, or M3 are each independently selected from N or CR a ;

[0142] M7 or M8 are each independently selected from N, C or CH;

[0143] M9 or M 10 Each is independently selected from O, S, NH or CH2;

[0144] R a Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S;

[0145] R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from C(O), N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, or containing 1-3 4-8 membered heterocyclic amino groups selected from N, O, S, SO2 or SONH -(CH2). n C(O)R b -(CH2) n NR a C(O)R b -(CH2) n OR b -(CH2) n NR a R b -(CH2) n SR b -(CH2) n S(O)2R b -(CH2) n S(O)(NH)R b -(CH2) n NR a S(O)2R b-(CH2) n NR a S(O)(NH)R b Or -(CH2) n NS(O)R a R b Optionally, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from C(O), N, O, S, SO2 or SONH, optionally further containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from C(O), N, O, S, SO2 or SONH, and optionally further containing one or more groups selected from R c Substituents;

[0146] R c Each is independently selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, -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 Optionally, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, optionally further modified by -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 The substituents in it are replaced;

[0147] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-Deuterated Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, C 6-10 aryl, containing 1-3 5-6 membered heteroaryl groups selected from N, O, S, or containing 1-3 4-8 membered heterocyclic groups 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 ;

[0148] R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, optionally, the C 3-8 Cycloalkyl, containing 1-3 5-8-membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O or S, further by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 heterocyclic or -SO2-C 1-6 Substituents in alkyl groups;

[0149] n is 0, 1, or 2;

[0150] x is 0, 1, or 2;

[0151] y is 0, 1 or 2.

[0152] In a preferred embodiment of the present invention, ring A is selected from...

[0153] In a preferred embodiment of the present invention, ring B is selected from phenyl or pyridine.

[0154] In a preferred embodiment of the present invention Selected from

[0155] In a preferred embodiment of the present invention, the ring C is selected from 5-7 member monocyclic cycloalkyl, 5-10 member fused cycloalkyl, 5-10 member spirocyclic cycloalkyl, 6-10 member bridged cycloalkyl, containing 1-3 4-7 member monocyclic heterocyclic groups selected from C(O), N, O, S, SO2 or SONH, containing 1-3 6-10 member fused cycloalkyl groups selected from C(O), N, O, S, SO2 or SONH, containing 1-3 5-10 member spirocyclic heterocyclic groups selected from C(O), N, O, S, SO2 or SONH, or containing 1-3 6-10 member bridged cycloalkyl groups selected from C(O), N, O, S, SO2 or SONH.

[0156] In a more preferred embodiment of the present invention, the ring C is selected from the following groups:

[0157] In a preferred embodiment of the present invention, ring D is selected from the following groups:

[0158] In a more preferred embodiment of the present invention, ring D is selected from the following groups:

[0159] in, It indicates that it is connected to L.

[0160] In a preferred embodiment of the present invention, ring E is selected from...

[0161] In a preferred embodiment of the present invention, ring E is selected from...

[0162] In a more preferred embodiment of the present invention, R a It is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl or isopropyl.

[0163] In a more preferred embodiment of the present invention, R b Independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 3-6 The cycloalkyl group, containing 1-3 5-6-membered heteroaryl groups selected from N, O, or S, or containing 1-3 4-6-membered heterocyclic groups selected from C(O), N, O, or S, optionally, the 5-6-membered heteroaryl group containing 1-3 5-6-membered heteroaryl groups selected from N, O, or S, or the 4-6-membered heterocyclic group containing 1-3 4-6-membered heterocyclic groups selected from C(O), N, O, or S, is further surrounded by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1- 3-alkoxy group, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 Substituents in cycloalkyl or 3-6 membered heterocyclic groups.

[0164] In a preferred embodiment of the present invention, the compounds or specific compounds included in each general formula are further stereoisomers.

[0165] On the other hand, the present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the shown general formula compounds or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0166] In some embodiments of the invention, the pharmaceutical composition, based on free base, comprises 0.1% to 95% by weight of the compound or its pharmaceutically acceptable salt, preferably 5% to 70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%.

[0167] In some embodiments of the invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations or injections, preferably also containing a filler, optionally a disintegrant, or further containing one or more of a flow aid or lubricant.

[0168] In some embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0169] In some embodiments of the invention, the unit dose of the pharmaceutical composition, calculated as free base, of the compound or its pharmaceutically acceptable salt 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.

[0170] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof may be administered by any convenient method, such as oral, parenteral, oral, sublingual, nasal, rectal, intrathecal, or transdermal administration, and accordingly modified pharmaceutical compositions.

[0171] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof may be formulated into liquid or solid dosage forms, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0172] On the other hand, the present invention further relates to the use of any of the general formula compounds shown or their pharmaceutically acceptable salts, or the pharmaceutical compositions thereof, in the preparation of medicaments for treating diseases related to CYP11B2.

[0173] The present invention further relates to the use of any compound of the general formula shown or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the treatment or prevention of chronic kidney disease, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, primary aldosteronism, and Cushing's syndrome.

[0174] In a preferred embodiment of the present invention, the hypertension is refractory hypertension.

[0175] In a preferred embodiment of the present invention, the chronic kidney disease is chronic kidney disease accompanied by type II diabetes.

[0176] Detailed description of the invention

[0177] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0178] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, 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 their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0179] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0180] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic 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 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0181] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 6, 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0182] wait;

[0183] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0184] wait.

[0185] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0186] wait.

[0187] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0188] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0189] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being 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; even more preferably, it contains a 4-8 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 spirocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0190] Non-limiting examples of monocyclic heterocyclic groups include aziridine, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, acrylonitrile, 1,4-diazaheptanyl, pyranyl, etc., preferably pyrrolyl, morpholinyl, piperidinyl, acrylonitrile, 1,4-diazaheptanyl, and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0191] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The heteroatom is a carbon atom (where m is an integer from 0 to 2). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 fused, more preferably 7 to 10 fused. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiro atoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, they are 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups. Non-limiting examples of spirocyclic groups include:

[0192] wait.

[0193] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0194] wait.

[0195] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0196] wait.

[0197] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0198] wait.

[0199] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0200] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) 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 benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further comprise a ternary nitrogen-containing fused ring containing a benzene ring.

[0201] The ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0202] wait.

[0203] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0204] The term "heteroaryl" refers to a heteroaryl system comprising 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- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrroleyl, and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0205] wait.

[0206] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0207] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups 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, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0208] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0209] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0210] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0211] "Alkenyl" refers to an alkenyl group, also known as an olefinic group, which is 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 anywhere within the alkenyl group. Alkenyl groups have a carbon density of 2 to 20 carbon atoms. 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 A straight-chain or branched unsaturated hydrocarbon group containing 1 carbon atom. Non-limiting examples of alkenyl groups include: The alkenyl group described therein may be further substituted with other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0212] "Alynyl" refers to (CH≡C-) that contains at least one carbon-carbon triple bond, which can be located anywhere within the alkynyl group, and at least one carbon-carbon double bond, which can be located anywhere within the alkenyl group. The alkynyl group has 2 to 20 carbon atoms. 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 A straight-chain or branched unsaturated hydrocarbon group containing 1 carbon atom. Non-limiting examples of alkynyl groups include: The alkynyl group may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0213] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as described above. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, and butenyl carbonyl. Alkenyl carbonyl 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, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0214] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0215] The compounds of this invention, such as all general formulas or specific compounds, are intended to include one or more of the following: a free base of the compound or a pharmaceutically acceptable salt thereof, a stereoisomer, or a mixture of two or more stereoisomers. A stereoisomer is a compound that differs only in its spatial arrangement. Stereoisomers include all diastereomers and enantiomers of the compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more distinct chiral centers that are not mirror images of each other.

[0216] Any formula or structure given in this invention is also intended to represent the unlabeled form and isotopically labeled form of the compound. The isotopically labeled compound has the general formula given in this invention or the structure described for a specific compound, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes of the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine.

[0217] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0218] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0219] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0220] "Pharmaceutical acceptable salt" or "medicinal salt" refers to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity. Detailed Implementation

[0221] Example

[0222] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (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). The internal standard was tetramethylsilane (TMS).

[0223] MS measurements were performed using a Finnigan LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0224] HPLC determinations were performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6mm column).

[0225] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0226] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0227] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0228] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0229] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0230] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0231] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0232] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0233] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0234] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0235] The reaction process in the examples was monitored using 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.

[0236] The eluent systems for column chromatography and the developing solvent systems for thin-layer chromatography used to purify the compounds include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, and C: dichloromethane and acetone system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0237] Detailed Implementation

[0238] Intermediate 1

[0239] first step

[0240] 2,3-Dihydro-4H-pyrano[3,2-c]pyridin-4-one (1 g, 6.70 mmol) was dissolved in DMF (20 mL), and NBS (1.31 g, 7.38 mmol) was added under nitrogen protection. The mixture was stirred at 70 °C for 3 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product 8-bromo-2,3-dihydro-4H-pyrano[3,2-c]pyridin-4-one (400 mg, yellow solid), yield: 26.16%.

[0241] MS m / z(ESI):228.0, 230.0[M+H].

[0242] Step 2

[0243] In a 50 mL reaction flask, 200 mg (877.03 μmol) of 8-bromo-2,3-dihydro-4H-pyrano[3,2-c]pyridin-4-one was dissolved in 5 mL of methanol, followed by the addition of sodium borohydride (33.18 mg, 877.03 μmol). The reaction mixture was stirred at 25 °C for 10 minutes. The reaction was stopped, and water (5 mL) was added to quench the reaction. 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 purified by silica gel column chromatography using dichloromethane and methanol as eluents to obtain the title product, 200 mg (yellow solid), 8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-phenol (99.12%).

[0244] MS m / z(ESI):230.0, 232.0[M+H].

[0245] Step 3

[0246] In a 50 mL reaction flask, 200 mg (869.34 μmol) of 8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridine-4-phenol was dissolved in 5 mL of dichloromethane. Then, thionyl chloride (517.13 mg, 4.35 mmol, 315.71 μL) was slowly added dropwise. The reaction mixture was stirred at 50 °C for 10 minutes. The reaction was stopped, and the reaction mixture was concentrated to give the title product, 210 mg (yellow solid), 8-bromo-4-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridine, in 97.21% yield.

[0247] MS m / z(ESI):247.9, 249.9[M+H].

[0248] Step 4

[0249] 200 mg of 8-bromo-4-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridine (804.82 μmol) was dissolved in 10 mL of ammonia and isopropanol solution. The mixture was stirred under microwave at 100 °C for 3 hours. The reaction solution was concentrated to give the title product, 180 mg of 8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridine-4-amine (yellow solid), in 97.63% yield.

[0250] MS m / z(ESI):229.0, 231.0[M+H].

[0251] Step 5

[0252] 8-Bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridine-4-amine was chirally resolved to give the title product (R)-8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridine-4-amine

[0253] MS m / z(ESI):229.0, 231.0[M+H].

[0254] Intermediate 2

[0255] first step

[0256] 5-Bromo-4-methylpyridine-3-carboxylic acid (20 g, 92.58 mmol) was dissolved in anhydrous N,N-dimethylformamide (200 mL), and anhydrous ethanol (42.65 g, 925.79 mmol, 54.06 mL), HATU (52.39 g, 138.87 mmol), and TEA (28.10 g, 277.74 mmol, 38.74 mL) were added to the solution. The reaction mixture was stirred at room temperature (20 °C) for 16 hours. After the reaction was complete, 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, filtered, and concentrated to obtain crude ethyl 5-bromo-4-methylpyridine-3-carboxylic acid (21 g). MS m / z (ESI): 244.0, 246.0 [M+H].

[0257] Step 2

[0258] Ethyl 5-bromo-4-methylpyridine-3-carboxylic acid (7 g, 28.68 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL). Diisopropylaminolithium (2 M, 17.21 mL) was added dropwise at -78 °C while stirring for 1 hour. Then, methyl acrylate (6.17 g, 71.70 mmol, 6.46 mL) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for another 5 hours. After the reaction was complete, water (20 mL) was slowly added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated by filtration to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 3:1, UV = 254 nm) to finally obtain methyl 4-bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylic acid (4 g, yellow solid), yield: 48.8%.

[0259] MS m / z(ESI):284.0, 286.0[M+H].

[0260] Step 3

[0261] Methyl 4-bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylic acid (7 g, 24.64 mmol) was dissolved in 30 mL of 6 M hydrochloric acid. The reaction mixture was stirred in an oil bath at 100 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and the pH was adjusted to 7-8 with 6 M sodium hydroxide solution. The mixture was washed with ethyl acetate (50 mL x 3) and saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 4-bromo-6,7-dihydro-5H-isoquinoline-8-one (4.8 g, yellow solid), yield: 86.17%. The crude product was used directly in the next reaction step.

[0262] MS m / z(ESI):226.0, 228.0[M+H].

[0263] Step 4

[0264] 4-Bromo-6,7-dihydro-5H-isoquinoline-8-one (7 g, 30.96 mmol) was dissolved in an ammonia-methanol solution (2 M, 100 mL), and tetraisopropyl titanate (17.60 g, 61.93 mmol, 18.33 mL) was added. The reaction mixture was stirred at 20 °C for 16 hours, and then sodium borohydride (1.76 g, 46.45 mmol) was added in portions over an ice-water bath. The reaction mixture was stirred for another 2 hours at room temperature. After the reaction was complete, 20 mL of water was added.

[0265] The reaction was quenched, filtered through diatomaceous earth, extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated by filtration to obtain the crude product. The crude product was purified by column chromatography (Dichloromethane:Methanol = 10:1, UV = 254 nm) to give 4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine (4.5 g, yellow solid), yield: 63.99%.

[0266] MS m / z(ESI):227.0, 229.0[M+H].

[0267] Step 5: (R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine

[0268] 4-Bromo-5,6,7,8-tetrahydroisoquinoline-8-amine (4.5 g, 19.82 mmol) was chirally separated to obtain intermediate 2.

[0269] MS m / z(ESI):227.0, 229.0[M+H].

[0270] Intermediate 3

[0271] 4-Bromo-6,7-dihydro-5H-cyclopentadieno[c]pyridine-7-amine (purchased) was chirally resolved to give the title product (R)-4-bromo-6,7-dihydro-5H-cyclopentadieno[c]pyridine-7-amine.

[0272] MS m / z(ESI):213.0, 215.0[M+H].

[0273] Intermediate 4

[0274] The title product (S)-7-bromo-2,3-dihydrofurano[3,2-c]pyridine-3(2H)-one was synthesized from 7-bromofurano[3,2-c]pyridine-3-amine via reference intermediate 1.

[0275] MS m / z(ESI):214.9,216.9[M+H].

[0276] Intermediate 5

[0277] first step:

[0278] 6-Bromo-3H-1,3-benzothiazol-2-one (30 g, 130.39 mmol), iodomethane-d3 (37.80 g, 260.78 mmol), and DMF (500 mL) were added to a 1000 mL flask. Cesium carbonate (84.97 g, 260.78 mmol) was added at 25 °C, and the reaction mixture was then reacted at 40 °C for 1 h. The reaction mixture was then added to ice water (500 mL), extracted with EA (500 mL * 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the product, a yellow solid 6-bromo-3-(methyl-d3)benzo[d]thiazol-2(3H)-one (30 g, yield: 93.10%).

[0279] MS m / z(ESI): 248.9 246.9 [M+1]

[0280] Step Two:

[0281] 6-Bromo-3-(methyl-d3)benzo[d]thiazolyl-2(3H)-one (32 g, 129.49 mmol), potassium acetate (24.12 g, 258.98 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (10.50 g, 12.95 mmol), dipinacol diborone (49.32 g, 194.23 mmol) and 1,4-dioxane (500 mL) were added to a 1000 mL flask, and the reaction was carried out under liquid nitrogen protection at 90 °C for 3 h. LCMS showed that the reaction was complete. The reaction solution was filtered and concentrated, and then passed through a column with PE / EA = 3 / 1 to give 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzo[d]thiazol-2(3H)-one (30 g, yield: 78.8%).

[0282] MS m / z(ESI): 295.1 [M+1]

[0283] Intermediate 6

[0284] first step:

[0285] 6-Bromo-3H-1,3-benzothiazol-2-one (5 g, 21.73 mmol), methyl iodoform (6.17 g, 43.46 mmol), and DMF (50 mL) were added to a 100 mL flask. Cesium carbonate (14.16 g, 43.46 mmol) was added at room temperature, and the reaction mixture was then reacted at 40 °C for 3 h. The reaction mixture was then added to ice water (100 mL), extracted with EA (100 mL * 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid 6-bromo-3-methyl-1,3-benzothiazol-2-one (5 g, yield: 94.25%).

[0286] MS m / z(ESI): 245.9 243.9 [M+1]

[0287] Step Two:

[0288] 6-Bromo-3-methyl-1,3-benzothiazol-2-one (5 g, 20.48 mmol), potassium acetate (4.02 g, 40.97 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (1.66 g, 2.05 mmol), diboron dipinalyl (7.80 g, 30.72 mmol), and 1,4-dioxane (100 mL) were added to a 250 mL flask. The reaction mixture was then subjected to nitrogen protection at 90 °C for 3 h. LC-MS showed that the reaction was complete. The reaction mixture was filtered, concentrated, and column chromatography (PE / EA = 3 / 1) yielded 3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxoboropentane-2-yl)-3H-benzothiazol-2-one (5 g, yield: 83.8%).

[0289] MS m / z(ESI): 292.1 [M+1]

[0290] Intermediate 7

[0291] first step:

[0292] Following the first step of intermediate 1, the title product 6-bromothiazo[4,5-b]pyridine-2(3H)-one was obtained.

[0293] MS m / z(ESI): 232.9 230.9 [M+1]

[0294] Step Two:

[0295] Following the synthetic method of intermediate 5, the title product 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)thiazo[4,5-b]pyridin-2(3H)-one was obtained.

[0296] MS m / z(ESI): 293.1 [M+1]

[0297] Intermediate 8

[0298] Following the synthesis of intermediate 5, the title product 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)thiazo[4,5-b]pyridin-2(3H)-one was obtained.

[0299] MS m / z(ESI): 296.1 [M+1]

[0300] Intermediate 9

[0301] 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)quinoline-2(1H)-one

[0302] Following the synthesis method of intermediate 5, the title product was obtained.

[0303] MS m / z(ESI): 286.2 [M+1].

[0304] Intermediate 10

[0305] 1-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-3,4-dihydroquinoline-2(1H)-one

[0306] Following the synthesis method of intermediate 5, the title product was obtained.

[0307] MS m / z(ESI): 291.2 [M+1].

[0308] Intermediate 11

[0309] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxoboropentane-2-yl)imidazo[1,2-a]pyridine

[0310] Following the synthesis method of intermediate 5, the title product was obtained.

[0311] MS m / z(ESI): 245.1 [M+1].

[0312] Example 1

[0313] (R)-N-(8-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazo-6-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propionamide

[0314] first step:

[0315] 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzo[d]thiazolyl-2(3H)-one (100 mg, 0.34 mmol) and (R)-8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-amine (78 mg, 0.34 mmol) were dissolved in a mixed solvent of H2O (2 mL) and EtOH (6 mL). Pd(PPh3)4 (39.3 mg, 33.9 μmol) and Na2CO3 (108.1 mg, 1.02 mmol) were added sequentially. After purging the reaction system with nitrogen several times, it was placed in an oil bath at 100 °C and stirred for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by prep-TLC (DCM / MeOH = 10:1, UV = 254 nm) to finally obtain a pale yellow solid (R)-6-(4-amino-3,4-dihydro-2H-pyrano[3,2-c]pyridin-8-yl)-3-(methyl-d3)benzo[d]thiazolyl-2(3H)-one (61 mg, 56.7% yield).

[0316] MS m / z(ESI): 317.1 [M+1]

[0317] Step Two:

[0318] The (R)-6-(4-amino-3,4-dihydro-2H-pyrano[3,2-c]pyridin-8-yl)-3-(methyl-d3)benzo[d]thiazolyl-2(3H)-one (61 mg, 0.19 mmol) obtained above was dissolved in anhydrous dichloromethane (10 mL), and triethylamine (58.4 mg, 0.57 mmol) and propionyl chloride (21.4 mg, 0.23 mmol) were added sequentially. The reaction system was stirred at room temperature (20 °C) for 4 hours. After the reaction was completed, the mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL x 2), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by prep-HPLC to finally obtain a light white solid (26.1 mg, 36.4% yield).

[0319] MS m / z(ESI): 373.1 [M+1]

[0320] Example 2

[0321] (R)-N-(8-(3-(methyl-d3)-2-carbonyl-2,3-dihydrothiazo[4,5-b]pyridin-6-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propionamide

[0322] first step:

[0323] Starting with 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)thiazo[4,5-b]pyridin-2(3H)-one and (R)-8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-amine, the target product (R)-6-(4-amino-3,4-dihydro-2H-pyrano[3,2-c]pyridin-8-yl)-3-(methyl-d3)thiazo[4,5-b]pyridin-2(3H)-one was obtained by referring to the first step of Example 1.

[0324] MS m / z(ESI): 318.1 [M+1]

[0325] Step Two:

[0326] Using the (R)-6-(4-amino-3,4-dihydro-2H-pyrano[3,2-c]pyridin-8-yl)-3-(methyl-d3)thiazo[4,5-b]pyridin-2(3H)-one obtained above as a raw material, the target product was obtained by referring to the second step of Example 1.

[0327] MS m / z(ESI): 374.1 [M+1]

[0328] Example 3

[0329] (R)-N-(4-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazolyl-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)butyramide

[0330] Step 1: (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-3-(methyl-d3)benzo[d]thiazolyl-2(3H)-one

[0331] Using 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzo[d]thiazol-2(3H)-one and (R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine, referring to the first step of Example 1, the target product (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinoline-4-yl)-3-(methyl-d3)benzo[d]thiazol-2(3H)-one was obtained.

[0332] MS m / z(ESI): 315.1 [M+1]

[0333] Step 2: (R)-N-(4-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazolyl-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)butyramide

[0334] Using the (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinoline-4-yl)-3-(methyl-d3)benzo[d]thiazol-2(3H)-one obtained above as a raw material, and referring to the second step of Example 1, the target product (R)-N-(4-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazol-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)butyramide was obtained.

[0335] MS m / z(ESI): 385.1 [M+1]

[0336] Example 4

[0337] (R)-N-(4-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazo-6-yl)-6,7-dihydro-5H-cyclopentadien[c]pyridin-7-yl)propionamide

[0338] Step 1: (R)-6-(7-amino-6,7-dihydro-5H-cyclopentadien[c]pyridin-4-yl)-3-(methyl-d3)benzo[d]thiazolyl-2(3H)-one

[0339] Using 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzo[d]thiazol-2(3H)-one and (R)-4-bromo-6,7-dihydro-5H-cyclopentadieno[c]pyridin-7-amine, referring to the first step of Example 1, the target product (R)-6-(7-amino-6,7-dihydro-5H-cyclopentadieno[c]pyridin-4-yl)-3-(methyl-d3)benzo[d]thiazol-2(3H)-one was obtained.

[0340] MS m / z(ESI): 301.1 [M+1]

[0341] Step 2: (R)-N-(4-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazo-6-yl)-6,7-dihydro-5H-cyclopentadien[c]pyridin-7-yl)propionamide

[0342] Using the (R)-6-(7-amino-6,7-dihydro-5H-cyclopentadieno[c]pyridin-4-yl)-3-(methyl-d3)benzo[d]thiazol-2(3H)-one obtained above as a raw material, the target product (R)-N-(4-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazol-6-yl)-6,7-dihydro-5H-cyclopentadieno[c]pyridin-7-yl)propionamide was obtained by referring to the second step of Example 1.

[0343] MS m / z(ESI): 357.1 [M+1]

[0344] Method 2:

[0345] Under a nitrogen atmosphere, tetraisopropyl titanate (107.23 g, 377.28 mmol, 111.70 mL) was added to a methanol solution (800 mL) of 4-bromo-5,6-dihydrocyclopentadieno[c]pyridin-7-one (40 g, 188.64 mmol) and ammonia-methanol (7 M, 538.98 mL). The mixture was heated to 60 °C and stirred for 4 hours. After cooling to room temperature, sodium borohydride (14.27 g, 377.28 mmol) was added, and stirring continued for 1 hour. The reaction solution turned black, and a large amount of solid byproducts were produced. The reaction solution was filtered, concentrated to remove methanol, and slowly diluted with saturated brine (2000 mL). The reaction solution was extracted with ethyl acetate (1500 mL × 3), the organic phases were combined, washed with saturated brine (1000 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. A crude product of low purity, 4-bromo-6,7-dihydro-5H-cyclopentadienyl[c]pyridine-7-amine (20 g, 93.86 mmol, 49.76% yield), was obtained and used directly in the next step.

[0346] MS m / z(ESI):213.0, 215.0[M+1]

[0347] Step Two:

[0348] Under a nitrogen atmosphere, DIEA (48.52 g, 375.46 mmol, 65.40 mL) was added to a solution of 4-bromo-6,7-dihydro-5H-cyclopentadien[c]pyridine-7-amine (20 g, 93.86 mmol) and di-tert-butyl dicarbonate (20.49 g, 93.86 mmol, 21.59 mL) in 500 mL of dichloromethane. The mixture was stirred at 25 °C for 8 hours. The reaction solution was quenched slowly with 200 mL of saturated brine. The reaction solution was extracted with 300 mL of dichloromethane (3 times). The organic phases were combined, washed with 500 mL of saturated brine (2 times), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography with an eluent system (petroleum ether: ethyl acetate = 10:1). The crude product was then chirally resolved to give tert-butyl N-[(7R)-4-bromo-6,7-dihydro-5H-cyclopentadienyl[c]pyridin-7-yl]carbamate (P1) (5.8 g, 18.52 mmol, 19.73% yield).

[0349] MS m / z(ESI):313.0, 315.0[M+1]

[0350] Step 3:

[0351] Under a nitrogen atmosphere, sodium carbonate (3.25 g, 30.65 mmol) was added to a mixture of tert-butyl N-[(7R)-4-bromo-6,7-dihydro-5H-cyclopentadien[c]pyridin-7-yl]carbamate (3.2 g, 10.22 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-3-(trideuteriomethyl)-1,3-benzothiazol-2-one (3.91 g, 13.28 mmol) and tetraphenylphosphine palladium (1.18 g, 1.02 mmol) in ethanol (20 mL) and water (5 mL). After purging with nitrogen, the reaction mixture was heated to 85 °C and stirred for 4 hours. The reaction solution was cooled to room temperature, quenched slowly with saturated brine (20 mL), concentrated to remove ethanol, 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, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product, tert-butyl N-[(7R)-4-[2-carbonyl-3-(methyl-d3)-1,3-benzothiazo-6-yl]-6,7-dihydro-5H-cyclopentadien[c]pyridin-7-yl]carbamate (3.7 g, 9.24 mmol, 90.42% yield), was purified by silica gel column chromatography with an eluent system (PE:EA = 25:75).

[0352] MS m / z(ESI): 401.2 [M+1]

[0353] Step 4:

[0354] Under a nitrogen atmosphere, dioxane hydrochloride (4M, 30 mL) was added to tert-butyl N-[(7R)-4-[2-carbonyl-3-(methyl-d3)-1,3-benzothiazol-6-yl]-6,7-dihydro-5H-cyclopentadien[c]pyridin-7-yl]carbamate (2.5 g, 6.24 mmol), and the mixture was stirred at 25 °C for 0.5 hr. The reaction solution was directly evaporated to dryness. 6-[(7R)-7-amino-6,7-dihydro-5H-cyclopentadien[c]pyridin-4-yl]-3-(methyl-d3)-1,3-benzothiazol-2-one (1.85 g, 6.16 mmol, 98.66% yield) was used directly in the next step.

[0355] MS m / z(ESI): 301.1 [M+1]

[0356] Step 5:

[0357] Under a nitrogen atmosphere, triethylamine (7.58 g, 74.90 mmol, 10.45 mL) was added to a solution of 6-[(7R)-7-amino-6,7-dihydro-5H-cyclopentadien[c]pyridin-4-yl]-3-(methyl-d3)-1,3-benzothiazol-2-one (4.5 g, 14.98 mmol) in 100 mL of dichloromethane. Propionyl chloride (1.66 g, 17.98 mmol, 1.56 mL) was added dropwise with stirring. The reaction mixture was stirred at 25 °C for 3 hours. The reaction solution was quenched slowly with 20 mL of saturated brine. The reaction solution was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with 50 mL of saturated brine (2 times), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (mobile phase: pure water (0.1% FA)-ACN) to give N-[(7R)-4-[2-carbonyl-3-(methyl-d3)-1,3-benzothiazo-6-yl]-6,7-dihydro-5H-cyclopentadien[c]pyridin-7-yl]propionamide (3.8 g, 10.66 mmol, 71.16% yield).

[0358] MS m / z(ESI): 357.1 [M+1]

[0359] 1H NMR (400MHz, DMSO) δ8.48(s,1H),8.39-8.33(m,1H),8.27(d,1H),7.92-7.85(m,1H),7.59-7.51(m,1H),7.46-7.39( m,1H),5.48-5.35(m,1H),3.09-2.92(m,2H),2.44-2.35(m,1H),2.23-2.10(m,2H),1.86-1.74(m,1H),1.06(t,3H).

[0360] Example 5

[0361] first step:

[0362] Using 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzo[d]thiazol-2(3H)-one and (S)-7-bromo-2,3-dihydrofurano[3,2-c]pyridin-3-amine, referring to the first step of Example 1, the target product (S)-6-(3-amino-2,3-dihydrofurano[3,2-c]pyridin-7-yl)-3-(methyl-d3)benzo[d]thiazol-2(3H)-one was obtained.

[0363] MS m / z(ESI): 303.0 [M+1]

[0364] Step 2: (S)-N-(7-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazo-6-yl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)propionamide

[0365] Using the (S)-6-(3-amino-2,3-dihydrofurano[3,2-c]pyridin-7-yl)-3-(methyl-d3)benzo[d]thiazol-2(3H)-one obtained above as a raw material, the target product (S)-N-(7-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazol-6-yl)-2,3-dihydrofurano[3,2-c]pyridin-3-yl)propionamide was obtained by referring to the second step of Example 1.

[0366] MS m / z(ESI): 359.1 [M+1]

[0367] Example 6

[0368] Step 1 (R)-3-chloro-N-(4-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazolyl-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0369] Under ice bath conditions, (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-3-(methyl-d3)benzo[d]thiazolyl-2(3H)-one (0.31 g, 1 mmol) was dissolved in anhydrous dichloromethane (6 mL), followed by the sequential addition of triethylamine (0.30 g, 3 mmol) and 3-chloropropionyl chloride (0.14 g, 1.1 mmol). The mixture was stirred at room temperature for one hour, and the reaction was considered complete by LCMS. The reaction solution was diluted with dichloromethane (20 mL), washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the target product, which was directly used in the next step (0.36 g, yield: 90%).

[0370] MS m / z(ESI): 405.2 [M+1].

[0371] Step 2

[0372] At room temperature, (R)-3-chloro-N-(4-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazolyl-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide (0.10 g, 0.25 mmol) was dissolved in acetonitrile (6 mL), followed by the addition of cesium carbonate (0.16 g, 0.5 mmol). The mixture was heated to 80 °C and reacted for 14 hours. LC-MS indicated the formation of the target product. The mixture was then cooled to room temperature. The residue was evaporated to dryness, dissolved in ethyl acetate (20 mL), and then washed with saturated brine (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by reversed-phase preparative chromatography to obtain the target (R)-3-(methyl-d3)-6-(8-(2-carbonylacetidin-1-yl)-5,6,7,8-tetrahydroisoquinoline-4-yl)benzo[d]thiazolyl-2(3H)-one (0.018 g, yield: 20%).

[0373] MS m / z(ESI): 369.2 [M+1].

[0374] Example 7

[0375] first step

[0376] tert-Butyl-6-(5-bromo-4-methylpyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester

[0377] 3,5-Dibromo-4-methylpyridine (3.18 g, 12.66 mmol) and tert-butyl-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ester 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(diphenylphosphine-9,9-dimethyloxanthracene) (733 mg, 1.27 mmol), and tris(dibenzylideneacetone)palladium (580 mg, 633 μmol) were added to the solution. After the reaction system was purged with nitrogen three times, it was stirred in an oil bath at 100 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the title product (2 g, pale yellow solid), yield: 42.9%.

[0378] MS m / z(ESI):368.1, 370.1[M+1].

[0379] Step 2

[0380] 2-(5-bromo-4-methylpyridin-3-yl)-2,6-diazaspiro[3.3]heptane was dissolved in dioxane hydrochloride (4M, 35mL) under nitrogen and ice bath protection. The mixture was stirred at 25°C for 2 hours. The reaction solution was evaporated to dryness, and the crude hydrochloride (1.65g) was used directly in the next step.

[0381] MS m / z(ESI):268.0, 270.0[M+1].

[0382] Step 3

[0383] 1-(6-(5-bromo-4-methylpyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)ethane-1-one: 2-(5-bromo-4-methylpyridin-3-yl)-2,6-diazaspiro[3.3]heptane (1.65 g, 5.42 mmol, CL) and triethylamine (2.74 g, 27.08 mmol, 3.77 mL) were dissolved in dichloromethane (40 mL). Acetyl chloride (510.24 mg, 6.50 mmol) was added under ice-water bath cooling and nitrogen protection. The mixture was stirred at 0 °C for 0.5 h. The reaction was quenched with saturated brine (150 mL), the organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether: ethyl acetate = 100:0 to 50:50) to give the target product (1.5 g, yield: 89.27%).

[0384] MS m / z(ESI):310.1, 312.1[M+1].

[0385] Step 4

[0386] 1-(6-(5-(imidazo[1,2-a]pyridin-6-yl)-4-methylpyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)ethane-1-one

[0387] The target compound was synthesized using 1-(6-(5-bromo-4-methylpyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)ethane-1-one and intermediate 11 as starting materials, referring to the first step of Example 1.

[0388] MS m / z(ESI): 348.2 [M+1].

[0389] Example 8

[0390] first step

[0391] Under ice bath conditions, (7R)-4-bromo-6,7-dihydro-5H-cyclopentane[c]pyridine-7-amine (0.10 g, 0.47 mmol) was dissolved in dichloromethane (5 mL), followed by the sequential addition of triethylamine (0.14 g, 1.41 mmol) and 4-chloro-2-methylbutyryl chloride (0.087 g, 0.56 mmol). The mixture was stirred at room temperature for one hour, and the reaction was considered complete by LC-MS. The reaction solution was diluted with dichloromethane (25 mL) and washed with saturated brine (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was used directly in the next step (0.15 g, yield: 96%).

[0392] MS m / z(ESI): 331.1, 333.1 [M+1].

[0393] Step 2

[0394] Under ice bath conditions, N-((R)-4-bromo-6,7-dihydro-5H-cyclopentan[c]pyridin-7-yl)-4-chloro-2-methylbutyramide (0.15 g, 0.45 mmol) was dissolved in N,N-dimethylformamide (5 mL), and nitrogen gas was purged. Then, sodium hydrogen (0.036 g, 0.90 mmol, 60%) was added, and the mixture was stirred under ice bath conditions for one hour. The reaction was considered complete by LCMS. The reaction solution was quenched with saturated ammonium chloride solution (10 mL), and then extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated brine (15 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the crude product 1-((R)-4-bromo-6,7-dihydro-5H-cyclopentan[c]pyridin-7-yl)-3-methylpyrrolidone-2-one (0.12 g, yield: 90%).

[0395] MS m / z (ESI): 295.1, 297.1 [M+1].

[0396] Step 3

[0397] At room temperature, 1-((R)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-3-methylpyrrolidine-2-one (0.12 g, 0.40 mmol) was dissolved in ethanol (5 mL) and water (1 mL), and then 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-(trideutermethyl)-4H-3,1-benzoxazin-2-one (0.14 g, 0.48 mmol), tetrakis(triphenylphosphine)palladium (0.023 g, 0.02 mmol) and sodium carbonate (0.13 g, 1.2 mmol) were added, nitrogen was purged, the mixture was heated to 85 °C, and the reaction was carried out for 14 hours. After cooling to room temperature, the reaction was indicated to be complete by LCMS. The residue was evaporated to dryness, dissolved in ethyl acetate (25 mL), filtered, washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by reversed-phase preparative chromatography to give 1-(methyl-d3)-6-((7R)-7-(3-methyl-2-oxopyrrolidone-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (0.061 g, yield: 40%).

[0398] MS m / z(ESI): 381.2 [M+1].

[0399] Step 4

[0400] 1-(methyl-d3)-6-((R)-7-((S)-3-methyl-2-oxopyrrolidone-1-yl)-6,7-dihydro-5H-cyclopentan[c]pyridin-4-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one; 1-(methyl-d3)-6-((R)-7-(R)-3-methyl-2-oxopyrrolidone-1-yl)-6,7-dihydro-5H-cyclopentan[c]pyridin-4-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0401] Compound 8 was chiralized to obtain compounds 8-1 and 8-2.

[0402] MS m / z(ESI): 381.2 [M+1].

[0403] Example 9

[0404] N-(6-methyl-4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-7,8-dihydroisoquinoline-8-yl)propionamide

[0405] first step:

[0406] Using N-(4-bromo-6-(hydroxymethyl)-5,6,7,8-tetrahydroisoquinoline-8-yl)-2-methylprop-2-sulfonamide as a raw material, and referring to Example 1, the target product N-(6-(hydroxymethyl)-4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)-2-methylprop-2-sulfonamide was obtained.

[0407] MS m / z(ESI): 444.2 [M+1].

[0408] Step Two:

[0409] To a solution of N-(6-(hydroxymethyl)-4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)-2-methylprop-2-sulfonamide (600 mg, 1.35 mmol) in 10 mL of dichloromethane, add 6 mL of trifluoroacetic acid and 2 mL of triethylsilane, respectively. Stir at room temperature for 12 hours, then evaporate to dryness. The pH was adjusted to 10 with saturated NaHCO3, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Preparative chromatography was performed under acidic conditions to obtain the target product 6-(8-amino-6-methyl-5,6,7,8-tetrahydroisoquinoline-4-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (230 mg, yield: 52.7%).

[0410] MS m / z(ESI): 324.2 [M+1].

[0411] Step 3:

[0412] Using 6-(8-amino-6-methyl-5,6,7,8-tetrahydroisoquinoline-4-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one as a starting material, and referring to Example 1, the target product N-(6-methyl-4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide was obtained.

[0413] MS m / z(ESI): 380.2 [M+1].

[0414] Step 4:

[0415] Using N-(6-methyl-4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide as the starting material, the synthetic method described in reference [ACS Catalysis, 2021, vol. 11, 6, 3251-3256] was used to obtain the target product N-(6-methyl-4-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-7,8-dihydroisoquinoline-8-yl)propionamide. Chiral separation yielded 115A and 115B.

[0416] MS m / z(ESI): 378.2 [M+1].

[0417] Example 10

[0418] N-(6-methyl-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazo-6-yl)-7,8-dihydroisoquinoline-8-yl)propionamide

[0419] Following the synthetic method of Example 9, the target product N-(6-methyl-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazo-6-yl)-7,8-dihydroisoquinoline-8-yl)propionamide was obtained, and 10A and 10B were obtained by chiral resolution.

[0420] MS m / z(ESI): 380.1 [M+1]

[0421] Example 11

[0422] first step:

[0423] A mixture of 3,5-dibromo-4-methylpyridine (4 g, 15.94 mmol), 1-(tert-butyl)-3-methylpiperazine-1,3-dicarboxylate (4.67 g, 19.13 mmol), cesium carbonate (12.99 g, 39.85 mmol), Pd2dba3 (1.46 g, 1.59 mmol), BINAP (1.98 g, 3.19 mmol), and 1',4-Dioxane (80 mL) was dissolved in water. After purging with liquid nitrogen three times, the mixture was stirred at 100°C for 12 hours under nitrogen protection, quenched with saturated ammonium chloride solution, extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (PE / EtOAc = 2:1) to obtain 1-(tert-butyl)-3-methyl-4-(5-bromo-4-methylpyridin-3-yl)piperazine-1,3-dicarboxylate (1.3 g, yield: 19.7%).

[0424] MS m / z(ESI): 414.1 416.1 [M+1]

[0425] Step Two:

[0426] Lithium aluminum hydride (2.5 M, 2.61 mL) was added dropwise to a THF solution of 1-(tert-butyl)-3-methyl-4-(5-bromo-4-methylpyridin-3-yl)piperazine-1,3-dicarboxylate (900 mg, 2.17 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, quenched with sodium sulfate decahydrate, filtered, and the filtrate was evaporated to dryness. Column chromatography (PE / EtOAc = 1:1) was performed to give a pale yellow oily substance, tert-butyl 4-(5-bromo-4-methylpyridin-3-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (500 mg, yield: 59.6%).

[0427] MS m / z (ESI): 386.1 388.1 [M+1]

[0428] Step 3:

[0429] Triphenylphosphine (679.00 mg, 2.59 mmol) and NBS (276.46 mg, 1.55 mmol) were added to a DCM (10 mL) solution of 4-(5-bromo-4-methylpyridin-3-yl)-3-(bromomethyl)piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.29 mmol). The mixture was stirred at room temperature for 12 hours, quenched with saturated ammonium chloride solution, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (PE / EtOAc = 2:1) to obtain 4-(5-bromo-4-methylpyridin-3-yl)-3-(bromomethyl)piperazine-1-carboxylic acid tert-butyl ester (320 mg, yield: 55%).

[0430] MS m / z(ESI): 450.0 [M+1]

[0431] Step 4:

[0432] To a THF (20 mL) solution of 260 mg (578.83 μmol) of 4-(5-bromo-4-methylpyridin-3-yl)-3-(bromomethyl)piperazin-1-carboxylic acid tert-butyl ester (1 M, 1.74 mL) under nitrogen protection, the mixture was stirred dropwise at room temperature for 0.5 h, quenched with saturated ammonium chloride solution, extracted with EtOAc, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (PE / EtOAc = 2:1) to obtain 160 mg (75% yield) of 4-bromo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,7]naphthyl-8-carboxylic acid tert-butyl ester.

[0433] MS m / z(ESI): 368.1 370.1 [M+1]

[0434] Step 5:

[0435] TFA (2 mL) was added dropwise to a DCM (4 mL) solution of 4-bromo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,7]naphthyl-8-carboxylic acid tert-butyl ester (140 mg, 380.16 μmol). The mixture was stirred at room temperature for 30 minutes, evaporated to dryness, and the pH was adjusted to 10 with saturated NaHCO3. The mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain solid 4-bromo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,7]naphthylidine (100 mg, crude product). MS m / z (ESI): 268.0 270.0 [M+1]

[0436] Step 6:

[0437] To a DCM solution of 4-bromo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,7]naphthylidine (100 mg, 372.92 μmol) and triethylamine (75.33 mg, 745.84 μmol) in 3 mL, propionyl chloride (51.76 mg, 559.38 μmol) was added dropwise. The mixture was stirred at room temperature for 5 minutes, quenched with saturated ammonium chloride solution, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (DCM / MeOH = 10:1) to obtain 1-(4-bromo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,7]naphthyl-8-yl)prop-1-one (105 mg, yield: 86.8%).

[0438] MS m / z(ESI): 324.1 326.1 [M+1]

[0439] Step 7:

[0440] The following substances were added: 1-(4-bromo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,7]naphthidin-8-yl)prop-1-one (70 mg, 215.91 μmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-(trideutermethyl)-4H-3,1-benzoxazin-2-one (94.62 mg, 323.86 μmol), Pd(PPh3)4 (19.95 mg, 17.27 μmol), and sodium carbonate (68.66 mg, 647.72 μmol). A mixture of mol), EtOH (5 mL), and water (1 mL) was purged with nitrogen three times, then stirred at 85 °C for 12 hours under nitrogen protection. The mixture was then evaporated to dryness with silica gel, separated by column chromatography (DCM / MeOH = 10:1), and then separated by preparative chromatography to obtain 1-(methyl-d3)-6-(8-propionyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,7]naphthid-4-yl)-3,4-dihydroquinoline-2(1H)-one (50 mg, yield: 56.6%). 11 was chirally resolved to obtain 11A and 11B.

[0441] MS m / z(ESI): 408.2 [M+1]

[0442] Example 12

[0443] Following the synthesis method of Example 11, target product 12 was obtained, and 12 was chirally resolved to obtain 12A and 12B.

[0444] MS m / z(ESI): 410.2 [M+1]

[0445] Example 13

[0446] Following the synthesis method of Example 11, target product 13 was obtained, and 13 was chirally resolved to obtain 13A and 13B.

[0447] MS m / z(ESI): 412.2 [M+1]

[0448] Method 2:

[0449] Step 1: 13-P1 and 13-P2

[0450] The partitioning yields 13-P1 and 13-P2, with the following conditions:

[0451] Step 2: 13-A and 13-B

[0452] Using 13-P1 and 13-P2 as raw materials, respectively, and following the synthesis method of Example 11, the target products 13-A and 13-B were obtained.

[0453] MS m / z(ESI): 412.2 [M+1].

[0454] The proton spectrum of 13-A is as follows:

[0455] 1 H NMR (400MHz, DMSO) δ8.23(d,1H),7.79(s,1H),7.68(d,1H),7.42-7.30(m,2H),4.48-4.32(m,1H),4.06-4.03(m 1H),3.98–3.83(m,1H),3.27-3.24(m,1H),3.05-2.69(m,4H),2.48-2.30(m,3H),1.94-1.89(m,1H),1.60-1.45(m,1H),1.03-0.99(m,3H).

[0456] The proton spectrum of 13-B is as follows:

[0457] 1 H NMR (400MHz, DMSO) δ8.23(d,1H),7.79(s,1H),7.68(d,1H),7.43-7.31(m,2H),4.48-4.31(m,1H),4.07-4.03(m,1H),3.98-3. 83(m,1H),3.27-3.24(s,1H),3.07-2.64(m,4H),2.47-2.25(m,3H),1.94-1.90(m,1H),1.59-1.38(m,1H),1.03-0.99(m,3H).

[0458] Example 14

[0459] Following the synthesis method of Example 11, target product 14 was obtained, and 14 was chirally resolved to obtain 14A and 14B.

[0460] MS m / z(ESI): 406.2 [M+1]

[0461] Example 15

[0462] first step

[0463] In a 50 mL reaction flask under nitrogen protection, 5-bromo-4-methylpyridin-3-ol (500 mg, 2.66 mmol), N-(3-hydroxycyclobutyl)carbamate tert-butyl ester (497.91 mg, 2.66 mmol), and triphenylphosphine (837.00 mg, 3.19 mmol) were dissolved in tetrahydrofuran (10 mL). Then, diisopropyl azodicarbonate (699.05 mg, 3.46 mmol, 680.67 μL) was added at 0 °C. The reaction mixture was then protected with nitrogen and stirred at 70 °C for 10 hours. The reaction was stopped, quenched with an aqueous solution (10 mL), and extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product N-[3-[(5-bromo-4-methyl-3-pyridyl)oxy]cyclobutyl]carbamate tert-butyl ester (600 mg), yield: 63.16%.

[0464] MS m / z(ESI):357.0, 359.0[M+H].

[0465] Step 2

[0466] In a 50 mL reaction flask, N-[3-[(5-bromo-4-methyl-3-pyridyl)oxy]cyclobutyl]carbamate tert-butyl ester (300 mg, 839.77 μmol) and trifluoroacetic acid (957.50 mg, 8.40 mmol) were dissolved in dichloromethane (5 mL). The reaction mixture was then protected with nitrogen and stirred at 25 °C for 1 hour. After concentration, the reaction mixture yielded the title product 3-[(5-bromo-4-methyl-3-pyridyl)oxy]cyclobutane (210 mg, yellow oil), yield: 97.26%.

[0467] MS m / z(ESI):257.0, 259.0[M+H].

[0468] Step 3

[0469] 3-[(5-bromo-4-methyl-3-pyridyl)oxy]cyclobutane (200 mg, 777.83 μmol), triethylamine (157.42 mg, 1.56 mmol, 216.98 μL), and dichloromethane (4.91 mL) were added to a 50 mL flask. 4-chlorobutyryl chloride (131.60 mg, 933.39 μmol) was slowly added at 25 °C. The reaction mixture was kept under nitrogen protection at 25 °C for 1 hour. The reaction was stopped, quenched with 10 mL of aqueous solution, and extracted with 10 mL of dichloromethane (2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using a dichloromethane and methanol eluent system to give the title product N-[3-[(5-bromo-4-methyl-3-pyridyl)oxy]cyclobutyl]-4-chlorobutyramide (280 mg), yield: 99.53%.

[0470] MS m / z(ESI):361.0, 363.0[M+H].

[0471] Step 4

[0472] In a 50 mL reaction flask, N-[3-[(5-bromo-4-methyl-3-pyridinyl)oxy]cyclobutyl]-4-chlorobutyramide (280 mg, 774.21 μmol) was dissolved in DMF (5 mL). Sodium hydride (61.94 mg, 1.55 mmol, 60% purity) was then added at 0 °C. The reaction mixture was kept under nitrogen protection and stirred at 25 °C for 1 hour. The reaction was stopped, and the reaction was quenched with ammonium chloride aqueous solution (10 mL). The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol as eluents to give the title product 1-[3-[(5-bromo-4-methyl-3-pyridinyl)oxy]cyclobutyl]pyrrolidone-2-one (200 mg), yield: 79.44%.

[0473] MS m / z(ESI):325.0, 327.0[M+H].

[0474] Step 5

[0475] 1-[3-[(5-bromo-4-methyl-3-pyridinyl)oxy]cyclobutyl]pyrrolidone-2-one (60 mg, 184.50 μmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)imidazo[1,5-a]pyridine (45.04 mg, 184.50 μmol), tetra(triphenylphosphine)palladium (10.66 mg, 9.23 μmol), sodium carbonate (58.67 mg, 553.51 μmol), water (1 mL), and ethanol (3 mL) were added to a 10 mL flask. The reaction mixture was then subjected to nitrogen protection at 90 °C for 3 h. The reaction was stopped, and the reaction was quenched with aqueous solution (10 mL). The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by prep-HPLC yielded the title product 1-(3-((5-(imidazo[1,5-a]pyridin-6-yl)-4-methylpyridin-3-yl)oxy)cyclobutyl)pyrrolidone-2-one (30 mg), yield: 44.86%.

[0476] MS m / z(ESI): 363.1 [M+H].

[0477] Step 6

[0478] Chiral resolution of 1-(3-((5-(imidazo[1,5-a]pyridin-6-yl)-4-methylpyridin-3-yl)oxy)cyclobutyl)pyrrolidine-2-one yielded the title products 1-((1s,3s)-3-((5-(imidazo[1,5-a]pyridin-6-yl)-4-methylpyridin-3-yl)oxy)cyclobutyl)pyrrolidine-2-one 15A and 1-((1r,3r)-3-((5-(imidazo[1,5-a]pyridin-6-yl)-4-methylpyridin-3-yl)oxy)cyclobutyl)pyrrolidine-2-one 15B.

[0479] The LCMS of samples 15A and 15B are as follows:

[0480] MS m / z(ESI): 363.1 [M+H].

[0481] Example 16

[0482] first step:

[0483] Using 1-[3-[(5-bromo-4-methyl-3-pyridinyl)oxy]cyclobutyl]pyrrolidone-2-one and 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)benzo[d]thiazol-2(3H)-one as starting materials, the title product 3-(methyl-d3)-6-(4-methyl-5-(3-(2-oxopyrrolidone-1-yl)cyclobutoxy)pyridin-3-yl)benzo[d]thiazol-2(3H)-one was obtained by referring to the synthesis method in step 5 of Example 15.

[0484] MS m / z(ESI): 413.1 [M+H].

[0485] Step 2

[0486] After splitting, 16 yields the title products 16A and 16B.

[0487] LCMS: MS m / z(ESI):413.1[M+H].

[0488] The HPLC analysis conditions for 16-A are as follows:

[0489] The proton spectrum of 16-A is as follows:

[0490] 1 H NMR(400MHz,MeOD)δ8.04(d,2H),7.55(t,1H),7.36(d,2H),4.75-4.61(m,1H),4.43-4.31( m,1H),3.58(t,2H),2.91-2.78(m,2H),2.51-2.34(m,4H),2.20(s,3H),2.12-2.01(m,2H).

[0491] Example 17

[0492] Using 1-(2-(5-bromo-4-methylpyridin-3-yl)-2-azaspiro[3.3]heptane-6-yl)pyrrolidine-2-one and 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[d]thiazol-2(3H)-one as starting materials, the title product 3-(methyl-d3)-6-(4-methyl-5-(6-(2-oxopyrrolidine-1-yl)-2-azaspiro[3.3]heptane-2-yl)pyridin-3-yl)benzo[d]thiazol-2(3H)-one was obtained by referring to the synthesis method in step 5 of Example 15.

[0493] MS m / z(ESI): 438.2 [M+H].

[0494] Example 18

[0495] first step:

[0496] 1-Methylpyrazole-4-ol (1 g, 10.19 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (2.46 g, 12.23 mmol) were dissolved in anhydrous toluene (20 mL), and cyanomethylenetri-n-butylphosphine (4.92 g, 20.39 mmol) was added. The reaction system was stirred in an oil bath at 120 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and the excess solvent was concentrated to obtain a crude product. The crude product was purified by column chromatography (Petroleum ether:Ethyl acetate = 3:1, UV = 254 nm) to obtain tert-butyl 4-((1-methyl-1H-pyrazole-4-yl)oxy)piperidine-1-carboxylate (2.5 g, 8.89 mmol, 87.17% yield).

[0497] MS m / z(ESI): 282.2 [M+1]

[0498] Step Two:

[0499] 4-((1-methyl-1H-pyrazole-4-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (1 g, 3.55 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added. The reaction system was stirred at room temperature (20 °C) for 5 hours. After the reaction was completed, the reaction was quenched by adding saturated sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude 4-((1-methyl-1H-pyrazole-4-yl)oxy)piperidine (700 mg, crude).

[0500] MS m / z(ESI): 182.2 [M+1]

[0501] Step 3:

[0502] 3,5-Dibromo-4-methylpyridine (2 g, 7.97 mmol), 4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidine (1.59 g, 8.77 mmol) were dissolved in anhydrous dioxane (30 mL). Tris(dibenzylacetone)dipalladium (729.89 mg, 797.07 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (922.40 mg, 1.59 mmol), and sodium tert-butoxide (1.53 g, 15.94 mmol) were added sequentially. After the reaction system was purged with nitrogen several times, it was stirred in an oil bath at 100 °C for 16 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (30 mL x 2), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (Petroleum ether:Ethyl acetate = 2:1, UV = 254nm) to finally obtain 3-bromo-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyridine (1.2g, crude).

[0503] MS m / z(ESI):351.0, 353.0[M+1]

[0504] Step 4: 1-(methyl-d3)-6-(4-methyl-5-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyridin-3-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0505] 1-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (50 mg, 171.14 μmol) and 3-bromo-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyridine (60.11 mg, 171.14 μmol) were dissolved in a mixture of water (5 mL) and ethanol (15 mL). Tetraphenylphosphine palladium (19.78 mg, 17.11 μmol) and sodium carbonate (54.42 mg, 513.43 μmol) were added sequentially. After purging the reaction system with nitrogen several times, it was stirred in an oil bath at 80 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, and the excess solvent was directly concentrated to obtain the crude product. The crude product was purified by prep-HPLC to obtain 1-(methyl-d3)-6-(4-methyl-5-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyridin-3-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (6.3 mg, 8.43% yield).

[0506] MS m / z(ESI): 437.2 [M+1]

[0507] Example 19

[0508] Using 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[d]thiazol-2(3H)-one and 3,5-dibromo-4-methylpyridine as starting materials, and referring to Example 18, the target product 3-(methyl-d3)-6-(4-methyl-5-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyridin-3-yl)benzo[d]thiazol-2(3H)-one was finally obtained.

[0509] MS m / z(ESI): 439.2 [M+1]

[0510] Example 20

[0511] first step:

[0512] 3,5-Dibromo-4-methylpyridine (1 g, 3.99 mmol) and N-(4-piperidinylmethyl)carbamate tert-butyl ester (854.08 mg, 3.99 mmol) were dissolved in anhydrous dioxane (20 mL). Tris(dibenzylacetone)dipalladium (364.95 mg, 398.54 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (461.20 mg, 797.07 μmol), and sodium tert-butoxide (766.01 mg, 7.97 mmol) were added sequentially. After the reaction system was purged with nitrogen several times, it was stirred in an oil bath at 100 °C for 6 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5:1, UV = 254 nm) to obtain tert-butyl 1-(5-bromo-4-methylpyridin-3-yl)piperidin-4-yl)methyl)carbamate (610 mg, 40% yield).

[0513] MS m / z (ESI): 384.1, 386.1 [M+1]

[0514] Step Two:

[0515] 1-(5-bromo-4-methylpyridin-3-yl)piperidin-4-yl)methyl)tert-butyl carbamate (610 mg, 1.59 mmol) was dissolved in anhydrous dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added. The reaction system was stirred at room temperature (20 °C) for 4 hours. After the reaction was completed, the reaction was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude (1-(5-bromo-4-methylpyridin-3-yl)piperidin-4-yl)methylamine (350 mg, crude).

[0516] MS m / z(ESI): 284.1, 286.1 [M+1]

[0517] Step 3:

[0518] (1-(5-bromo-4-methylpyridin-3-yl)piperidin-4-yl)methylamine (350 mg, 1.23 mmol) and 4-chlorobutyryl chloride (208.37 mg, 1.48 mmol) were dissolved in dichloromethane (10 mL), and TEA (373.86 mg, 3.69 mmol, 515.32 μL) was added. The reaction system was stirred at room temperature for 6 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate (10 mL), extracted with dichloromethane (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 (DCM:Methanol = 10:1, uv = 254 nm) to obtain N-[[1-(5-bromo-4-methyl-3-pyridyl)-4-piperidinyl]methyl]-4-chlorobutyramide (170 mg, 437.32 μmol, 35.51% yield).

[0519] MS m / z(ESI): 388.0, 390.0 [M+1]

[0520] Step 4:

[0521] N-[[1-(5-bromo-4-methyl-3-pyridinyl)-4-piperidinyl]methyl]-4-chlorobutyramide (170 mg, 437.32 μmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). Sodium hydroxide (34.98 mg, 874.64 μmol, 60% purity) was added at room temperature. The reaction mixture was stirred at 20°C for 3 hours. After the reaction was complete, a saturated ammonium chloride solution (10 mL) was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (10 mL x 2), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 1-(1-(5-bromo-4-methylpyridin-3-yl)piperidin-4-yl)methyl)pyrrolidone-2-one (140 mg, crude).

[0522] MS m / z(ESI): 352.0, 354.0 [M+1]

[0523] Step 5:

[0524] Using the 1-(1-(5-bromo-4-methylpyridin-3-yl)piperidin-4-yl)methyl)pyrrolidine-2-one and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)imidazo[1,5-a]pyridine obtained above as raw materials, the target product 1-(1-(5-(imidazo[1,5-a]pyridin-6-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)pyrrolidine-2-one was finally obtained.

[0525] MS m / z(ESI): 390.2 [M+1]

[0526] Example 21

[0527] first step:

[0528] Diisopropyl azodicarbonate (699.04 mg, 3.46 mmol, 680.66 μL) was added to a solution of 5-bromo-4-methylpyridin-3-ol (500 mg, 2.66 mmol) and 5-bromo-4-methylpyridin-3-ol (597.49 mg, 3.19 mmol), triphenylphosphine (697.49 mg, 2.66 mmol) in tetrahydrofuran (20 mL). After purging with nitrogen, the mixture was heated to 70 °C and stirred for 10 hours. The reaction solution was cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (eluent: petroleum ether: ethyl acetate = 3:1) to give the title product (3-((5-bromo-4-methylpyridin-3-yl)oxy)cyclobutyl)carbamate (500 mg, 1.40 mmol, 52.63% yield).

[0529] MS m / z(ESI):357.1, 359.1[M+1]

[0530] Step Two:

[0531] Under a nitrogen atmosphere, sodium carbonate (267.02 mg, 2.52 mmol) was added to a mixture of tert-butyl 3-((5-bromo-4-methylpyridin-3-yl)oxy)cyclobutyl)carbamate (500 mg, 839.77 μmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)imidazo[1,5-a]pyridine (204.98 mg, 839.77 μmol), tetraphenylphosphine palladium (97.04 mg, 83.98 μmol), 1,4-dioxane (12 mL), and water (3 mL). After purging with nitrogen, the mixture was heated to 90 °C and reacted for 3 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (mobile phase: dichloromethane: methanol = 10:1) to obtain tert-butyl (3-((5-(imidazo[1,5-a]pyridin-6-yl)-4-methylpyridin-3-yl)oxy)cyclobutyl)carbamate (300 mg, 760.52 μmol, 90.56% yield).

[0532] MS m / z(ESI): 395.1 [M+1]

[0533] Step 3:

[0534] Dioxane hydrochloride (4M, 3mL) was added to a methanol (3mL) solution of (3-((5-(imidazo[1,5-a]pyridin-6-yl)-4-methylpyridin-3-yl)oxy)cyclobutyl)carbamate (100mg, 253.51μmol), and the mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated and diluted with saturated sodium bicarbonate solution (20mL), extracted with ethyl acetate (40mL x 3), and the combined organic phases were washed with saturated brine (50mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. 3-((5-(imidazo[1,5-a]pyridin-6-yl)-4-methylpyridin-3-yl)oxy)cyclobutane-1-amine (70mg, 237.81μmol, 93.81% yield) was directly used in the next step.

[0535] MS m / z(ESI): 295.1 [M+1]

[0536] Step 4:

[0537] Under a nitrogen atmosphere, methanesulfonic acid (2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (20.24 mg, 25.48 μmol) was added to a suspension of 3-((5-(imidazo[1,5-a]pyridin-6-yl)-4-methylpyridin-3-yl)oxo)cyclobutane-1-amine (70 mg, 237.80 μmol), 4-iodo-1-methyl-1H-pyrazole (68.90 mg, 331.24 μmol), and sodium tert-butoxide (73.46 mg, 764.40 μmol) in 1'4-dioxane (3 mL). After purging with nitrogen, the reaction mixture was heated to 85 °C and stirred for 5 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (40 mL x 3), and the combined organic phases were washed with saturated brine (50 mL x 3). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) to obtain N-((1s,3s)-3-((5-(imidazo[1,5-a]pyridin-6-yl)-4-methylpyridin-3-yl)oxy)cyclobutyl)-1-methyl-1H-pyrazole-4-amine (8.8 mg, 23.50 μmol, 9.22% yield) and N-((1r,3r)-3-((5-(imidazo[1,5-a]pyridin-6-yl)-4-methylpyridin-3-yl)oxy)cyclobutyl)-1-methyl-1H-pyrazole-4-amine (12 mg, 32.05 μmol, 12% yield).

[0538] MS m / z(ESI): 375.1 [M+1]

[0539] 1 H NMR (400MHz, CDCl3) δ8.28–7.99(m,3H),7.88(s,1H),7.69–7.36(m,2H),7.13(s,1H),6.94(s,1H),6.68(d,J=9. 2Hz,1H),4.64–4.50(m,1H),3.82(s,3H),3.55–3.42(m,1H),3.18–2.98(m,2H),2.20(s,3H),2.13–1.99(m,2H).

[0540] 1 H NMR (400MHz, CDCl3) δ8.28–8.10(m,2H),8.01(s,1H),7.88(s,1H),7.51(d,J=9.2Hz,2H),7.13(s,1H),6.91(s,1H),6. 73–6.65(m,1H),5.11–4.95(m,1H),3.98–3.90(m,1H),3.83(s,3H),2.63–2.55(m,2H),2.50–2.43(m,2H),2.22(s,3H).

[0541] Example 22

[0542] Using 3,5-dibromo-4-methylpyridine and 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[d]thiazol-2(3H)-one as starting materials, and referring to Example 20, the target product 3-(methyl-d3)-6-(4-methyl-5-(4-((2-oxopyrrolidone-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)benzo[d]thiazol-2(3H)-one was finally obtained.

[0543] MS m / z(ESI): 440.2 [M+1]

[0544] Example 23

[0545] Step 1: 3-Bromo-5-fluoro-4-iodopyridine

[0546] Under a nitrogen atmosphere, 3-bromo-5-fluoropyridine (5 g, 28.41 mmol) was dissolved in tetrahydrofuran (80 mL). The temperature was cooled to -70 °C, and diisopropylaminolithium (2 M, 21.31 mL) was added dropwise. The mixture was stirred for 30 minutes while maintaining the temperature. Elemental iodine (8.65 g, 34.09 mmol) was then added to the reaction solution. The reaction system was stirred for 4 hours while maintaining the temperature. The reaction solution was quenched with ammonium chloride solution (50 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phases were washed with saturated brine (100 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to give 3-bromo-5-fluoro-4-iodopyridine (6 g, 19.88 mmol, 69.96% yield).

[0547] MS m / z(ESI):301.9, 303.9[M+1]

[0548] Step 2: 3-Bromo-4-cyclopropyl-5-fluoropyridine

[0549] Under a nitrogen atmosphere, potassium phosphate (1.69 g, 7.95 mmol) was added to a suspension of 1',4-dioxane (20 mL) containing 3-bromo-5-fluoro-4-iodopyridine (1.2 g, 3.98 mmol), cyclopropylboronic acid (409.74 mg, 4.77 mmol), and (1,1'-bis(diphenylphosphine)ferrocene)palladium dichloride (145.43 mg, 198.75 μmol), silver oxide (184.23 mg, 795.01 μmol, 25.80 μL). After purging with nitrogen, the reaction mixture was heated to 80 °C and stirred for 5 hours. The reaction mixture was cooled to room temperature, filtered, and quenched slowly with water (50 mL). The reaction mixture was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at room temperature to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (mobile phase: pure water (0.1% FA)-ACN), the fraction was extracted with dichloromethane, and the organic phase was concentrated under reduced pressure at room temperature. This yielded 3-bromo-4-cyclopropyl-5-fluoropyridine (360 mg, 1.67 mmol, 41.92% yield).

[0550] MS m / z(ESI):216.0, 218.0[M+1]

[0551] Step 3: Tert-butyl (3-((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutyl)carbamate

[0552] Under a nitrogen atmosphere, tert-butyl N-(3-hydroxycyclobutyl)carbamate (207.99 mg, 1.11 mmol) was dissolved in N,N-dimethylacetamide (10 mL). The temperature was cooled to 0 °C, and sodium hydride (48.14 mg, 1.20 mmol, 60% purity) was added in portions. The mixture was stirred for 30 minutes while maintaining the temperature. 3-Bromo-4-cyclopropyl-5-fluoropyridine (200 mg, 925.71 μmol) was added to the above reaction solution. The reaction system was allowed to warm naturally to room temperature and stirred for 8 hours. The reaction was quenched by slowly adding water (20 mL). The reaction solution was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using an eluent system (petroleum ether: ethyl acetate = 7:3) to obtain tert-butyl (3-((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutyl)carbamate (130 mg, 339.18 μmol, 36.64% yield).

[0553] MS m / z(ESI):383.1, 385.1[M+1]

[0554] Step 4: 3-((5-bromo-4-cyclopropylpyridin-3-yl)oxo)cyclobutane-1-amine

[0555] Using tert-butyl (3-((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutyl)carbamate as a raw material, 3-((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutane-1-amine was obtained by referring to the third step of Example 21.

[0556] MS m / z(ESI):283.1,285.1[M+1]

[0557] Step 5: N-(3-((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutyl)-1-methyl-1H-pyrazole-4-amine

[0558] Using 3-((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutane-1-amine as a starting material, N-(3-(((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutyl)-1-methyl-1H-pyrazole-4-amine was obtained by referring to step 4 of Example 21.

[0559] MS m / z(ESI):363.1, 365.1[M+1]

[0560] Step 6: N-(3-((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutyl)-N,1-dimethyl-1H-pyrazole-4-amine

[0561] Under a nitrogen atmosphere, N-(3-(((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutyl)-1-methyl-1H-pyrazole-4-amine (363 mg, 1.0 mmol) was dissolved in N,N-dimethylacetamide (10 mL). The temperature was cooled to 0 °C, and sodium hydride (48.14 mg, 1.20 mmol, 60% purity) was added in portions. The mixture was stirred for 30 minutes while maintaining the temperature. Iodomethane (280 mg, 2.0 μmol) was then added to the reaction solution. The reaction system was allowed to warm naturally to room temperature and stirred for 2 hours. The reaction was quenched by slowly adding water (20 mL). The reaction solution was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using an eluent system (petroleum ether: ethyl acetate = 1:1) to give N-(3-(((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutyl)-N,1-dimethyl-1H-pyrazole-4-amine (300 mg).

[0562] MS m / z(ESI):377.0, 379.0[M+1]

[0563] Step 7: N-(3-((4-cyclopropyl-5-(imidazo[1,5-a]pyridin-6-yl)pyridin-3-yl)oxy)cyclobutyl)-N,1-dimethyl-1H-pyrazole-4-amine

[0564] Under a nitrogen atmosphere, [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II) dichloride (33.7 mg, 52.2 μmol) was added to a suspension of N-(3-((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutyl)-N,1-dimethyl-1H-pyrazole-4-amine (196 mg, 522 μmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)imidazo[1,5-a]pyridine (204.98 mg, 839.77 μmol) and cesium carbonate (510.00 mg, 1.54 mmol) in 1',4-dioxane (3 mL). After purging with nitrogen, the reaction mixture was heated to 10 °C and stirred for 2 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (40 mL x 3), and the combined organic phases were washed with saturated brine (50 mL x 3). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) to obtain N-((1s,3s)-3-((4-cyclopropyl-5-(imidazo[1,5-a]pyridin-6-yl)pyridin-3-yl)oxy)cyclobutyl)-N,1-dimethyl-1H-pyrazole-4-amine (60 mg) and N-((1r,3r)-3-((4-cyclopropyl-5-(imidazo[1,5-a]pyridin-6-yl)pyridin-3-yl)oxy)cyclobutyl)-N,1-dimethyl-1H-pyrazole-4-amine (60 mg).

[0565] MS m / z(ESI): 414.2 [M+1]

[0566] Example 24

[0567] The target product was obtained using N-(3-((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutyl)-1-methyl-1H-pyrazole-4-amine as a starting material, referring to steps six and seven of Example 23.

[0568] MS m / z (ESI): 468.2 [M+1]

[0569] Example 25

[0570] Using N-(3-((5-bromo-4-cyclopropylpyridin-3-yl)oxy)cyclobutyl)-1-methyl-1H-pyrazole-4-amine as a starting material, 6-(4-cyclopropyl-5-((1s,3s)-3-((1-methyl-1H-pyrazole-4-yl)amino)cyclobutoxy)pyridin-3-yl)-3-(methyl-d3)benzo[d]thiazol-2(3H)-one and 6-(4-cyclopropyl-5-((1r,3r)-3-((1-methyl-1H-pyrazole-4-yl)amino)cyclobutoxy)pyridin-3-yl)-3-(methyl-d3)benzo[d]thiazol-2(3H)-one were obtained by referring to step 7 of Example 23.

[0571] MS m / z (ESI): 451.2 [M+1]

[0572] Example 26

[0573] Step 1: 4'-Bromo-1-((4-nitrophenyl)sulfonyl)-5',6'-dihydro-8'H-spiro[azacyclobutane-3,7'-isoquinoline]-8'-one

[0574] Using 4-bromo-6,7-dihydroisoquinoline-8(5H)-one as the starting material, the target product 4'-bromo-1-((4-nitrophenyl)sulfonyl)-5',6'-dihydro-8'H-spiro[azacyclobutane-3,7'-isoquinoline]-8'-one was obtained by referring to the synthetic method in the literature [Org. Lett. 2021, 23, 4152-4157].

[0575] MS m / z(ESI): 452.0 454.0 [M+1]

[0576] Step 2: 4'-Bromo-1-((4-nitrophenyl)sulfonyl)-5',8'-dihydro-6'H-spiro[azacyclobutane-3,7'-isoquinoline]

[0577] Using 4'-bromo-1-((4-nitrophenyl)sulfonyl)-5',6'-dihydro-8'H-spiro[azacyclobutane-3,7'-isoquinoline]-8'-one as the starting material, the target product 4'-bromo-1-((4-nitrophenyl)sulfonyl)-5',8'-dihydro-6'H-spiro[azacyclobutane-3,7'-isoquinoline] was obtained by following the synthetic method described in [Organic Process Research and Development, 2019, vol. 23, 11, 2445-2455].

[0578] MS m / z(ESI): 438.0 440.0 [M+1]

[0579] Step 3: 4'-Bromo-5',8'-Dihydro-6'H-spiro[azacyclobutane-3,7'-isoquinoline]

[0580] Using 4'-bromo-1-((4-nitrophenyl)sulfonyl)-5',8'-dihydro-6'H-spiro[azacyclobutane-3,7'-isoquinoline] as the starting material, the target product 4'-bromo-5',8'-dihydro-6'H-spiro[azacyclobutane-3,7'-isoquinoline] was obtained by following the synthetic method described in the reference [New Journal of Chemistry, 2018, vol. 42, 22, 18363-18380].

[0581] MS m / z(ESI): 253.0 255.0 [M+1]

[0582] Step 4: 1-(methyl-d3)-6-(1-propionyl-5',8'-dihydro-6'H-spiro[azacyclobutane-3,7'-isoquinoline]-4'-yl)-3,4-dihydroquinoline-2(1H)-one

[0583] The target product was obtained by referring to the synthesis method of Example 1.

[0584] MS m / z(ESI): 393.2 [M+1]

[0585] Example 27

[0586] The target product was obtained by referring to the synthesis method of Example 26.

[0587] MS m / z(ESI): 397.2 [M+1]

[0588] Example 28

[0589] Step 1: 3'-Methyl-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazolyl-6-yl)-5,8-dihydro-6H-spiro[isoquinoline-7,4'-oxazolidine]-2'-one

[0590] Using intermediate 8 as a raw material, the target compound was synthesized in the first step of Example 1.

[0591] MS m / z(ESI): 385.1 [M+1]

[0592] Step 2: (R)-3'-methyl-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazo-6-yl)-5,8-dihydro-6H-spiro[isoquinoline-7,4'-oxazolidine]-2'-one and (S)-3'-methyl-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazo-6-yl)-5,8-dihydro-6H-spiro[isoquinoline-7,4'-oxazolidine]-2'-one

[0593] The target compound was obtained by chiral resolution.

[0594] MS m / z(ESI): 385.1 [M+1]

[0595] Example 29

[0596] first step

[0597] In a 100 mL reaction flask, methyl 5-methyl-1H-pyrazole-4-carboxylate (1.48 g, 10.53 mmol) was dissolved in DMF (30 mL). Sodium hydride (420.98 mg, 10.53 mmol, 60% purity) was added in portions at 0 °C. The reaction mixture was kept under nitrogen protection and stirred at 25 °C for 1 hour. Then, a DMF solution of 3-bromo-5-fluoro-4-methylpyridine (2.0 g, 10.53 mmol) was slowly added, and the reaction mixture was stirred at 25 °C for another 1 hour. The reaction was stopped, quenched with an aqueous solution of ammonium chloride (50 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the title product methyl 1-(5-bromo-4-methylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylate (700 mg), yield: 21.44%.

[0598] MS m / z(ESI):310.0, 312.0[M+H].

[0599] Step 2

[0600] In a 50 mL reaction flask, methyl 1-(5-bromo-4-methylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylate (700 mg, 2.26 mmol), N-bromosuccinimide (482.05 mg, 2.71 mmol), and azobisisobutyronitrile (37.06 mg, 225.70 μmol) were dissolved in carbon tetrachloride (10 mL). The reaction mixture was kept under nitrogen protection and stirred at 80 °C for 12 hours. The reaction was stopped, quenched with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product methyl 1-(5-bromo-4-(bromomethyl)pyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylate (300 mg), yield: 34.1%.

[0601] MS m / z (ESI): 389.9 [M+H].

[0602] Step 3

[0603] In a 50 mL reaction flask, methyl 1-(5-bromo-4-(bromomethyl)pyridin-3-yl)-5-methyl-1H-pyrazol-4-carboxylate (300 mg, 771.12 μmol) was dissolved in tetrahydrofuran (5 mL). Then, lithium diisopropylamino (771.12 μL, 771.12 μmol, 1 M) was added at -50 °C. The reaction mixture was protected with nitrogen and stirred at -50 °C for 1 hour. The reaction was stopped, and the reaction was quenched with ammonium chloride aqueous solution (5 mL). The mixture was extracted with ethyl acetate (5 mL × 2), and the combined organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product, methyl 6-bromo-4,5-dihydropyrazolo[1,5-a][1,7]naphthyl-3-carboxylate (120 mg), yield: 50.50%.

[0604] MS m / z(ESI):308.0, 310.0[M+H].

[0605] Step 4

[0606] Methyl 6-bromo-4,5-dihydropyrazolo[1,5-a][1,7]naphthyl-3-carboxylic acid (120 mg, 389.44 μmol) was dissolved in methanol (2 mL) in a 50 mL reaction flask. Then, an aqueous solution of sodium hydroxide (1.95 mL, 1.95 mmol, 1 M) was added at 25 °C. The reaction mixture was kept under nitrogen protection and stirred at 25 °C for 12 hours. The reaction was stopped, quenched with 1 N hydrochloric acid (2 mL), and 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 concentrated. The title product, 6-bromo-4,5-dihydropyrazolo[1,5-a][1,7]naphthyl-3-carboxylic acid (100 mg), was obtained in 87.31% yield.

[0607] MS m / z(ESI):294.0, 296.0[M+H].

[0608] Step 5

[0609] In a 50 mL reaction flask, 6-bromo-4,5-dihydropyrazolo[1,5-a][1,7]naphthyl-3-carboxylic acid (30 mg, 102 μmol), ethylamine hydrochloride (9.98 mg, 122.4 μmol), DIEA (26.37 mg, 204.01 μmol), and HATU (46.54 mg, 122.40 μmol) were dissolved in DMF (2 mL). The reaction mixture was then protected with nitrogen and stirred at 25 °C for 10 hours. The reaction was stopped, and the reaction was quenched with an aqueous solution (5 mL). The mixture was extracted with dichloromethane (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 prepared by prep-HPLC to give the title product 6-bromo-N-ethyl-4,5-dihydropyrazolo[1,5-a][1,7]naphthyl-3-carboxamide (25 mg), yield: 76.31%.

[0610] MS m / z(ESI):321.0, 323.0[M+H].

[0611] Step 6

[0612] Using 6-bromo-N-ethyl-4,5-dihydropyrazolo[1,5-a][1,7]naphthidine-3-carboxamide and 1-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4-dihydroquinoline-2(1H)-one as starting materials, the title product N-ethyl-6-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)-4,5-dihydropyrazolo[1,5-a][1,7]naphthidine-3-carboxamide was obtained by referring to the synthesis method in step 5 of Example 15.

[0613] MS m / z (ESI): 405.2 [M+H].

[0614] Example 30

[0615] Using 6-bromo-N-ethyl-4,5-dihydropyrazolo[1,5-a][1,7]naphthidine-3-carboxamide and 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[d]thiazol-2(3H)-one as starting materials, the title product N-ethyl-6-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-4,5-dihydropyrazolo[1,5-a][1,7]naphthidine-3-carboxamide was obtained by referring to the synthesis method in step 5 of Example 15.

[0616] MS m / z (ESI): 409.1 [M+H].

[0617] Example 31

[0618] first step

[0619] At room temperature, 2.26 g (10 mmol) of 4-bromo-6,7-dihydroisoquinoline-8(5H)-one was dissolved in 25 mL of carbon tetrachloride, followed by the addition of N-bromosuccinimide (1.96 g, 11 mmol). The mixture was stirred at room temperature for half an hour, and the reaction was stopped by LC-MS. The solution was evaporated to dryness, and the residue was dissolved in 35 mL of ethyl acetate and washed with 15 mL × 3 saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was separated by Flash column chromatography to give 0.90 g (40% yield).

[0620] MS m / z(ESI):224.1, 226.1[M+1].

[0621] Step 2

[0622] Under ice bath conditions, 4-bromoisoquinoline-8(5H)-one (0.9 g, 4 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methylamine (0.57 g, 2.4 mmol) were dissolved in dichloromethane (20 mL), followed by the addition of trifluoroacetic acid (0.33 g, 2.88 mmol). The mixture was stirred under ice bath conditions and allowed to warm to room temperature while stirring overnight. The reaction mixture was neutralized with saturated sodium bicarbonate solution, separated, and the organic phase was washed with saturated brine (15 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to give 2-benzyl-8-bromo-1,2,3,3a,9,9a-hexahydro-4H-pyrrolo[3,4-g]isoquinoline-4-one (0.71 g, yield: 50%).

[0623] MS m / z (ESI): 357.1, 359.1 [M+1].

[0624] Step 3

[0625] At room temperature, 0.71 g (2 mmol) of 2-benzyl-8-bromo-1,2,3,3a,9,9a-hexahydro-4H-pyrrolo[3,4-g]isoquinoline-4-one was dissolved in 10 mL of trifluoroacetic acid, followed by the addition of triethylsilane (1.16 g, 10 mmol). The mixture was heated to 60 °C and reacted for 3 hours. After cooling to room temperature, the reaction was considered complete by LC-MS. The solution was evaporated to dryness, and the residue was dissolved in 25 mL of ethyl acetate. The solution was then washed successively with 15 mL (3 times) of saturated sodium bicarbonate solution and 15 mL (1 time) of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was separated by Flash column chromatography to give 0.55 g (80% yield) of 2-benzyl-8-bromo-2,3,3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-g]isoquinoline.

[0626] MS m / z (ESI): 343.1, 345.1 [M+1].

[0627] Step 4

[0628] At room temperature, 2-benzyl-8-bromo-2,3,3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-g]isoquinoline (0.55 g, 1.6 mmol) was dissolved in 1,2-dichloromethane (15 mL), followed by the addition of 1-chloroethyl chloroformate (0.46 g, 3.2 mmol). The mixture was heated under reflux for three hours, cooled to room temperature, and evaporated to dryness. The residue was dissolved in methanol (15 mL) and heated under reflux for 2 hours. The residue was evaporated to dryness, dissolved in ethyl acetate (25 mL), and then washed successively with saturated sodium bicarbonate solution (15 mL × 3) and saturated brine (15 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product, which was used directly in the next step (0.41 g, yield: 100%).

[0629] MS m / z(ESI): 253.1, 255.1 [M+1].

[0630] Step 5

[0631] Using 8-bromo-2,3,3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-g]isoquinoline and propionyl chloride as raw materials, 1-(8-bromo-1,3,3a,4,9,9a-hexahydro-2H-pyrrolo[3,4-g]isoquinoline-2-yl)prop-1-one was obtained by referring to the first step of Example 8.

[0632] MS m / z (ESI): 309.1, 311.1 [M+1].

[0633] Step 6

[0634] Using 1-(8-bromo-1,3,3a,4,9,9a-hexahydro-2H-pyrrolo[3,4-g]isoquinoline-2-yl)prop-1-one and intermediate 10 as raw materials, 1-(methyl-d3)-6-(2-propionyl-2,3,3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-g]isoquinoline-8-yl)-3,4-dihydroquinoline-2(1H)-one was obtained by referring to the third step of Example 8.

[0635] MS m / z(ESI): 393.2 [M+1].

[0636] Step 7

[0637] Compound 31 was chirally resolved to obtain the target product.

[0638] MS m / z(ESI): 393.2 [M+1].

[0639] Example 32

[0640] first step

[0641] 3-(methyl-d3)-6-((3aR, 9aS)-2-propionyl-2,3,3a, 4,9,9a-hexahydro-1H-pyrrolo[3,4-g]isoquinoline-8-yl)benzo[d]thiazolyl-2(3H)-one; 3-(methyl-d3)-6-((3aS, 9aS)-2-propionyl-2,3,3a, 4,9,9a-hexahydro-1H-pyrrolo[3,4-g]isoquinoline-8-yl)benzo[d]thiazolyl-2(3H)-one 3-(methyl-d3)-6-((3aS, 9aR)-2-propionyl-2,3,3a, 4,9,9a-hexahydro-1H-pyrrolo[3,4-g]isoquinoline-8-yl)benzo[d]thiazol-2(3H)-one; 3-(methyl-d3)-6-((3aR, 9aR)-2-propionyl-2,3,3a, 4,9,9a-hexahydro-1H-pyrrolo[3,4-g]isoquinoline-8-yl)benzo[d]thiazol-2(3H)-one

[0642] The target product was obtained with reference to Example 31.

[0643] MS m / z(ESI): 397.2 [M+1].

[0644] Example 33

[0645] first step

[0646] At room temperature, 3,5-dibromo-4-methylpyridine (1.25 g, 5 mmol), tert-butyl 3-ethynylazetane-1-carboxylate (1.08 g, 6 mmol), cuprous iodide (0.19 g, 1 mmol), and dichlorotriphenylphosphine palladium (0.35 g, 0.5 mmol) were dissolved in triethylamine (25 mL), purged with nitrogen, heated to 100 °C, and reacted for 14 hours. The reaction was considered complete by LC-MS, and the mixture was cooled to room temperature. The solution was evaporated to dryness, and the residue was dissolved in ethyl acetate (25 mL), then washed with saturated brine (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was separated by Flash column chromatography to give tert-butyl 3-((5-bromo-4-methylpyridin-3-yl)ethynyl)azetane-1-carboxylate (1.23 g, yield: 70%).

[0647] MS m / z (ESI): 351.2, 353.1 [M+1].

[0648] Step 2

[0649] At room temperature, tert-butyl 3-((5-bromo-4-methylpyridin-3-yl)ethynyl)azacyclobutane-1-carboxylate (1.23 g, 3.5 mmol) was dissolved in dichloromethane (20 mL), and then hydrochloric acid / dioxane solution (4 N, 15 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was stopped by LCMS. The mixture was evaporated to dryness, and the residue was dissolved in ethyl acetate (25 mL). The residue was then washed successively with saturated sodium bicarbonate solution (15 mL × 3) and saturated brine (15 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 3-(azacyclobutane-3-ylethynyl)-5-bromo-4-methylpyridine (0.79 g, yield: 90%).

[0650] MS m / z (ESI): 251.2, 253.2 [M+1].

[0651] Step 3

[0652] Using 3-(azacyclobutane-3-ylethynyl)-5-bromo-4-methylpyridine as a raw material, 1-(3-((5-bromo-4-methylpyridin-3-yl)ethynyl)azacyclobutane-1-yl)prop-1-one was obtained by referring to the first step of Example 8.

[0653] MS m / z (ESI): 307.1, 309.1 [M+1].

[0654] Step 4

[0655] Using 1-(3-((5-bromo-4-methylpyridin-3-yl)ethynyl)azacyclobutan-1-yl)prop-1-one and intermediate 10 as raw materials, 1-(methyl-d3)-6-(4-methyl-5-((1-propionylazacyclobutan-3-yl)ethynyl)pyridin-3-yl)-3,4-dihydroquinoline-2(1H)-one was obtained by referring to step 3 of Example 8.

[0656] MS m / z(ESI): 391.2 [M+1].

[0657] Example 34

[0658] Referring to Example 33, compound 34 was obtained.

[0659] MS m / z(ESI): 395.2 [M+1].

[0660] Example 35

[0661] first step:

[0662] To a mixture of 4-bromo-5,6-dihydrocyclopentadieno[c]pyridin-7-one (600 mg, 2.8 mmol), tert-butyldimethylsilyl chloride (725 mg, 4.8 mmol), and toluene (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (862 mg, 5.67 mmol) was added dropwise. The mixture was stirred at room temperature for 24 hours, quenched with water, extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and separated by preparative chromatography (acidic) to give a white solid (4-bromo-5H-cyclopentadieno[c]pyridin-7-yl)oxo-tert-butyl-dimethylsilane (300 mg, yield: 32.5%).

[0663] MS m / z(ESI): 326.0 328.0 [M+1]

[0664] Step Two:

[0665] Using (4-bromo-5H-cyclopentadieno[c]pyridin-7-yl)oxo-tert-butyl-dimethyl-silane as a starting material, the target product 4-bromo-5-methyl-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one was obtained by following the synthetic method described in the European Journal of Medicinal Chemistry 93(2015)121-134.

[0666] MS m / z(ESI): 226.0 228.0 [M+1]

[0667] Step 3:

[0668] Following the synthetic method of intermediate 2, the target product (7R)-4-bromo-5-methyl-6,7-dihydro-5H-cyclopentadien[c]pyridine-7-amine was obtained.

[0669] MS m / z(ESI): 227.0 229.0 [M+1]

[0670] Step 4:

[0671] The target product was obtained by referring to the synthesis method of Example 1.

[0672] MS m / z(ESI): 371.2 [M+1]

[0673] The compounds were separated to obtain four compounds: P1, P2, P3, and P4. The separation conditions are shown in the figure below.

[0674] The proton spectrum of P1 is as follows:

[0675] 1H NMR(400MHz,DMSO)δ8.37(s,2H),8.28(d,1H),7.86(d,1H),7.52(dd,1H),7.42(d, 1H),5.48(q,1H),3.76-3.73(m,1H),2.25-1.95(m,4H),1.07(t,3H),0.83(d,3H).

[0676] Example 36

[0677] first step

[0678] Ethyl 3-(3,5-dibromopyridin-4-yl)-2-methylpropionate

[0679] 3,5-Dibromo-4-methylpyridine (100.0 g, 398.53 mmol, 1.0 eq.) was added to a 3 L three-necked flask, followed by 1 L of dry THF. After purging with nitrogen three times, the mixture was cooled to 0 °C. LDA (239.0 mL, 478.24 mmol, 1.2 eq.) was slowly added dropwise. After the addition was complete, the mixture was kept at the same temperature and stirred for 1 hour. Then, ethyl 2-bromopropionate (108.2 g, 597.80 mmol, 1.5 eq.) was slowly added dropwise. After the addition was complete, the mixture was kept at the same temperature and stirred for another 16 hours. After LCMS confirmed that the reactants had reacted completely, 100 mL of saturated ammonium chloride solution was slowly added to the reaction mixture. After the mixture was brought to room temperature, 500 mL of H2O was added to extract and separate the layers. The aqueous phase was extracted with ethyl acetate (200 mL for the phase). The combined organic phases were washed with saturated brine (300 mL for the organic phase), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography to obtain product 2 (104.92 g, 298.88 mmol, 75.00% yield), which was a yellow oily compound.

[0680] MS m / z(ESI): 351.9 [M+1]

[0681] Step 2

[0682] 4-Bromo-6-methyl-5,6-dihydro-7H-cyclopentan[c]pyridin-7-one

[0683] Product 2 (100.0 g, 284.87 mmol, 1.0 eq.) was added to a 3 L three-necked flask, followed by the addition of 1 L of dry THF. After purging with nitrogen three times, the mixture was cooled to -78 °C. n-BuLi (228.0 mL, 569.74 mmol, 2.0 eq.) was slowly added dropwise, and the mixture was stirred and kept at this temperature for 2 hours. After LC-MS confirmed complete reaction of the starting material, 100 mL of saturated ammonium chloride solution was slowly added to the reaction mixture. The mixture was allowed to return to room temperature, and then 500 mL of H₂O was added to extract and separate the layers. The aqueous phase was extracted with ethyl acetate (200 mL for the phase). The combined organic phases were washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give product 3 (2.65 g, 11.72 mmol, 4.11% yield) as a yellow-brown solid compound.

[0684] MS m / z(ESI):225.9, 227.9[M+1]

[0685] Step 3

[0686] (E)-4-bromo-6-methyl-5,6-dihydro-7H-cyclopentan[c]pyridine-7-one oxime

[0687] Product 3 (2.6 g, 11.50 mmol, 1.0 eq.) and hydroxylamine hydrochloride (2.0 g, 28.75 mmol, 2.5 eq.) were dissolved in anhydrous ethanol (20 mL), and the system was reacted at 50 °C for 2 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to 7–8 with saturated sodium carbonate solution. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give product 4 (2.60 g, 10.79 mmol, 93.79% yield) as a white solid.

[0688] MS m / z(ESI):240.9, 242.9[M+1]

[0689] Step 4

[0690] 4-Bromo-6-methyl-6,7-dihydro-5H-cyclopentan[c]pyridine-7-amine

[0691] Product 4 (2.60 g, 10.79 mmol, 1.0 eq.) and sodium acetate (1.77 g, 21.58 mmol, 2.0 eq.) were added to a 100 mL single-necked flask, followed by glacial acetic acid (20 mL) and THF (10 mL). After purging with nitrogen three times, zinc powder (7.05 g, 107.90 mmol, 10.0 eq.) was added. The mixture was then incubated under nitrogen for 2 hours at 50 °C. After LC-MS showed complete reaction, the reaction solution was cooled to room temperature, and the pH was adjusted to 7-8 with saturated sodium carbonate solution. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. Product 5 (1.28 g, 5.65 mmol, 52.33% yield) was obtained as a brown oily substance.

[0692] MS m / z(ESI):227.0, 229.0[M+1]

[0693] Step 5

[0694] (4-Bromo-6-methyl-6,7-dihydro-5H-cyclopentan[c]pyridin-7-yl)tert-butyl carbamate

[0695] Product 5 (1.20 g, 5.28 mmol, 1.0 eq.) was dissolved in dichloromethane (20 mL), and DIPEA (2.05 g, 15.84 mmol, 3.0 eq.) and (Boc)₂O (1.73 g, 7.92 mmol, 1.5 eq.) were added. The mixture was stirred at room temperature for 3 hours after the addition was complete. After LC-MS showed that the reaction was complete, the reaction solution was concentrated to dryness. The residue was subjected to silica gel column chromatography to give product 6 (1.65 g, 5.04 mmol, 95.46% yield) as a yellow solid compound.

[0696] MS m / z(ESI):327.0, 329.0[M+1]

[0697] Step 6

[0698] 4-Bromo-6-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-7-amine hydrochloride

[0699] Product 6 (1.65 g, 5.04 mmol, 1.0 eq.) was dissolved in ethyl acetate (20 mL), cooled to 0 °C in an ice bath, and then HCl / EA (12.6 mL, 50.42 mmol, 10.0 eq., 4 M in EA) was slowly added dropwise. After the addition was complete, the reaction mixture was allowed to react at room temperature for 5 hours. LC-MS showed that the reaction was complete. The reaction solution was then concentrated to dryness to obtain product 7 (1.42 g, 5.41 mmol, 107.34% yield), a yellow solid compound. MS m / z (ESI): 227.0, 229.0 [M+1]

[0700] Step 7

[0701] N-(4-bromo-6-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide

[0702] Product 7 (1.42 g, 5.41 mmol, 1.0 eq.) was dissolved in dry dichloromethane (10.0 mL), followed by the addition of TEA (2.74 g, 27.04 mmol, 5.0 eq.). After the addition was complete, the mixture was purged with nitrogen three times, cooled to 0 °C in an ice bath, and propionyl chloride (751 mg, 8.12 mmol, 1.5 eq.) was slowly added dropwise. After the addition was complete, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 12 hours. After LCMS showed that the reaction was complete, 10 mL of H2O was added to the system for extraction and separation. The aqueous phase was extracted with ethyl acetate (20 mL of aqueous phase), and the organic phases were combined, washed with saturated brine (20 mL of sodium sulfate), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give product 8 (984 mg, 3.47 mmol, 64.22% yield) as a brown oily compound.

[0703] MS m / z(ESI):283.0, 285.0[M+1]

[0704] Step 8

[0705] Following the synthesis method of Example 1, N-(6-methyl-4-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazo-6-yl)-6,7-dihydro-5H-cyclopentadien[c]pyridin-7-yl)propionamide was obtained.

[0706] MS m / z(ESI): 371.1 [M+1]

[0707] Step 9

[0708] Chiral separation yielded four isomers.

[0709] MS m / z(ESI): 371.1 [M+1]

[0710] The splitting conditions for P2 are as follows:

[0711] Example 37

[0712] first step:

[0713] A mixed solution of 3,5-dibromo-4-methylpyridine (24 g, 95 mmol), 1-(tert-butyl)-3-methylpiperazine-1,3-dicarboxylic acid ester (28 g, 114.8 mmol), cesium carbonate (77.92 g, 239.2 mmol), Pd2dba3 (5.3 g, 5.74 mmol), BINAP (7.1 g, 11.4 mmol), and toluene (300 mL) was purged three times with nitrogen. Then, under nitrogen protection, the mixture was stirred in liquid nitrogen at 100°C for 2 hours, quenched with saturated ammonium chloride solution, extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (PE / EtOAc = 2:1) to obtain a pale yellow solid O1-tert-butylO3-methyl 4-(5-bromo-4-methyl-3-pyridyl)piperazine-1,3-dicarboxylic acid ester (4 g, yield: 10.1%).

[0714] MS m / z (ESI): 413.1 415.1 [M+1]

[0715] Step Two:

[0716] To a THF (60 mL) solution of O1-tert-butylO3-methyl-4-(5-bromo-4-methyl-3-pyridyl)piperazine-1,3-dicarboxylic acid ester (4 g, 9.65 mmol), lithium aluminum hydride (2.5 M, 5.02 mL) was added dropwise. The mixture was stirred for 0.5 h, quenched with sodium sulfate decahydrate, filtered, and the filtrate was evaporated to dryness. Column chromatography (PE / EtOAc = 1:1) yielded a pale yellow oil, tert-butyl-4-(5-bromo-4-methyl-3-pyridyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid ester (2.5 g, yield: 67%).

[0717] MS m / z (ESI): 386.1 388.1 [M+1]

[0718] Step 3:

[0719] Triphenylphosphine (3.39 g, 12.94 mmol) and NBS (1.38 g, 7.77 mmol) were added to a DCM (40 mL) solution of tert-butyl 4-(5-bromo-4-methyl-3-pyridyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid ester (2.5 g, 6.47 mmol). The mixture was stirred at room temperature for 12 hours, quenched with saturated ammonium chloride solution, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and separated by column chromatography (PE / EtOAc = 2:1) to give a pale yellow solid tert-butyl 3-(bromomethyl)-4-(5-bromo-4-methyl-3-pyridyl)piperazine-1-carboxylic acid ester (1.2 g, yield: 41.3%).

[0720] MS m / z(ESI): 450.0 [M+1]

[0721] Step 4:

[0722] To a nitrogen-protected solution of tert-butyl 3-(bromomethyl)-4-(5-bromo-4-methyl-3-pyridyl)piperazine-1-carboxylate (1.2 g, 2.67 mmol) in 80 mL of THF, lithium bis(trimethylsilylamino)carboxylate (1 M, 8.01 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 h, quenched with saturated ammonium chloride solution, extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and separated by column chromatography (PE / EtOAc = 2:1) to give a pale yellow solid, tert-butyl-4-bromo-5,6,6a,7,9,10-hexahydropyrano[1,2-a][1,7]diazanaphthalene-8-carboxylate (800 mg, yield: 81.3%).

[0723] MS m / z(ESI): 368.1 370.1 [M+1]

[0724] Step 5:

[0725] TFA (2 mL) was added dropwise to a DCM (4 mL) solution of tert-butyl-4-bromo-5,6,6a,7,9,10-hexahydro-5H-pyrano[1,2-a][1,7]diazanaphthalene-8-carboxylic acid ester (250 mg, 678.85 8.1 3). The mixture was stirred at room temperature for 20 minutes, evaporated to dryness, and the pH was adjusted to 10 with saturated NaHCO3. The mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a pale yellow solid 4-bromo-6,6a,7,8,9,10-hexahydro-5H-pyrano[1,2-a][1,7]diazanaphthalene (180 mg, crude product).

[0726] MS m / z(ESI): 268.0 270.0 [M+1]

[0727] Step 6:

[0728] To a DCM solution of 4-bromo-6,6a,7,8,9,10-hexahydro-5H-pyrano[1,2-a][1,7]diazanaphthalene (80 mg, 298.34 μmol / L) and triethylamine (90.40 mg, 895.01 μmol / L) in 3 mL, ethylsulfonyl chloride (57.54 mg, 447.51 μmol / L) was added dropwise. The mixture was stirred at room temperature for 2 hours, then water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was separated by column chromatography (DCM / MeOH = 10:1) to obtain a white solid 4-bromo-8-ethylsulfonyl-5,6,6a,7,9,10-hexahydropyrano[1,2-a][1,7]diazanaphthalene (80 mg, yield: 74.4%).

[0729] MS m / z(ESI): 360.0 362.0 [M+1]

[0730] Step 7:

[0731] 4-Bromo-8-ethylsulfonyl-5,6,6a,7,9,10-hexahydropyrano[1,2-a][1,7]diazanaphthalene (60 mg, 166.54--.0), 6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1-(methyl-d3)-3,4-dihydroquinoline-2-one (72.49 mg, 249.81-362.0), Pd(PPh3)4 (15.39 mg, 13.32+1) were subjected to reduced pressure, and Na2CO3 (52.96 mg, 499.63) was added. A mixture of [2+1], EtOH (5 mL), and water (1 mL) was purged with nitrogen three times, then stirred under nitrogen at 85°C for 12 hours under nitrogen protection. The mixture was then evaporated to dryness with silica gel and separated by column chromatography (DCM / MeOH = 10:1) to obtain a white solid 6-(8-(ethylsulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyranazono[1,2-a][1,7]diazanaphth-4-yl)-1-(methyl-d3)-3,4-dihydroquinoline-2(1H)-one (50 mg).

[0732] MS m / z(ESI): 444.2 [M+1]

[0733] Then, chiral resolution was performed to obtain a white solid (R)-6-(8-(ethylsulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrano[1,2-a][1,7]diazanaphth-4-yl)-1-(methyl-d3)-3,4-dihydroquinoline-2(1H)-one (20 mg) and a white solid (S)-6-(8-(ethylsulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrano[1,2-a][1,7]diazanaphth-4-yl)-1-(methyl-d3)-3,4-dihydroquinoline-2(1H)-one (19 mg).

[0734] MS m / z(ESI): 448.2 [M+1].

[0735] Example 38

[0736] first step:

[0737] 0.13 g of 4-bromo-6,7-dihydroisoquinoline-8(5H)-one (575.04 μL) was dissolved in anhydrous tetrahydrofuran (4 mL). Methyl magnesium bromide (3 M, 575.04 μL) was added under ice-water bath cooling and nitrogen protection. The mixture was stirred at 25 °C for 12 hours. The reaction was quenched with saturated brine (15 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic phases were combined and washed successively with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 50:50) to give the target product, 4-bromo-8-methyl-5,6,7,8-tetrahydroisoquinoline-8-phenol (60 mg, yield: 43.10%).

[0738] MS m / z(ESI):242.0, 244.0[M+1].

[0739] Step Two:

[0740] 4-Bromo-8-methyl-5,6,7,8-tetrahydroisoquinoline-8-phenol (60 mg, 247.82 mmol, residue 2.0 mmol) was dissolved in dichloromethane (2.0 mL) with triethylamine (125.38 mg, 1.24 mmol). Under ice-water bath cooling and nitrogen protection, trifluoroacetic anhydride (62.46 mg, 297.38 mmol) was added for color correction. The mixture was stirred at 25°C for 12 hours. The reaction solution was quenched with saturated brine (5 mL). The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was evaporated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product 4-bromo-8-methyl-5,6-dihydroisoquinoline (20 mg, yield: 36.01%).

[0741] MS m / z(ESI):224.0, 226.0[M+1].

[0742] Step 3:

[0743] 4-Bromo-8-methyl-5,6-dihydroisoquinoline (20 mg, 89.25-24.0 mg sodium) was dissolved in acetic acid (2 mL). Under nitrogen protection, 37% formaldehyde aqueous solution (36.21 mg, 446.24 mg sodium) was added. The mixture was dried over 70°C and the reaction was stirred for 0.5 hours. Then, under nitrogen protection, ethanesulfonamide (29.22 mg, 267.74 mg sodium) was added. The mixture was stirred at 70°C for 12 hours. The reaction solution was evaporated to dryness, and saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (10 mL methane) were added for extraction. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (dichloromethane:methanol = 10:1) to obtain the target product 4-bromo-8-(ethylsulfonyl)-5,6,7,8,9,10-hexahydro-2,8-ferrous reagent (o-phenanthroline) (20 mg, yield: 62.73%), as a white solid.

[0744] MS m / z(ESI):357.0, 359.0[M+1].

[0745] Step 4:

[0746] 4-Bromo-8-(ethylsulfonyl)-5,6,7,8,9,10-hexahydro-2,8-ferrous reagent (o-phenanthroline) (20 mg, 55.98 g, 7.0 g, dry) was dissolved in ethanol (1.5 mL) and water (0.4 mL) under reduced pressure under nitrogen protection. Then, tetrakis(triphenylphosphine)palladium (3.23 mg, 2.8 g, 0.0 g) and sodium carbonate (17.80 mg, 167.94 g, 0.0 ... l) Evaporate to dryness under pressure. The mixture was stirred at 90°C for 12 hours. The reaction solution was evaporated to dryness under reduced pressure to obtain the crude product, which was purified by rapid silica gel plate chromatography (dichloromethane:methanol = 10:1) to give the target product 6-(8-(ethylsulfonyl)-5,6,7,8,9,10-hexahydro-2,8-phenanthroline-4-yl)-1-(methyl-d3)-3,4-dihydroquinoline-2(1H)-one (15 mg, yield: 60.82%).

[0747] MS m / z(ESI): 441.2 [M+1].

[0748] Step 5:

[0749] 6-(8-(ethylsulfonyl)-5,6,7,8,9,10-hexahydro-2,8-phenanthroline-4-yl)-1-(methyl-d3)-3,4-dihydroquinoline-2(1H)-one (15 mg, 34.05-10,10) was dissolved in ethanol (3 mL), and 10% palladium on carbon (containing 50% water) (3.62 mg) was added under nitrogen protection. The mixture was stirred at 25 °C for 3 hours under a hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the liquid phase was evaporated to dryness to obtain the target product 6-(8-(ethylsulfonyl)-5,6,6a,7,8,9,10,10a-octahydro-2,8-phenanthroline-4-yl)-1-(methyl-d3)-3,4-dihydroquinoline-2(1H)-one (15 mg).

[0750] MS m / z(ESI): 443.2 [M+1].

[0751] Step 6: Four isomers were obtained through chiral separation.

[0752] MS m / z(ESI): 443.2 [M+1].

[0753] Example 39

[0754] first step

[0755] At room temperature, 3,5-dibromopyridine (0.5 g, 2.11 mmol), 1-ethylsulfonylpiperazine (0.38 g, 2.11 mmol), tris(diphenylmethyleneacetone)dipalladium (0.096 g, 0.11 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.12 g, 0.21 mmol), and sodium tert-butoxide (0.30 g, 3.17 mmol) were dissolved in 1,4-dioxane (10 mL), purged with nitrogen, heated to 100 °C, and reacted for 14 hours. The mixture was then cooled to room temperature, and the reaction was considered complete by LC-MS. The solution was evaporated to dryness, and the residue was directly separated by Flash column chromatography to give 1-(5-bromopyridin-3-yl)-4-(ethylsulfonyl)piperazine (0.39 g, yield: 55.3%).

[0756] MS m / z (ESI): 334.1, 336.1 [M+1].

[0757] Step 2

[0758] At room temperature, 6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1-(methyl-d3)-4H-3,1-benzoxazin-2-one (59.00 mg, 0.20 mmol), 1-(5-bromopyridin-3-yl)-4-(ethylsulfonyl)piperazine (45 mg, 0.13 mmol), sodium carbonate (42.81 mg, 0.40 mmol), and tetrakis(triphenylphosphine)palladium (15.56 mg, 0.013 mmol) were dissolved in water (1 mL) and ethanol (5 mL). Nitrogen gas was purged, and the mixture was heated to 85°C and purged with nitrogen. The reaction was carried out for 14 hours, cooled to room temperature, and the reaction was considered complete by LC-MS. The mixture was filtered, and the residue was washed with ethyl acetate (10 mL), evaporated to dryness, dissolved in ethyl acetate (25 mL), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by reversed-phase preparative chromatography to give 6-(5-(4-(ethylsulfonyl)piperazin-1-yl)pyridin-3-yl)-1-(methyl-d3)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (22 mg, yield: 39%).

[0759] MS m / z(ESI): 420.2 [M+1].

[0760] Example 40

[0761] first step:

[0762] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazole (2 g, 10.31 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). Sodium hydroxide (824.50 mg, 20.61 mmol, 60% purity) was added in portions under ice-water bath conditions. After stirring for 0.5 hours, deuterated iodomethane (2.99 g, 20.61 mmol) was added. The reaction mixture was stirred at room temperature (20 °C) for another 3.5 hours. The reaction was quenched by slowly adding saturated ammonium chloride solution (10 ml) dropwise to the reaction system in an ice-water bath. Extraction was performed with ethyl acetate (20 ml x 2), followed by washing with saturated brine (20 ml x 2), drying with anhydrous sodium sulfate, and filtration and concentration to obtain crude 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1-(methyl-d3)pyrazole (2 g). The crude product was used directly in the next reaction step without further purification.

[0763] MS m / z(ESI): 212.2 [M+1]

[0764] Step Two:

[0765] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxoboropentane-2-yl)-1-(methyl-d3)pyrazole (2 g, 9.47 mmol) was dissolved in methanol (30 mL), and 30% aq·H2O2 (5 mL) was added dropwise under ice-water bath conditions. The reaction system was stirred at room temperature (20 °C) for 4 hours. Under ice-water bath conditions, a saturated sodium thiosulfate solution (20 mL) was slowly added dropwise to quench the reaction, followed by extraction with ethyl acetate (20 mL x 2), washing with saturated brine (20 mL x 2), drying with anhydrous sodium sulfate, filtration, and concentration to obtain the crude product. The crude product was purified by column chromatography (PE:EtOAc:=3:1, UV=254 nm) to finally obtain the target product 1-(methyl-d3)-1H-pyrazole-4-ol (800 mg, 7.91 mmol, 83.50% yield).

[0766] MS m / z(ESI): 102.1 [M+1]

[0767] Step 3:

[0768] 1-(methyl-d3)-1H-pyrazole-4-ol (800 mg, 7.91 mmol) and tert-butyl-4-hydroxypiperidine-1-carboxylic acid ester (1.91 g, 9.49 mmol) were dissolved in anhydrous toluene (30 mL), and cyanomethylenetri-n-butylphosphine (2.86 g, 11.87 mmol) was added. The reaction system was refluxed at 120 °C in an oil bath for 2 hours. After the reaction was complete, the crude product was directly concentrated. The crude product was purified by column chromatography (PE:EtOAc = 3:1, UV = 254 nm) to finally obtain a pale yellow oil, tert-butyl-4-[1-(methyl-d3)pyrazole-4-yl]oxopiperidin-1-carboxylic acid ester (2 g, 7.03 mmol, 88.90% yield).

[0769] MS m / z(ESI): 285.2 [M+1]

[0770] Step 4:

[0771] 2 g (7.03 mmol) of tert-butyl-4-[1-(methyl-d3)pyrazol-4-yl]oxoperidin-1-carboxylic acid ester was dissolved in dichloromethane (10 mL), and HCl-dioxane (10 mL) was added dropwise under ice-water bath conditions. The reaction system was stirred at room temperature (20 °C) for 4 hours. After the reaction was completed, the reaction was quenched by adding saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude 4-[1-(methyl-d3)pyrazol-4-yl]oxoperidinine (2 g, crude).

[0772] MS m / z (ESI): 185.2 [M+1]

[0773] Step 5:

[0774] 3,5-Dibromo-4-methylpyridine (1 g, 3.99 mmol), 4-[1-(methyl-d3)pyrazol-4-yl]oxoperididine (734.31 mg, 3.99 mmol) were dissolved in 1,4-dioxane (30 mL). Tris(diphenylmethyleneacetone)dipalladium (364.95 mg, 398.54 mol), bis(diphenylphosphine-9,9-dimethyloxanthracene) (461.20 mg, 797.07 mol), and sodium tert-butoxide (766.01 mg, 7.97 mmol) were added sequentially. The reaction system was purged with nitrogen several times and then stirred in an oil bath at 100 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (30 mL x 2), washed with saturated brine (30 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 = 254nm) to obtain the target product 3-bromo-4-methyl-5-(4-((1-(methyl-d3)-1H-pyrazol-4-yl)oxo)piperidin-1-yl)pyridine (410 mg, 29% yield).

[0775] MS m / z (ESI): 354.1, 356.1 [M+1]

[0776] Step 6:

[0777] Using the 3-bromo-4-methyl-5-(4-((1-(methyl-d3)-1H-pyrazol-4-yl)oxo)piperidin-1-yl)pyridine and 1-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one obtained above as raw materials, and referring to Example 1, the target product 1-(methyl-d3)-6-(4-methyl-5-(4-((1-(methyl-d3)-1H-pyrazol-4-yl)oxo)piperidin-1-yl)pyridin-3-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was finally obtained.

[0778] MS m / z(ESI): 440.2 [M+1]

[0779] Example 41

[0780] first step

[0781] 4-Iodo-1H-pyrazole (10 g, 51.55 mmol) and tetrahydrofuran (100 mL) were added to a 250 mL flask. NaH (2.27 g, 56.71 mmol, 60% purity) was added in portions at 25°C. The reaction mixture was then held under nitrogen protection at 25°C for 2 h. Deuterated iodomethane (14.95 g, 103.11 mmol) was then slowly added, and the reaction mixture was stirred under nitrogen protection for another 10 h. The reaction was stopped, quenched with 100 mL of aqueous solution, and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated product was 4-iodo-1-deuterated methylpyrazole (10 g, yellow solid), yield: 91.92%.

[0782] MS m / z(ESI): 211.9 [M+H].

[0783] Step 2

[0784] 4-Iodo-1-deuterated methylpyrazole (10 g, 47.39 mmol) and dichloromethane (60 mL) were added to a 250 mL flask. Under nitrogen protection, isopropyl magnesium chloride (47.39 mL, 1 M, 47.39 mmol) was slowly added dropwise to the flask at 0°C. The reaction mixture was kept under nitrogen protection at 0°C for 1 h. Then, 4-formylpiperidin-1-carboxylic acid methyl ester (11.72 g, 47.39 mmol) was added, and the reaction mixture was stirred at 0°C for another 1 h. The reaction was stopped, and the reaction was quenched by adding 100 mL of ammonium chloride aqueous solution. The mixture was extracted with 100 mL of dichloromethane, and the combined organic phases were washed with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated product was 4-[hydroxy-[1-deuterated methylpyrazol-4-yl]methyl]piperidine-1-carboxylic acid benzyl ester (10 g, yellow solid), yield: 63.48%.

[0785] MS m / z(ESI): 333.1 [M+H].

[0786] Step 3

[0787] 4-[hydroxy-[1-deuterated methylpyrazol-4-yl]methyl]piperidine-1-carboxylic acid benzyl ester (3 g, 9.02 mmol), dichloromethane (20 mL), and trifluoroacetic acid (20 mL) were added to a 100 mL flask. Triethylsilane (5.25 g, 45.12 mmol) was added to the flask under nitrogen protection at 25°C for 10 h. The reaction was then stopped, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as eluents to give the title product 4-[[1-deuterated methylpyrazol-4-yl]methyl]piperidine-1-carboxylic acid benzyl ester (2 g, yellow solid), yield: 70.04%.

[0788] MS m / z (ESI): 317.2 [M+H].

[0789] Step 4

[0790] 4-[[1-Deuterated methylpyrazol-4-yl]methyl]piperidine-1-carboxylic acid benzyl ester (1 g, 3.16 mmol) and methanol (10 mL) were added to a 100 mL flask. Palladium 10% on Carbon (336.33 mg, 3.16 mmol) was added at 25°C. The reaction mixture was then purged with hydrogen five times and reacted under hydrogen atmosphere for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The concentrated filtrate yielded the title product 4-[[1-Deuterated methylpyrazol-4-yl]methyl]piperidine (0.5 g, yellow solid), yield: 86.79%.

[0791] MS m / z (ESI): 183.1 [M+H].

[0792] Step 5

[0793] 3,5-Dibromo-4-methylpyridine (0.5 g, 1.99 mmol), 4-[[1-deuterated methylpyrazol-4-yl]methyl]piperidine (363.23 mg, 1.99 mmol), Pd2dba3 (91.24 mg, 99.63 μmol), Xantphos (115.30 mg, 199.27 μmol), sodium tert-butoxide (287.24 mg, 2.99 mmol), and dioxane (10 mL) were added to a 50 mL flask, and the reaction mixture was then reacted at 100 °C for 2 h under nitrogen protection. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). The mixture was extracted with dichloromethane (10 mL), and the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol as the eluent system to give the title product 3-bromo-4-methyl-5-[4-[[1-deuterated methylpyrazol-4-yl]methyl]-1-piperidinyl]pyridine (160 mg, yellow solid), yield: 22.79%.

[0794] MS m / z(ESI):352.1, 354.1[M+H].

[0795] Step 6

[0796] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxoboropentane-2-yl)-1-deuterated methyl-4H-3,1-benzoxazin-2-one (120 mg, 410.74.1) and residual bromo-4-methyl-5-[4-[[1-deuterated methylpyrazol-4-yl]methyl]-1-piperidinyl]pyridine (144.70 mg, 410.74) and residual tetra(triphenylphosphine)palladium (23.73 mg, 20.54) obtained by purification of alkyl and methanol. 4. Sodium carbonate (130.60 mg, 1.23 mmol), water (2 mL), and ethanol (10 mL) were added to a 50 mL flask and the reaction mixture was kept under nitrogen protection at 90 °C for 3 h. The reaction was stopped, and the reaction was quenched with aqueous solution (10 mL). The mixture was extracted with dichloromethane (10 mL), and the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give the title product 6-[4-methyl-5-[4-[[1-deuterated methylpyrazol-4-yl]methyl]-1-piperidinyl]-3-pyridinyl]-1-deuterated methyl-4H-3,1-benzoxazin-2-one (34 mg, white solid), yield: 18.92%.

[0797] MS m / z(ESI): 438.2 [M+H].

[0798] Example 42

[0799] first step

[0800] Using 4-iodo-1-methyl-1H-pyrazole-4-formylpiperidine-1-carboxylic acid benzoate as a raw material, the title product 4-(hydroxy(1-methyl-1H-pyrazole-4-yl)methyl)piperidine-1-carboxylic acid benzoate was obtained by referring to the second step of Example 41.

[0801] MS m / z(ESI): 330.1 [M+H].

[0802] Step 2 ester

[0803] 4-(hydroxy(1-methyl-1H-pyrazole-4-yl)methyl)piperidine-1-carboxylic acid benzyl ester (3 g, 9.11 mmol) and dichloromethane (30 mL) were added to a 100 mL flask. The mixture was heated to 25 °C with the addition of Dys-Martin oxidant (4.59 g, 10.83 mmol). The reaction was then carried out under nitrogen protection at 25 °C for 2 h. The reaction was stopped, quenched with 20 mL of aqueous solution, and extracted with 20 mL of dichloromethane. The combined organic phases were washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as eluent to give the title product 4-(1-methyl-1H-pyrazole-4-carbonyl)piperidine-1-carboxylic acid benzyl ester (2 g, yellow solid), yield: 67.08%.

[0804] MS m / z (ESI): 328.1 [M+H].

[0805] Step 3

[0806] 4-(1-methyl-1H-pyrazole-4-carbonyl)piperidine-1-carboxylic acid benzyl ester (1 g, 3.05 mmol) and trifluoroacetic acid (10 mL) were added to a 100 mL flask, and the reaction mixture was stirred at 70 °C under nitrogen protection for 1 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol as eluent to give the title product (1-methyl-1H-pyrazole-4-yl)(piperidine-4-yl) methyl ketone (0.5 g, yellow solid), yield: 84.70%.

[0807] MS m / z(ESI): 194.1 [M+H].

[0808] Step 4

[0809] Using (1-methyl-1H-pyrazol-4-yl)(piperidin-4-yl)methyl ketone as a starting material, the title product 1-(methyl-d3)-6-(4-methyl-5-(4-(1-methyl-1H-pyrazol-4-carbonyl)piperidin-1-yl)pyridin-3-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was obtained by referring to steps five and six of Example 41.

[0810] MS m / z(ESI): 449.2 [M+H].

[0811] Example 43

[0812] first step

[0813] In a 100 mL reaction flask, tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylic acid (797.10 mg, 3.69 mmol) was dissolved in tetrahydrofuran (20 mL). Sodium hydride (589.62 mg, 14.74 mmol, 60% purity) was added in portions at 0 °C. The reaction mixture was kept under nitrogen protection and stirred at 25 °C for 1 hour. Then, 3,5-dibromo-4-chloropyridine (1 g, 3.69 mmol) was added, and the reaction mixture was kept under nitrogen protection and stirred at 25 °C for 3 hours. The reaction was stopped, and the reaction was quenched with ammonium chloride aqueous solution (10 mL). The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by silica gel column chromatography with dichloromethane and methanol as eluent yielded the title product 3-(((3,5-dibromopyridin-4-yl)oxo)methyl)piperazine-1-carboxylic acid tert-butyl ester (1.2 g, yellow solid), yield: 72.12%. MS m / z (ESI): 452.0 [M+H].

[0814] Step 2

[0815] A mixture of tert-butyl 3-(((3,5-dibromopyridin-4-yl)oxo)methyl)piperazine-1-carboxylic acid (1.2 g, 2.66 mmol), cesium carbonate (1.73 g, 5.32 mmol), Pd2dba3 (121.78 mg, 132.99 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (153.91 mg, 265.98 μmol), and toluene (20 mL) was purged three times with nitrogen and stirred at 100 °C for 2 hours under nitrogen protection. The reaction was stopped, quenched with water (20 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using a dichloromethane and methanol eluent system to give the title product 4-bromo-6a,7,9,10-tetrahydropyrano[1,2-d]pyrido[4,3-b][1,4]oxazine-8(6H)-carboxylic acid tertiary ester (600 mg, white solid), yield: 60.93%.

[0816] MS m / z(ESI):370.0, 372.0[M+H].

[0817] Step 3

[0818] Using 4-bromo-6a,7,9,10-tetrahydropyrano[1,2-d]pyrido[4,3-b][1,4]oxazine-8(6H)-carboxylic acid tertiary ester as a starting material, the title product 6-(8-(cyclopropylsulfonyl)-6,6a,7,8,9,10-hexahydropyrano[1,2-d]pyrido[4,3-b][1,4]oxazine-4-yl)-1-(methyl-d3)-3,4-dihydroquinoline-2(1H)-one was obtained by referring to steps five to seven of Example 37.

[0819] MS m / z (ESI): 458.1 [M+H].

[0820] Step 4

[0821] 43 was chirally separated to obtain title products 43-1 and 43-2.

[0822] The conditions for chiral splitting are as follows:

[0823] MS m / z (ESI): 458.1 [M+H].

[0824] Example 44

[0825] first step:

[0826] 3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (3.99 g, 18.43 mmol) was dissolved in tetrahydrofuran (50 mL) under nitrogen protection in a 250 mL reaction flask. Then, NaH (2.21 g, 55.28 mmol, 60%) was added in portions at 0 °C, and the reaction mixture was then reacted at 25 °C for 1 h under nitrogen protection. Next, 3,5-dibromo-4-chloropyridine (5 g, 18.43 mmol) was added, and the reaction mixture was stirred under nitrogen protection for another 3 h. The reaction was then stopped, quenched with an aqueous solution (40 mL), extracted with ethyl acetate (40 mL × 2), and the combined organic phases were washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product tert-butyl 3-(((3,5-dibromopyridin-4-yl)oxy)methyl)piperazine-1-carboxylate (5 g, white solid), yield: 60.14%.

[0827] MS m / z(ESI): 452.0 [M+H].

[0828] Step Two:

[0829] 3-(((3,5-dibromopyridin-4-yl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester (1 g, 2.22 mmol), tris(dibenzylacetone)palladium (202.97 mg, 221.65 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (256.51 mg, 443.31 μmol), Cs₂CO₃ (1.44 g, 4.43 mmol), and 1,4-dioxane (10 mL) were added to a 25 mL flask, and the reaction mixture was then subjected to nitrogen protection at 90 °C for 3 h. The reaction was stopped, quenched with an aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the title product 4-bromo-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[4,3-b][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester (400 mg, white solid), yield: 48.74%.

[0830] MS m / z(ESI):370.0, 372.0[M+H].

[0831] Step 3:

[0832] Using 4-bromo-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[4,3-b][1,4]oxazin-8(6H)-carboxylic acid tert-butyl ester as a starting material, the synthetic method described in steps five to seven of Example 37 yielded the title product 6-(8-(ethylsulfonyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[4,3-b][1,4]oxazin-4-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one 44, which was chirally resolved to yield the title products 44-1 and 44-2.

[0833] MS m / z(ESI): 443.1 [M+H].

[0834] Example 45

[0835] first step:

[0836] Following the synthetic method described in reference [Org. Lett. 2017, 19, 870-873], the target product 4-bromo-8-(ethanesulfonyl)-6a, 7, 8, 9-tetrahydropyrazino[1,2-d]pyridino[4,3-b][1,4]oxazin-10(6H)-one was obtained.

[0837] MS m / z(ESI): 375.9 377.9 [M+1].

[0838] Step Two:

[0839] Following the synthesis method of Example 44, target product 45 was obtained, and 45 was chirally separated to obtain 45-1 and 45-2.

[0840] MS m / z(ESI): 457.1 [M+1].

[0841] Example 46

[0842] Following the synthesis method of Example 45, target product 46 was obtained. 46 was chirally resolved to obtain 46-1 and 46-2.

[0843] MS m / z(ESI): 461.1 [M+1].

[0844] Example 47

[0845] first step:

[0846] The target compound was synthesized using ethylsulfonyl chloride as a starting material, following step 6 of Example 37.

[0847] MS m / z(ESI):319.0, 321.0[M+1]

[0848] Step Two:

[0849] The target compound 47 was synthesized in the first step of Example 1. Chiral resolution yielded target compounds 47-1, 47-2, 47-3, and 47-4.

[0850] MS m / z(ESI): 401.2 [M+1]

[0851] Example 48

[0852] The target compound was synthesized using 4-bromo-6-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-7-amine and intermediate 6 as starting materials, referring to Example 47.

[0853] MS m / z(ESI): 404.1 [M+1]

[0854] Example 49

[0855] The target compound was synthesized using 4-bromo-6-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-7-amine and intermediate 5 as starting materials, referring to Example 47.

[0856] MS m / z(ESI): 407.1 [M+1]

[0857] Example 50

[0858] first step

[0859] At room temperature, 2,6-dibromopyrazine (0.5 g, 2.11 mmol) and 1-(piperazin-1-yl)prop-1-one (0.30 g, 2.11 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of potassium carbonate (0.87 g, 6.33 mmol). The reaction was carried out at room temperature for 14 hours, and LC-MS indicated the formation of the target product. The reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated brine (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was directly separated by Flash column chromatography to give 1-methyl-6-(6-(4-propionylpiperazin-1-yl)pyrazin-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (0.33 g, yield: 52.4%).

[0860] MS m / z(ESI): 299.1, 301.1 [M+1].

[0861] Step 2

[0862] Referring to the second step of Example 39, compound 50 was obtained.

[0863] MS m / z(ESI): 382.1 [M+1].

[0864] Example 51

[0865] first step:

[0866] 6-Bromo-1-methyl-3,4-dihydroquinoline-2(1H)-one (10 g, 41.65 mmol, 1.0 eq.), pinacol diborate (12.67 g, 49.98 mmol, 1.2 eq.), potassium acetate (12.30 g, 124.95 mmol, 3.0 eq.), and Pd(dppf)Cl2 (3.05 g, 4.17 mmol, 0.1 eq.) were dissolved in dioxane (100 mL) and water (20 mL). After purging with nitrogen three times, the mixture was stirred at 95 °C for 8 hours. After the reaction was confirmed to be complete by LCMS, the reaction solution was cooled to room temperature, and 100 mL of ethyl acetate and 100 mL of H2O were added to the system for extraction and separation. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (PE / EA: 0–5%) to give the product 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,4-dihydroquinoline-2(1H)-one (9.8 g, 34.13 mmol, 81.94% yield) as a yellow solid compound.

[0867] MS m / z(ESI): 288.2

[0868] Step Two:

[0869] 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4-dihydroquinoline-2(1H)-one (3.00 g, 12.61 mmol, 1.0 eq.), 3,5-dibromopyridine (2.68 g, 11.35 mmol, 0.9 eq.), anhydrous sodium carbonate (3.34 g, 31.53 mmol, 2.5 eq.), and tetra(triphenylphosphine)palladium (1.46 g, 1.26 mmol, 0.1 eq.) were added sequentially to a 250 mL three-necked flask, followed by dioxane (60 mL) and water (12 mL). After purging with nitrogen three times, the reaction was carried out at 95 °C for 12 h. After LCMS confirmed the reaction was complete, the reaction solution was cooled to room temperature. 100 mL of H₂O was added to the system for extraction and separation. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA: 0–50%) to give 6-(5-bromopyridin-3-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one (2.56 g, 8.07 mmol, 71.11% yield) as a pale yellow solid.

[0870] MS m / z (ESI): 317.0, 319.0

[0871] Step 3:

[0872] 6-(5-bromopyridin-3-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one (1.50 g, 4.73 mmol, 1.0 eq.), 3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (1.13 g, 5.68 mmol, 1.2 eq.), cesium carbonate (3.85 g, 11.83 mmol, 2.5 eq.), tris(dibenzylideneacetone)palladium (0.43 g, 0.47 mmol, 0.1 eq.), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.89 g, 1.42 mmol, 0.3 eq.) were sequentially added to a 100 mL three-necked flask, followed by dioxane (30 mL). After purging with nitrogen three times, the reaction was carried out at 95 °C for 12 h. After LCMS confirmed the complete reaction of the starting materials, the reaction solution was cooled to room temperature. 30 mL of H₂O was added to the system for extraction and separation. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (MeOH / DCM: 0–5%) to give 6-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (1.56 g, 3.59 mmol, 75.90% yield) as a pale yellow solid.

[0873] MS m / z (ESI): 435.2

[0874] Step 4

[0875] 6-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (1.00 g, 2.30 mmol, 1.0 eq.) was dissolved in dry dichloromethane (20 mL), cooled to 0 °C in an ice bath, and then trifluoroacetic acid (2.6 g, 23.00 mmol, 10.0 eq.) was slowly added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred for 5 h. After the reaction of the starting material was confirmed to be complete by LCMS, 20 mL of H2O was added to the system, the pH was adjusted to 7-8 with saturated NaHCO3 solution, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (MeOH / DCM: 0–10%) to give 6-(5-(3,6-diazabicyclo[3.1.1]heptane-6-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one (0.70 g, 2.09 mmol, 90.85% yield) as a pale yellow solid compound.

[0876] MS m / z (ESI): 335.2

[0877] Step 5:

[0878] 6-(5-(3,6-diazabicyclo[3.1.1]heptane-6-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one (0.50 g, 1.50 mmol, 1.0 eq.) was dissolved in dry dichloromethane (10 mL), and triethylamine (0.46 g, 4.50 mmol, 3.0 eq.) was added. Propionyl chloride (0.21 g, 2.25 mmol, 1.5 eq.) was slowly added dropwise under ice-water bath conditions. After the addition was complete, the mixture was stirred at room temperature for 3 hours. After LCMS showed that the reaction was complete, the reaction solution was concentrated to dryness. The residue was subjected to silica gel column chromatography (MeOH / DCM: 0–3%) to give 1-methyl-6-(5-(3-propionyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyridin-3-yl)-3,4-dihydroquinoline-2(1H)-one (0.52 g, 1.23 mmol, 82.00% yield) as a pale yellow solid compound.

[0879] MS m / z(ESI):[M+1] + =391.2

[0880] Example 52

[0881] 6-(6-(6-isopropylsulfonyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazin-2-yl)-3-methylbenzo[d]thiazolyl-2(3H)-one

[0882] first step

[0883] Referring to the first step of Example 50, 3-(6-bromopyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester was obtained.

[0884] MS m / z (ESI): 355.0, 357.0 [M+1].

[0885] Step 2

[0886] Referring to step four of Example 51, 3-(6-bromopyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane was obtained.

[0887] MS m / z (ESI): 255.1, 257.1 [M+1].

[0888] Step 3

[0889] Referring to step 5 of Example 51, 3-(6-bromopyrazin-2-yl)-6-(isopropylsulfonyl)-3,6-diazabicyclo[3.1.1]heptane was obtained.

[0890] MS m / z(ESI): 361.0, 363.0 [M+1].

[0891] Step 4

[0892] Referring to the second step of Example 39, 6-(6-(6-isopropylsulfonyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyrazin-2-yl)-3-methylbenzo[d]thiazol-2(3H)-one was obtained.

[0893] MS m / z(ESI): 446.1 [M+1].

[0894] Example 53

[0895] Referring to Example 51, the title product 6-(5-(5-(ethylsulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one was obtained.

[0896] MS m / z (ESI): 452.2 [M+H]

[0897] Example 54

[0898] Referring to Example 51, the title product 6-(5-(5-(ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one was obtained.

[0899] MS m / z (ESI): 452.2 [M+H]

[0900] Example 55

[0901] Referring to Example 51, the title product 6-(6-(5-(ethylsulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pyrazin-2-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one was obtained.

[0902] MS m / z (ESI): 453.2 [M+H]

[0903] Example 56

[0904] Referring to Example 51, the title product 6-(6-(5-(ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one was obtained.

[0905] MS m / z (ESI): 453.2 [M+H]

[0906] Example 57

[0907] Using 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[d]thiazol-2(3H)-one as a starting material, 6-(5-(5-(ethylsulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pyridin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one was obtained with reference to Example 53.

[0908] MS m / z(ESI): 456.1 [M+1]

[0909] Example 58

[0910] Using 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[d]thiazol-2(3H)-one as a starting material, 6-(5-(5-(ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-2-yl)pyridin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one was obtained with reference to Example 54.

[0911] MS m / z(ESI): 456.1 [M+1]

[0912] Example 59

[0913] Using 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[d]thiazol-2(3H)-one as a starting material, 6-(6-(5-(ethylsulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pyrazin-2-yl)-3-methylbenzo[d]thiazol-2(3H)-one was obtained with reference to Example 55.

[0914] MS m / z(ESI): 457.1 [M+1]

[0915] Example 60

[0916] Using 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[d]thiazol-2(3H)-one as a starting material, 6-(6-(5-(ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-2-yl)pyrazin-2-yl)-3-methylbenzo[d]thiazol-2(3H)-one was obtained with reference to Example 56.

[0917] MS m / z(ESI): 457.1 [M+1]

[0918] Example 61

[0919] first step:

[0920] Using 4-hydroxypiperidine-1-carboxylic acid benzyl ester and 1-cyclopropyl-1H-pyrazole-4-olone as raw materials, 4-((1-cyclopropyl-1H-pyrazole-4-yl)oxy)piperidine-1-carboxylic acid benzyl ester was obtained in the first step of Example 15.

[0921] MS m / z(ESI): 308.1 [M+1]

[0922] Step Two:

[0923] Using 4-((1-cyclopropyl-1H-pyrazole-4-yl)oxy)piperidine-1-carboxylic acid benzyl ester as a raw material, 4-((1-cyclopropyl-1H-pyrazole-4-yl)oxy)piperidine was obtained in step 2 of Example 15.

[0924] MS m / z(ESI): 208.0 [M+1]

[0925] Step 3:

[0926] Using 4-((1-cyclopropyl-1H-pyrazole-4-yl)oxy)piperidine as a raw material, 3-bromo-5-(4-((1-cyclopropyl-1H-pyrazole-4-yl)oxy)piperidine-1-yl)-4-methylpyridine was obtained by referring to the third step of Example 18.

[0927] MS m / z(ESI):377.1, 379.1[M+1]

[0928] Step 4:

[0929] Using 3-bromo-5-(4-(((1-cyclopropyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-4-methylpyridine as a starting material, 3-bromo-5-(4-(((1-cyclopropyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-4-methylpyridine was obtained by referring to step four of Example 18.

[0930] MS m / z(ESI): 463.2 [M+1]

[0931] Example 62

[0932] Using 3,5-dibromopyridine as a raw material, 6-(5-(4-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyridin-3-yl)-1-(methyl-d3)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was obtained with reference to Example 61.

[0933] MS m / z(ESI): 449.2 [M+1]

[0934] Example 62

[0935] first step:

[0936] In a 100 mL reaction flask under nitrogen protection, 1-cyclopropyl-4-iodopyrazole (1 g, 4.27 mmol) and tert-butyl 4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (1.16 g, 4.27 mmol) were dissolved in tetrahydrofuran (20 mL). Then, n-butyllithium (2.5 M, 2.05 mL) was slowly added at -70 °C, and the reaction mixture was then kept under nitrogen protection at -70 °C for 1 h. The reaction was stopped, and the reaction was quenched with ammonium chloride aqueous solution (40 mL). The mixture was extracted with ethyl acetate (40 mL × 2), and the combined organic phases were washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product tert-butyl 4-(1-cyclopropyl-1H-pyrazole-4-carbonyl)piperidine-1-carboxylate (700 mg, white solid), yield: 51.29%.

[0937] MS m / z(ESI): 320.1 [M+H].

[0938] Step Two:

[0939] The title product (1-cyclopropyl-1H-pyrazole-4-yl)(piperidin-4-yl) methyl ketone was obtained by referring to the synthesis method in step 2 of Example 7.

[0940] MS m / z(ESI): 220.1 [M+H].

[0941] Step 3:

[0942] The title product 6-(5-(4-(1-cyclopropyl-1H-pyrazole-4-carbonyl)piperidin-1-yl)-4-methylpyridin-3-yl)-1-(methyl-d3)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was obtained by referring to the synthesis method of Example 7.

[0943] MS m / z (ESI): 475.2 [M+H].

[0944] Example 64

[0945] The title product 6-(5-(4-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyridin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one was obtained by referring to the synthesis method of Example 61.

[0946] MS m / z (ESI): 448.1 [M+H].

[0947] Example 65

[0948] Using 4-((1-cyclopropyl-1H-pyrazole-4-yl)oxy)piperidine as a starting material, the title product 6-(6-(4-((1-cyclopropyl-1H-pyrazole-4-yl)oxy)piperidine-1-yl)pyrazin-2-yl)-3-methylbenzo[d]thiazol-2(3H)-one was obtained by referring to the synthesis method of Example 61.

[0949] MS m / z(ESI): 449.1 [M+H].

[0950] Example 66

[0951] Using 4-(cyclopentoxy)piperidine as a starting material, the title product 6-(5-(4-(cyclopentoxy)piperidine-1-yl)pyridin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one was obtained by referring to the synthesis method in steps three and four of Example 61.

[0952] MS m / z(ESI): 410.1 [M+H].

[0953] Example 67

[0954] Using 4-(cyclopentoxy)piperidine as a starting material, the title product 6-(6-(4-(cyclopentoxy)piperidin-1-yl)pyrazin-2-yl)-3-methylbenzo[d]thiazol-2(3H)-one was obtained by referring to the synthesis method in the first and fourth steps of Example 61.

[0955] MS m / z(ESI): 411.1 [M+H].

[0956] Example 68

[0957] The title product 6-(5-(4-(1-cyclopropyl-1H-pyrazole-4-carbonyl)piperidin-1-yl)pyridin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one was obtained by referring to the synthesis method of Example 62.

[0958] MS m / z (ESI): 460.1 [M+H].

[0959] Example 69

[0960] first step:

[0961] 2,6-Dibromopyrazine (1 g, 4.20 mmol) and N-(3-hydroxycyclobutyl)carbamate tert-butyl ester (787.10 mg, 4.20 mmol) were dissolved in DMSO (20 mL) under nitrogen protection in a 100 mL reaction flask. Then, Cs₂CO₃ (1.43 g, 4.38 mmol) was added, and the reaction mixture was kept under nitrogen protection at 25 °C for 10 h. The reaction was stopped, quenched with an aqueous solution (20 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product (3-((6-bromopyrazin-2-yl)oxy)cyclobutyl)carbamate tert-butyl ester (900 mg, white solid), yield: 62.2%.

[0962] MS m / z(ESI):344.0, 346.0[M+H].

[0963] Step Two:

[0964] The title product 6-(6-((1s,3s)-3-(3,3-dimethyl-2-oxopyrrolidone-1-yl)cyclobutoxy)pyrazin-2-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one was obtained by referring to the synthesis method of Example 15.

[0965] MS m / z(ESI): 423.2 [M+H].

[0966] Step 3:

[0967] The target product is obtained through chiral separation.

[0968] MS m / z(ESI): 423.2 [M+H].

[0969] Example 70

[0970] Step 1: 6-(5-((1s,3s)-3-(3,3-dimethyl-2-oxopyrrolidone-1-yl)cyclobutoxy)pyridin-3-yl)-3-methylbenzo[d]thiazolyl-2(3H)-one

[0971] The target product was separated according to the synthesis method of Example 15.

[0972] MS m / z(ESI): 424.1 [M+H].

[0973] Example 71

[0974] Step 1: 6-(6-((1s,3s)-3-(3,3-dimethyl-2-oxopyrrolidone-1-yl)cyclobutoxy)pyrazine-2-

[0975] 3-Methylbenzo[d]thiazolyl-2(3H)-one

[0976] The title product 6-(6-((1s,3s)-3-(3,3-dimethyl-2-oxopyrrolidone-1-yl)cyclobutoxy)pyrazin-2-yl)-3-methylbenzo[d]thiazol-2(3H)-one was obtained by referring to the synthesis method of Example 15, and the target product was obtained by resolution.

[0977] MS m / z (ESI): 425.1 [M+H].

[0978] Example 72

[0979] The target product was separated according to the synthesis method of Example 69.

[0980] MS m / z(ESI): 423.1 [M+H].

[0981] Example 73

[0982] Step 1: 4-Bromo-N,N-Dimethyl-5,6,7,8-Tetrahydroisoquinoline-8-amine

[0983] Referring to step four of intermediate 2, the target compound was synthesized using dimethylamine methanol solution as a raw material.

[0984] MS m / z(ESI):255.0, 257.0[M+1]

[0985] Step 2: 6-(8-(dimethylamino)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methylquinolin-2(1H)-one

[0986] Using intermediate 9 as a raw material, the target compound was synthesized in the first step of Example 1.

[0987] MS m / z(ESI): 334.2 [M+1]

[0988] Step 3: (S)-6-(8-(dimethylamino)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methylquinolin-2(1H)-one

[0989] The isomers were obtained by chiral resolution of (R)-6-(8-(dimethylamino)-5,6,7,8-tetrahydroisoquinoline-4-yl)-1-methylquinoline-2(1H)-one.

[0990] MS m / z(ESI): 334.2 [M+1]

[0991] Example 74

[0992] The target compound was obtained with reference to Example 73.

[0993] MS m / z(ESI): 340.1 [M+1]

[0994] Example 75

[0995] The target compound was obtained using N-methylcyclopropylamine as a starting material, referring to Example 73.

[0996] MS m / z(ESI): 366.2 [M+1]

[0997] Example 76

[0998] The target compound was obtained with reference to Example 62.

[0999] MS m / z (ESI): 451.2 [M+1]

[1000] Example 77

[1001] The target compound was obtained with reference to Example 62.

[1002] MS m / z(ESI): 452.2 [M+1]

[1003] Example 78

[1004] The target compound was obtained with reference to Example 39.

[1005] MS m / z(ESI): 420.1 [M+1]

[1006] Example 79

[1007] The target compound was obtained with reference to Example 39.

[1008] MS m / z(ESI): 421.1 [M+1]

[1009] Example 80

[1010] The target compound was obtained with reference to Example 68.

[1011] MS m / z(ESI): 463.2 [M+1]

[1012] Example 81

[1013] The target compound was obtained with reference to Example 68.

[1014] MS m / z(ESI): 464.2 [M+1]

[1015] Example 82

[1016] Step 1: N-(4-bromo-5-fluoro-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide

[1017] N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (1 g, 3.72 mmol) was dissolved in acetonitrile (10 mL). Under nitrogen protection, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanedi(tetrafluoroborate (selective fluorine)) (1.32 g, 3.72 mmol) and sodium bicarbonate (787.62 mg, 7.43 mmol) were added. The mixture was stirred at 25 °C for 12 hours. The reaction was quenched with saturated brine (50 mL), and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 50:50 elution) to give the target product (0.16 g, yield: 15.00%).

[1018] MS m / z(ESI):287.0, 289.0[M+1]

[1019] Step 2: N-(5-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazo-6-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide

[1020] Using intermediate 5 as a raw material, the target compound was synthesized in the first step of Example 1.

[1021] MS m / z(ESI): 375.1 [M+1]

[1022] Step 3: Four isomers were obtained through chiral separation.

[1023] MS m / z(ESI): 375.1 [M+1]

[1024] Example 83

[1025] first step:

[1026] Under a nitrogen atmosphere, 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo2,2,2-octanebis(tetrafluoroborate) salt (1.67 g, 4.72 mmol) was added to a methanol (30 mL) solution containing 4-bromo-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one (1 g, 4.72 mmol), concentrated sulfuric acid (462.54 mg, 4.72 mmol, 251.38 μL), and the mixture was heated to 50 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, quenched slowly with saturated brine (20 mL), and the reaction solution was concentrated to remove methanol. The mixture was then extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using an eluent system (petroleum ether: ethyl acetate = 3:1) to give 4-bromo-6-fluoro-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one (600 mg, 2.61 mmol, 55.31% yield).

[1027] MS m / z(ESI):229.9,231.9[M+1]

[1028] Step Two:

[1029] Referring to the third step of Example 36, 4-bromo-6-fluoro-5,6-dihydro-7H-cyclopentadieno[c]pyridine-7-one oxime was obtained.

[1030] MS m / z(ESI):244.9, 246.9[M+1]

[1031] Step 3:

[1032] Referring to the fourth step of Example 36, 4-bromo-6-fluoro-6,7-dihydro-5H-cyclopentadien[c]pyridine-7-amine was obtained.

[1033] MS m / z(ESI):230.9, 232.9[M+1]

[1034] Step 4:

[1035] N-(4-bromo-6-fluoro-6,7-dihydro-5H-cyclopentadienyl[c]pyridin-7-yl)propionamide was obtained by referring to the second step of Example 1.

[1036] MS m / z(ESI):287.0, 289.0[M+1]

[1037] Step 5:

[1038] The target product was obtained by referring to step 8 of Example 36.

[1039] MS m / z(ESI): 375.1 [M+1]

[1040] Example 84

[1041] first step:

[1042] Under a nitrogen atmosphere, [bis(2-methoxyethyl)amine]sulfur trifluoride (1.56 g, 7.06 mmol) and N-(4-bromo-5-carbonyl-6,7-dihydro-5H-cyclopentadieno[c]pyridin-7-yl)propionamide (1 g, 3.53 mmol) were mixed at 0 °C and the mixture was heated to 60 °C and stirred for 7 h. The mixture was cooled to room temperature, diluted with ethyl acetate (30 ml), and washed with water (30 ml) and saturated brine (30 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30 / 70) to give N-(4-bromo-5,5-difluoro-6,7-dihydro-5H-cyclopentadieno[c]pyridin-7-yl)propionamide (500 mg, 1.64 mmol, 46.40% yield).

[1043] MS m / z(ESI):305.0, 307.0[M+1]

[1044] Step Two:

[1045] The target product was obtained by referring to step 8 of Example 36.

[1046] MS m / z(ESI): 393.1 [M+1]

[1047] Example 85

[1048] first step:

[1049] Under a nitrogen atmosphere, triethylamine (2.64 g, 26.08 mmol, 3.64 mL) was added to a solution of 4-bromo-6-fluoro-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one (3 g, 13.04 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonic acid (3.45 g, 13.04 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at 25 °C for 8 hours. The reaction solution was cooled to room temperature and quenched slowly with saturated brine (20 mL). The reaction solution was extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using an eluent system (petroleum ether: ethyl acetate = 3:1) to give 4-bromo-7-((tert-butyldimethylsilyl)oxo)-6-fluoro-5H-cyclopentadieno[c]pyridine (4 g, 11.62 mmol, 89.08% yield).

[1050] MS m / z(ESI):344.0, 346.0[M+1]

[1051] Step Two:

[1052] Under a nitrogen atmosphere, 1-fluoro-4-hydroxy-1,4-diazamonite-bicyclo[2.2.2]octane di(tetrafluoroborate) (4.20 g, 13.04 mmol) was added to a solution of 4-bromo-7-((tert-butyldimethylsilyl)oxo)-6-fluoro-5H-cyclopentadieno[c]pyridine (3 g, 8.71 mmol) in acetonitrile (50 mL), and the mixture was stirred at 25 °C for 8 hours. The reaction solution was quenched slowly with saturated brine (20 mL), then concentrated to remove acetonitrile. The aqueous phase was extracted with dichloromethane (30 mL × 3). The organic phases were combined and washed with saturated brine (50 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a petroleum ether:ethyl acetate = 3:1 eluent system to give 4-bromo-6,6-difluoro-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one (1 g, 4.03 mmol).

[1053] MS m / z(ESI):247.9, 249.9[M+1]

[1054] Step 3:

[1055] Referring to the third step of Example 36, 4-bromo-6,6-difluoro-5,6-dihydro-7H-cyclopentadieno[c]pyridine-7-one oxime was obtained.

[1056] MS m / z(ESI):262.9, 264.9[M+1]

[1057] Step 4:

[1058] Referring to the fourth step of Example 36, 4-bromo-6,6-difluoro-6,7-dihydro-5H-cyclopentadien[c]pyridine-7-amine was obtained.

[1059] MS m / z(ESI):248.9, 250.9[M+1]

[1060] Step 5:

[1061] N-(4-bromo-6,6-difluoro-6,7-dihydro-5H-cyclopentadienyl[c]pyridin-7-yl)propionamide was obtained by referring to the second step of Example 1.

[1062] MS m / z(ESI):305.0, 307.0[M+1]

[1063] Step 6:

[1064] The target product was obtained by referring to step 8 of Example 36.

[1065] MS m / z(ESI): 393.1 [M+1]

[1066] Example 86

[1067] The target product was obtained with reference to Example 85.

[1068] MS m / z(ESI): 393.1 [M+1]

[1069] Example 87

[1070] The target product was obtained with reference to Example 82.

[1071] MS m / z(ESI): 372.1 [M+1]

[1072] Example 88

[1073] N-(5-fluoro-4-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]thiazo-6-yl)-6,7-dihydro-5H-cyclopentadien[c]pyridin-7-yl)propionamide

[1074] The target product was obtained with reference to Example 83.

[1075] MS m / z(ESI): 372.1 [M+1]

[1076] Example 89

[1077] The target product was obtained with reference to Example 84.

[1078] MS m / z(ESI): 390.1 [M+1]

[1079] Example 90

[1080] The target product was obtained with reference to Example 85.

[1081] MS m / z(ESI): 390.1 [M+1]

[1082] Example 91

[1083] The target product was obtained with reference to Example 86.

[1084] MS m / z(ESI): 390.1 [M+1]

[1085] Example 92

[1086] 6-(6-(4-(ethylsulfonyl)piperazin-1-yl)pyridazin-4-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one

[1087] The target compound was synthesized according to Example 39.

[1088] MS m / z(ESI): 416.2 [M+1]

[1089] Example 93

[1090] first step

[1091] Using 3,5-dibromopyridazine as a raw material, 6-(6-bromopyridazine-4-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one was obtained in the second step of Example 39.

[1092] MS m / z(ESI): 318.0, 320.0 [M+1].

[1093] Step 2

[1094] Using 6-(6-bromopyridazin-4-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one as a starting material, referring to the first step of Example 39, tert-butyl 2-(5-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinoline-6-yl)pyridazin-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was obtained.

[1095] MS m / z(ESI): 461.2 [M+1].

[1096] Step 3

[1097] Using tert-butyl 2-(5-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester as a starting material, 6-(6-(5-(ethylsulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pyrazin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one was obtained in steps four and five of Example 51.

[1098] MS m / z(ESI): 453.2 [M+1].

[1099] Example 94

[1100] Using 3,5-dibromopyridazine as a starting material, the target compound was obtained according to Example 52.

[1101] MS m / z(ESI): 453.2 [M+1].

[1102] Example 95

[1103] The target compound was obtained using 3,5-dibromopyridazine as a starting material, referring to Example 93.

[1104] MS m / z(ESI): 432.1 [M+1].

[1105] Example 96

[1106] The target compound was obtained using 3,5-dibromopyridazine as a starting material, referring to Example 93.

[1107] MS m / z(ESI): 432.1 [M+1].

[1108] Example 97

[1109] Following the synthesis method of Example 92, the target product was obtained and chirally separated into 97-1 and 97-2.

[1110] MS m / z(ESI): 446.1 [M+1]

[1111] Example 98

[1112] Following the synthesis method of Example 39, the target product was obtained, and chiral separation yielded 98-1 and 98-2.

[1113] MS m / z(ESI): 446.1 [M+1]

[1114] Example 99

[1115] The target product was obtained by referring to the synthesis method of Example 93.

[1116] MS m / z(ESI): 457.1 [M+1]

[1117] Example 100

[1118] The target product was obtained by referring to the synthesis method of Example 94.

[1119] MS m / z(ESI): 457.1 [M+1]

[1120] Example 101

[1121] The target product was obtained using 3,5-dibromopyridazine as a starting material, following the synthesis methods described in Examples 40 and 92. MS m / z (ESI): 449.2 [M+1]

[1122] Example 102

[1123] Using 3,5-dibromopyridazine as a starting material, the target product was obtained by referring to the synthesis methods of Examples 40 and 92.

[1124] MS m / z(ESI): 449.2 [M+1]

[1125] Example 103

[1126] Using 3,5-dibromopyridazine as a starting material, the target product was obtained by referring to the synthesis methods of Examples 42 and 92.

[1127] MS m / z(ESI): 461.2 [M+1]

[1128] Example 104

[1129] The target product was obtained by using 3,5-dibromopyridazine as a starting material and following the synthesis methods of Examples 42 and 92.

[1130] MS m / z(ESI): 461.2 [M+1]

[1131] Example 105

[1132] Referring to Example 39, the title product 6-(6-(4-(1-cyclopropyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)pyridazin-4-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one was finally obtained.

[1133] MS m / z (ESI): 458.2 [M+H]

[1134] Example 106

[1135] Referring to Example 39, the title product 6-(5-(4-(1-cyclopropyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)pyridazin-3-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one was finally obtained.

[1136] MS m / z (ESI): 458.2 [M+H]

[1137] Example 107

[1138] Referring to Example 39, 3-methyl-6-(6-((3aR,6aS)-5-(1-methyl-1H-pyrazole-4-carbonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridazin-4-yl)benzo[d]thiazol-2(3H)-one and 3-methyl-6-(6-((3aR,6aR)-5-(1-methyl-1H-pyrazole-4-carbonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridazin-4-yl)benzo[d]thiazol-2(3H)-one were obtained.

[1139] MS m / z(ESI): 462.2 [M+1]

[1140] Example 108

[1141] Referring to Example 39, 3-methyl-6-(5-((3aR,6aS)-5-(1-methyl-1H-pyrazole-4-carbonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridazin-3-yl)benzo[d]thiazol-2(3H)-one and 3-methyl-6-(5-((3aR,6aR)-5-(1-methyl-1H-pyrazole-4-carbonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridazin-3-yl)benzo[d]thiazol-2(3H)-one were obtained.

[1142] MS m / z(ESI): 462.2 [M+1]

[1143] Example 109

[1144] Referring to Example 6, 6-(6-((3aR,6aS)-5-(1-cyclopropyl-1H-pyrazole-4-carbonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridazin-4-yl)-3-methylbenzo[d]thiazol-2(3H)-one and 6-(6-((3aR,6aR)-5-(1-cyclopropyl-1H-pyrazole-4-carbonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridazin-4-yl)-3-methylbenzo[d]thiazol-2(3H)-one were obtained.

[1145] MS m / z(ESI): 488.2 [M+1]

[1146] Example 110

[1147] Referring to Example 6, 6-(5-((3aR,6aS)-5-(1-cyclopropyl-1H-pyrazole-4-carbonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridazin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one and 6-(5-((3aR,6aR)-5-(1-cyclopropyl-1H-pyrazole-4-carbonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridazin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one were obtained.

[1148] MS m / z(ESI): 488.2 [M+1]

[1149] Example 111

[1150] Referring to Example 51, the title product 1-methyl-6-(6-(3-(1-methyl-1H-pyrazol-4-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrazin-2-yl)-3,4-dihydroquinoline-2(1H)-one was obtained.

[1151] MS m / z (ESI): 444.2 [M+H]

[1152] Example 112

[1153] Referring to Example 51, the title product 1-methyl-6-(5-(6-(1-methyl-1H-pyrazol-4-carbonyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)-3,4-dihydroquinoline-2(1H)-one was obtained.

[1154] MS m / z (ESI): 443.2 [M+H]

[1155] Example 113

[1156] Step 1: 2-Bromo-6-(1-(ethanesulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazine

[1157] Refer to Example 39 for the second step of synthesizing the target compound.

[1158] MS m / z(ESI):332.0, 334.0[M+1]

[1159] Step 2: 6-(6-(1-(ethylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)-1-methyl-3,4-dihydro-1,8-naphthopyridin-2(1H)-one

[1160] Refer to Example 39 for the second step of synthesizing the target compound.

[1161] MS m / z(ESI): 414.2 [M+1]

[1162] Example 114

[1163] The target compound was synthesized according to Example 113.

[1164] MS m / z(ESI): 417.1 [M+1]

[1165] Example 115

[1166] Step 1: N-(3,5-dibromopyridin-4-yl)-N-methylglycine ethyl ester

[1167] 3,5-Dibromo-N-methylpyridin-4-amine (3 g, 11.28 mmol) and ethyl bromoacetate (2.07 g, 12.41 mmol) were dissolved in acetonitrile (30 mL). Under nitrogen protection, potassium carbonate (4.68 g, 33.84 mmol) was added. The mixture was stirred at 50 °C for 12 hours. The mixture was evaporated to dryness, and saturated brine (100 mL) was added. Extraction was performed with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 60:40) to give the target product (3.5 g, yield: 88.14%).

[1168] MS m / z(ESI): 351.0 [M+1]

[1169] Step 2: 7-Bromo-1-methyl-1,2-dihydro-3H-pyrrolo[3,2-c]pyridin-3-one

[1170] N-(3,5-dibromopyridin-4-yl)-N-methylglycine ethyl ester (1 g, 2.84 mmol) was dissolved in tetrahydrofuran (15 mL) under nitrogen protection and cooled in a dry ice-ethanol bath. A 2.5 M solution of n-butyllithium (1.14 mL) was added. The mixture was stirred at -78 °C for 0.5 h. The reaction was quenched with saturated ammonium chloride aqueous solution (100 mL), and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 70:30) to give the target product (0.21 g, yield: 32.56%).

[1171] MS m / z(ESI):227.0, 229.0[M+1]

[1172] Step 3: 7-Bromo-1-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-3-amine

[1173] Refer to intermediate 2 for step 4 synthesis of the target compound.

[1174] MS m / z(ESI):228.0, 230.0[M+1]

[1175] Step 4: N-(1-methyl-7-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazo-6-yl)-2,3-dihydroxy-1H-pyrrolo[3,2-c]pyridin-3-yl)propionamide

[1176] The target compound was synthesized according to Example 1.

[1177] MS m / z(ESI): 372.1 [M+1]

[1178] Step 5: (S)-N-(1-methyl-7-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazolyl-6-yl)-2,3-dihydroxy-1H-pyrrolo[3,2-c]pyridin-3-yl)propionamide and (R)-N-(1-methyl-7-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazolyl-6-yl)-2,3-dihydroxy-1H-pyrrolo[3,2-c]pyridin-3-yl)propionamide

[1179] The target product was obtained through chiral separation.

[1180] MS m / z(ESI): 372.2 [M+1]

[1181] Example 116

[1182] Step 1: Methyl 5-bromo-4-(methylsulfonyl)nicotinate

[1183] Methyl 5-bromo-4-(methylthio)nicotinic acid (1 g, 3.81 mmol) was dissolved in dichloromethane (15 mL). Under ice-water bath cooling and nitrogen protection, m-chloroperoxybenzoic acid (1.55 g, 7.63 mmol, 85% w / w) was added. The mixture was stirred at 0 °C for 1 hour. The reaction was quenched with saturated sodium sulfite aqueous solution (50 mL), the organic phase was separated, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 50:50) to give the target product (0.97 g, yield: 86.45%).

[1184] MS m / z(ESI):294.0, 296.0[M+1]

[1185] Step 2: 7-Bromothieno[3,2-c]pyridine-3(2H)-one-1,1-dioxide

[1186] Methyl 5-bromo-4-(methylsulfonyl)nicotinic acid (0.98 g, 3.33 mmol) was dissolved in tetrahydrofuran (20 mL). Under ice-water bath cooling and nitrogen protection, potassium tert-butoxide (373.88 mg, 3.33 mmol) was added. The mixture was stirred at 25 °C for 12 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL), and 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 rapid silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 60:40 elution) to give the target product (0.31 g, yield: 35.50%).

[1187] MS m / z(ESI):261.9, 263.9[M+1]

[1188] Step 3: 3-Amino-7-bromo-2,3-dihydrothiopheno[3,2-c]pyridine-1,1-dioxide

[1189] Refer to intermediate 2 for step 4 synthesis of the target compound.

[1190] MS m / z(ESI):262.9, 264.9[M+1]

[1191] Step 4: N-(7-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazo-6-yl)-1,1-dioxide-2,3-dihydrate thiopheno[3,2-c]pyridin-3-yl)propionamide

[1192] The target compound was synthesized according to Example 1.

[1193] MS m / z(ESI): 407.1 [M+1]

[1194] Step 5: (S)-N-(7-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazolyl-6-yl)-1,1-dioxide-2,3-dihydrate thiopheno[3,2-c]pyridin-3-yl)propionamide and (R)-N-(7-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazolyl-6-yl)-1,1-dioxide-2,3-dihydrate thiopheno[3,2-c]pyridin-3-yl)propionamide

[1195] The target product was obtained through chiral separation.

[1196] MS m / z(ESI): 407.1 [M+1]

[1197] Example 117

[1198] first step

[1199] At room temperature, 20 g (79.71 mmol) of 3,5-dibromo-4-methylpyridine, 21.28 g (119.56 mmol) of N-bromosuccinimide, and 1.31 g (7.97 mmol) of azobisisobutyronitrile (DIBON) were dissolved in 200 mL of carbon tetrachloride, purged with nitrogen, and heated to 90 °C for 5 h. The reaction was initiated by LC-MS, cooled to room temperature, and quenched with 100 mL of water. The reaction mixture was extracted with 100 mL of dichloromethane (2). The combined organic phases were washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 15 g (57.06%) of 3,5-dibromo-4-(bromomethyl)pyridine.

[1200] MS m / z (ESI): 329.8, 331.8 [M+1].

[1201] Step 2

[1202] Under ice bath conditions, sodium hydroxide (1.46 g, 36.38 mmol, 60% purity) was dissolved in tetrahydrofuran (100 mL), and nitrogen gas was purged. Then, ethyl acetoacetate (3.95 g, 30.32 mmol) was slowly added, and the reaction was carried out at 0 °C for 15 min. Then, n-butyllithium solution (18.19 mL, 36.38 mmol, 2.0 M) was added dropwise at 0 °C, and the mixture was stirred under ice bath conditions for 15 min. The mixture was then cooled to -40 °C, and 3,5-dibromo-4-(bromomethyl)pyridine (10 g, 30.32 mmol) was added. The reaction mixture was stirred at -40 °C for 1 hour. LC-MS indicated the formation of the target product. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL), separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give ethyl 5-(3,5-dibromopyridin-4-yl)-3-carbonylpentanoate (0.6 g, yield: 5.22%).

[1203] MS m / z (ESI): 377.9, 379.9 [M+1].

[1204] Step 3

[1205] Ethyl 5-(3,5-dibromopyridin-4-yl)-3-carbonylpentanoate (0.3 g, 0.79 mmol) was dissolved in acetic anhydride (2 mL) at room temperature, followed by the addition of triethoxymethane (0.12 g, 0.79 mol), purging with nitrogen, and heating to 110 °C for 2 h. The reaction was completed by LCMS, cooled to room temperature, and evaporated to dryness to give ethyl(Z)-5-(3,5-dibromopyridin-4-yl)-2-(ethoxymethylene)-3-carbonylpentanoate, which was used directly in the next step (0.3 g, yield: 87.12%).

[1206] MS m / z (ESI): 433.9, 435.9 [M+1].

[1207] Step 4

[1208] At room temperature, ethyl(Z)-5-(3,5-dibromopyridin-4-yl)-2-(ethoxymethylene)-3-carbonylpentanoate was...

[1209] Dissolve 0.3 g (0.69 mmol) in ethanol (5 mL), add hydrazine (0.22 g, 6.89 mmol) at room temperature, replace with nitrogen, heat to 50 °C, react for 1 hour, and then stop the reaction. Cool to room temperature, quench the reaction with water (10 mL), extract the reaction solution with dichloromethane (10 mL × 2), combine the organic phases, wash the organic phase with saturated sodium chloride solution (10 mL), dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and give ethyl 5-(2-(3,5-dibromopyridin-4-yl)ethyl)-1H-pyrazole-4-carboxylic acid ester (0.06 g, yield: 21.59%).

[1210] MS m / z (ESI): 401.9, 403.9 [M+1].

[1211] Step 5

[1212] At room temperature, ethyl 5-(2-(3,5-dibromopyridin-4-yl)ethyl)-1H-pyrazole-4-carboxylic acid ester (0.06 g, 0.15 mmol), potassium carbonate (0.062 g, 0.45 mmol), cuprous iodide (0.03 g, 0.015 mmol), and dimethylethylenediamine (0.04 g, 0.45 mmol) were dissolved in 1',4-dioxane (5 mL), nitrogen gas was purged, and the mixture was heated to 90 °C and reacted for 1.5 h. The reaction was stopped by LCMS. After cooling to room temperature, the reaction was quenched with water (10 mL). The reaction solution was extracted with dichloromethane (10 mL × 2). The organic phases were combined and washed with saturated sodium chloride solution (10 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by Flash column chromatography to give ethyl 6-bromo-4,5-dihydropyrazolo[1,5-a][1,7]diazanaphthalene-3-carboxylic acid ester (0.04 g, yield: 83.41%).

[1213] MS m / z (ESI): 322.1, 324.1 [M+1].

[1214] Step 6

[1215] Ethyl 6-bromo-4,5-dihydropyrazolo[1,5-a][1,7]diazanaphthalene-3-carboxylic acid ester (40 mg, 0.12 mmol) was dissolved in ethanol (2 mL) at room temperature, followed by the addition of an aqueous solution of sodium hydroxide (50 mg, 1.24 mmol) (2 mL). The mixture was stirred at room temperature for one hour, and the reaction was brought to a completeness indicated by LCMS. The reaction was then quenched by the addition of an aqueous solution of formic acid (1 mL). The reaction solution was extracted with dichloromethane (10 mL × 2), and the organic phases were combined. The organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-bromo-4,5-dihydropyrazolo[1,5-a][1,7]diazanaphthalene-3-carboxylic acid (35 mg, yield: 95.85%).

[1216] MS m / z(ESI): 294.1, 296.1 [M+1].

[1217] Step 7

[1218] At room temperature, 0.29 g (1.0 mmol) of 6-bromo-4,5-dihydropyrazolo[1,5-a][1,7]diazanaphthalene-3-carboxylic acid was dissolved in toluene (5 mL), and nitrogen gas was purged. Then, diphenyl azidophosphate (0.41 g, 1.5 mmol) was added dropwise, and the mixture was heated to 100 °C and reacted for 2 hours. LCMS indicated the disappearance of the starting material. The mixture was then cooled to room temperature, and 2 mL of tert-butanol was added dropwise. The mixture was heated to 100 °C and reacted for 2 hours. LCMS indicated the end of the reaction, and the mixture was cooled to room temperature. The reaction solution was diluted with ethyl acetate (20 mL), and then washed successively with saturated sodium bicarbonate solution (20 mL × 2) and saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was separated by Flash column chromatography to give tert-butyl (6-bromo-4,5-dihydropyrazolo[1,5-a][1,7]naphthid-3-yl)carbamate (0.18 g, yield: 50%).

[1219] MS m / z (ESI): 365.1, 367.1 [M+1].

[1220] Step 8

[1221] Using (6-bromo-4,5-dihydropyrazolo[1,5-a][1,7]naphthidine-3-yl) tert-butyl carbamate as a starting material, following steps two to four of Example 7, N-(6-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinoline-6-yl)-4,5-dihydropyrazolo[1,5-a][1,7]diazanaphthalene-3-yl) ethanesulfonamide was obtained.

[1222] MS m / z(ESI): 438.2 [M+1].

[1223] Example 118

[1224] Referring to Example 117, N-(6-(3-(methyl-d3)-2-carbonyl-2,3-dihydrobenzo[d]thiazolyl-6-yl)-4,5-dihydropyrazolo[1,5-a][1,7]diazanaphthyl-3-yl) ethanesulfonamide was obtained.

[1225] MS m / z(ESI): 445.1 [M+1].

[1226] Example 119

[1227] first step:

[1228] Referring to Example 1, the target product 6-(3-amino-4,5-dihydropyrazolo[1,5-a][1,7]diazanaphth-6-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one was obtained in the first step.

[1229] MS m / z(ESI): 346.2 [M+1]

[1230] Step 2: 1-Methyl-6-(3-((1-methyl-1H-pyrazol-3-yl)amino)-4,5-dihydropyrazolo[1,5-a][1,7]diazanaphth-6-yl)-3,4-dihydroquinoline-2(1H)-one

[1231] Using 3-iodo-1-methylpyrazole as a raw material, the target product was obtained by referring to the first step of Example 7.

[1232] MS m / z(ESI): 426.2 [M+1]

[1233] Example 120

[1234] The target product was obtained by referring to Example 119.

[1235] MS m / z(ESI): 433.2 [M+1]

[1236] Example 121

[1237] Step 1: N,1-Dimethyl-5-(pyridin-3-yl)pyrrolidine-2-carboxamide

[1238] Using methyl 1-methyl-5-(pyridin-3-yl)pyrrolidine-2-carboxylic acid ester as a starting material, the target product was obtained by referring to steps four and five of Example 29.

[1239] MS m / z(ESI): 220.1 [M+1]

[1240] Step 2: 5-(5-bromopyridin-3-yl)-N,1-dimethylpyrrolidine-2-carboxamide

[1241] The target product was obtained from N,1-dimethyl-5-(pyridin-3-yl)pyrrolidine-2-carboxamide.

[1242] MS m / z(ESI): 298.0 300.0 [M+1]

[1243] Step 3: N-Ethyl-1-methyl-5-(5-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinoline-6-yl)pyridin-3-yl)pyrrolidine-2-carboxamide

[1244] Referring to the first step of Example 1, the target product is obtained.

[1245] MS m / z(ESI): 393.2 [M+1]

[1246] Example 122

[1247] The title product N-ethyl-1-methyl-5-(5-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazolyl-6-yl)pyridin-3-yl)pyrrolidine-2-carboxamide was obtained by the synthetic method of Example 121. The target product was obtained by chiral resolution.

[1248] MS m / z(ESI): 400.1 [M+H].

[1249] Example 122

[1250] first step:

[1251] Methyltriphenylphosphonium bromide (9.45 g, 26.54 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a 250 mL flask. Potassium tert-butoxide (2.98 g, 26.54 mmol) was slowly added at 0 °C under nitrogen protection. The reaction mixture was kept at 0 °C under nitrogen protection for 1 h. Then, a tetrahydrofuran solution of 4-bromo-6,7-dihydroisoquinoline-8(5H)-one (3.00 g, 13.27 mmol) was added, and the reaction mixture was stirred at 25 °C for 16 h. The reaction was stopped, and the reaction was quenched with an aqueous solution of ammonium chloride (60 mL). The mixture was extracted with ethyl acetate (60 mL × 2), and the combined organic phases were washed with saturated sodium chloride (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product 4-bromo-8-methylene-5,6,7,8-tetrahydroisoquinoline (2.1 g, yellow solid), yield: 70.62%.

[1252] MS m / z(ESI):224.0, 226.0[M+H].

[1253] Step Two:

[1254] 4-Bromo-8-methylene-5,6,7,8-tetrahydroisoquinoline (2.0 g, 8.92 mmol), ferric acetate (85.20 mg, 446.23 μmol), triethylamine (1.81 g, 17.85 mmol), azide-trimethylsilane (2.06 g, 17.85 mmol), ethyl diazonate (2.04 g, 17.85 mmol), tert-butyl hydroperoxide (2.41 g, 26.77 mmol), and isopropanol (60 mL) were added to a 100 mL flask. The reaction mixture was then protected with nitrogen and reacted at 50 °C for 24 h. The reaction was stopped, and an aqueous solution (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product 8-chloro-5-(2-ethoxyvinyl)-2-methylphthalazine-1(2H)-one (1.9 g, white solid), yield: 60.27%.

[1255] MS m / z(ESI):353.0, 355.0[M+H].

[1256] Step 3:

[1257] 1.9 g (5.38 mmol) of 8-chloro-5-(2-ethoxyvinyl)-2-methylphthalazine-1(2H)-one was dissolved in 30 mL of tetrahydrofuran. Triphenylphosphine (2.12 g, 8.07 mmol) was added at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours under nitrogen protection. The reaction mixture was concentrated, and 30 mL of aqueous solution was added. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (20 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product, ethyl 3-(8-amino-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionate (1.1 g, yellow solid), yield: 62.49%.

[1258] MS m / z(ESI):327.0, 329.0[M+H].

[1259] Step 4:

[1260] Ethyl 3-(8-amino-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionate (1 g, 3.06 mmol) was dissolved in 10 mL of ethanol. An aqueous solution of sodium hydroxide (244.46 mg, 6.11 mmol) was added at 25 °C, and the reaction mixture was stirred at 25 °C for 2 hours. 10 mL of aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product, 4-bromo-6,7-dihydro-5H-spiro[isoquinoline-8,2'-pyrrolidine]-5'-one (600 mg, white solid), yield: 69.83%.

[1261] MS m / z(ESI):281.0, 283.0[M+H].

[1262] Step 5:

[1263] The title product 3-(methyl-d3)-6-(5'-oxo-6,7-dihydro-5H-spiro[isoquinoline-8,2'-pyrrolidine]-4-yl)benzo[d]thiazol-2(3H)-one was obtained by referring to the synthesis method in the first step of Example 1.

[1264] MS m / z (ESI): 369.1 [M+H].

[1265] Step 6:

[1266] The title product was obtained by chiral separation.

[1267] MS m / z (ESI): 369.1 [M+H].

[1268] Example 123

[1269] The title product 3-(methyl-d3)-6-(6'-oxo-6,7-dihydro-5H-spiro[isoquinoline-8,2'-piperidin]-4-yl)benzo[d]thiazol-2(3H)-one was obtained by the synthetic method of Example 122. The target product was obtained by chiral resolution.

[1270] MS m / z (ESI): 383.1 [M+H].

[1271] Example 124

[1272] Starting with 3,3-dimethyl-3,4-dihydropyridine-2(1H)-one and 3,5-dibromopyridine, and referring to [Organic and Biomolecular Chemistry, 2016, vol. 14, #3, p. 830-834], the title product 6-(5-(5,5-dimethyl-6-carbonylpiperidin-2-yl)pyridin-3-yl)-3-(methyl-d3)benzo[d]thiazolyl-2(3H)-one was obtained.

[1273] MS m / z(ESI): 371.2 [M+H].

[1274] Example 125

[1275] first step:

[1276] Referring to [Tetrahedron, 2014, vol. 70, #25, pp. 3839-3846], we obtain 5-(5-chloropyridin-3-yl)-5-methylpyrrolidone-2-one.

[1277] MS m / z(ESI): 211.1 [M+1]

[1278] Step 2: Referring to the first step of Example 1, (S)-3-(methyl-d3)-6-(5-(2-methyl-5-carbonylpyrrolidone-2-yl)pyridin-3-yl)benzo[d]thiazol-2(3H)-one and (R)-3-(methyl-d3)-6-(5-(2-methyl-5-carbonylpyrrolidone-2-yl)pyridin-3-yl)benzo[d]thiazol-2(3H)-one were obtained.

[1279] MS m / z(ESI): 343.1 [M+1]

[1280] The following compounds were prepared according to the method of Example 1:

[1281] The following compounds were prepared according to the method of Example 4:

[1282] The following compounds were prepared according to the method in Example 5:

[1283] The following compounds were prepared according to the method described in Example 6:

[1284] The following compounds were prepared according to the method of Example 7:

[1285] The following compounds were prepared according to the method of Example 50:

[1286] The following compounds were prepared according to the method of Example 35:

[1287] The following compounds were prepared according to the method of Example 36:

[1288] The following compounds were prepared according to the method of Example 37:

[1289] The following compounds were prepared according to the method of Example 44:

[1290] The following compounds were prepared according to the method of Example 51:

[1291] The following compounds were prepared according to the method of Example 39:

[1292] The following compounds were prepared according to the method of Example 52:

[1293] The following compounds were prepared according to the method of Example 43:

[1294] The following compounds were prepared according to the method of Example 111:

[1295] The following compounds were prepared according to the method of Example 112:

[1296] The following compounds were prepared according to the method of Example 111:

[1297] The following compounds were prepared according to the method of Example 15:

[1298] The following compounds were prepared according to the method of Example 38:

[1299] Example 488

[1300] (S)-N-(7-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]thiazo-6-yl)-2,3-dihydroxy[3,2-c]pyridin-3-yl)acetamide

[1301] The target compound was obtained by using intermediates 4 and 5 as raw materials and by resolving them according to the synthesis method of Example 1.

[1302] MS m / z(ESI): 345.1 [M+1]

[1303] 1 H NMR (400MHz, DMSO) δ8.70-8.62(m,1H),8.61(s,1H),8.40(s,1H),8.07-8.01(m,1H),7.81-7. 73(m,1H),7.42(d,1H),5.63-5.52(m,1H),4.91-4.77(m,1H),4.48-4.35(m,1H),1.86(s,3H).

[1304] The splitting method is as follows:

[1305] Example 489

[1306] Using 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzo[d]thiazol-2(3H)-one and (6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)(1-methyl-1H-pyrazole-4-yl) methyl ketone as raw materials, the title product 3-methyl-6-(5-(6-(1-methyl-1H-pyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)benzo[d]thiazol-2(3H)-one was obtained by referring to step four of Example 1.

[1307] MS m / z(ESI): 447.1 [M+1].

[1308] 1H NMR(400MHz,MeOD)δ8.17(d,1H),8.06(s,1H),7.88–7.80(m,2H),7.78(d,1H),7.73–7.59(m,1H), 7.35(d,1H),7.16–7.07(m,1H),4.67(s,2H),4.33(s,2H),4.19(s,4H),3.93(s,3H),3.50(s,3H).

[1309] Example 490

[1310] Step 1: tert-butyl-3-((5-bromopyridin-3-yl)oxo)acetidine-1-carboxylic acid ester

[1311] A mixture of 3-bromo-5-iodopyridine (2 g, 7.04 mmol), tert-butyl-3-hydroxyacetidine-1-carboxylic acid ester (1.46 g, 8.45 mmol), cuprous iodide (66.93 mg, 352 μmol), 1,10-phenanthroline (126.96 mg, 704 μmol), cesium carbonate (6.89 g, 21.13 mmol), and toluene (20 mL) was purged with nitrogen three times, stirred at 110 °C for 12 hours under nitrogen protection, evaporated to dryness, and separated by column chromatography (PE / EtOAC = 3:1) to give tert-butyl-3-((5-bromopyridin-3-yl)oxo)acetidine-1-carboxylic acid ester (1.2 g, yield: 51.7%).

[1312] MS m / z(ESI): 329.0 331.0 [M+H]

[1313] Step 2: Tert-butyl-3-((5-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]thiazolyl-6-yl)pyridin-3-yl)oxo)acetidine-1-carboxylic acid ester

[1314] 3-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzo[d]thiazolyl-2(3H)-one (126 mg, 434 μmol), tert-butyl-3-((5-bromopyridin-3-yl)oxo)acetidine-1-carboxylic acid ester (110 mg, 334 μmol), sodium carbonate (106 mg, 1.00 mmol), tetra(triphenylphosphine)palladium (1 A mixture of 9 mg (16 μmol), ethanol (5 mL), and water (1 mL) was purged with nitrogen three times, then stirred at 90 °C for 2 hours under nitrogen protection, evaporated to dryness, and separated by column chromatography to give a pale yellow solid tert-butyl 3-((5-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]thiazolyl-6-yl)pyridin-3-yl)oxo)acetidine-1-carboxylic acid ester (130 mg, yield: 94.1%).

[1315] MS m / z (ESI): 414.1 [M+H]

[1316] Step 3: 6-(5-(acetidin-3-oxy)pyridin-3-yl)-3-methylbenzo[d]thiazolyl-2(3H)-one

[1317] A mixture of tert-butyl 3-((5-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]thiazolyl-6-yl)pyridin-3-yl)oxo)acetidine-1-carboxylic acid ester (130 mg, 314 μmol), trifluoroacetic acid (1 mL), and DCM (3 mL) was stirred at room temperature for 0.5 hours, evaporated to dryness, water was added, and the pH was adjusted to 10 with saturated NaHCO3 solution. The mixture was extracted with DCM, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a pale yellow oily substance, 6-(5-(acetidine-3-oxy)pyridin-3-yl)-3-methylbenzo[d]thiazolyl-2(3H)-one (100 mg, crude product).

[1318] MS m / z (ESI): 314.1 [M+H]

[1319] Step 4: 3-Methyl-6-(5-((1-(1-methyl-1H-pyrazole-4-carbonyl)acetidin-3-yl)oxo)pyridin-3-yl)benzo[d]thiazol-2(3H)-one

[1320] Add 11-methyl-1H-pyrazole-4-carboxylic acid (30 μmol) to a solution of 6-(5-(acididin-3-oxy)pyridin-3-yl)-3-methylbenzo[d]thiazolyl-2(3H)-one (50 mg, 159 μmol), (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (120 mg, 319 μmol), triethylamine (48.44 mg, 478 μmol), and DMF (3 mL). The mixture was stirred at room temperature for 2 hours (mg, 239 μmol), then water was added, and the mixture was extracted with dichloromethane (30 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The mixture was then separated by preparative chromatography using acidic conditions to obtain 3-methyl-6-(5-((1-(1-methyl-1H-pyrazole-4-carbonyl)acetidin-3-yl)oxo)pyridin-3-yl)benzo[d]thiazol-2(3H)-one (32.7 mg, yield: 48.1%).

[1321] MS m / z(ESI): 422.1 [M+1].

[1322] 1H NMR(400MHz,DMSO)δ8.59(d,J=1.8Hz,1H),8.25(d,J=2.6Hz,1H),8.18(s,1H),8 .12(d,J=1.9Hz,1H),7.81(dd,J=8.4,2.0Hz,1H),7.77(s,1H),7.56(t,J=2.3Hz ,1H),7.43(d,J=8.4Hz,1H),5.33(tt,J=6.7,3.7Hz,1H),4.87-4.81(m,1H),4.5 4-4.51(m,1H),4.39-4.37(m,1H),4.10–3.93(m,1H),3.86(s,3H),3.45(s,3H).

[1323] Example 491

[1324] Using 3,5-dibromopyridine and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester as raw materials, refer to Example 5, and replace 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one with

[1325] 3-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzo[d]thiazol-2(3H)-one yields the title product 3-methyl-6-(5-(7-(1-methyl-1H-pyrazole-4-carbonyl)-2,7-diazaspiro[3.5]nonane-2-yl)pyridin-3-yl)benzo[d]thiazol-2(3H)-one.

[1326] MS m / z(ESI): 475.1 [M+1].

[1327] 1 H NMR (400MHz, DMSO) δ8.23(d,J=1.9Hz,1H),8.06(d,J=1.9Hz,1H),8.04(s,1H),7.81(d,J=2.6Hz,1H),7.74(dd,J=8.4,1.9Hz,1H),7.65( s,1H),7.40(d,J=8.5Hz,1H),7.06(t,J=2.3Hz,1H),3.86(s,3H),3.75(s,4H),3.58(t,J=5.5Hz,4H),3.45(s,3H),1.81(t,J=5.5Hz,4H).

[1328] Example 492

[1329] Using 2-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane and 1-cyanocyclopropane-1-carboxylic acid as starting materials, the synthesis method of Example 42 was followed, and 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)quinoline was replaced with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzo[d]thiazol-2(3H)-one to obtain the title product 1-(6-(5-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]thiazol-6-yl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)cyclopropane-1-carboxylonitrile.

[1330] MS m / z(ESI): 432.1 [M+1].

[1331] 1 H NMR (400MHz, DMSO) δ8.25(d,J=1.9Hz,1H),8.05(d,J=1.9Hz,1H),7.82(d,J=2.6Hz,1H),7.73(dd,J=8.4,1.9Hz,1H),7.41( d,J=8.4Hz,1H),7.07(t,J=2.3Hz,1H),4.72(s,2H),4.30–4.03(m,6H),3.45(s,3H),1.60–1.54(m,2H),1.53–1.46(m,2H).

[1332] Biological test evaluation

[1333] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[1334] Test Example 1

[1335] The G-402 cell line was used as the host cell for the expression (transient or stable) of human CYP11 family enzymes. Specifically, G-402 cell lines stably expressing human CYP11B1 and human CYP11B2 were established. It has been demonstrated that the G-402 cell line expresses cofactors (corticoid ferredoxin and corticoid ferredoxin reductase) that are quite important for CYP11 family activity, and (compared to H295R cells) this cell line itself does not possess CYP11 family-related enzyme activity. Therefore, the G-402 cell line is highly suitable as a host cell for ectopic expression of CYP11 family enzymes.

[1336] 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 antibiotic marker (neomycin). The expression plasmid was transfected into G-402 cells using standard techniques, followed by selection with specific antibiotics. The activity of the enzyme expressed in the selected monoclonal cells was assessed using 11-deoxycorticosterone (a substrate of CYP11B2) and 11-deoxycortisol (a substrate of CYP11B1).

[1337] G-402 cells expressing the CYP11 plasmid, established according to 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. Cellular enzyme assays were performed using DMEM / F12 medium containing 2.5% charcoal-treated FBS and appropriate substrate concentrations (1 μM 11-deoxycorticosterone or 1 μM 11-deoxycortisol). To detect cellular enzyme activity, cells were seeded in 96-well plates and incubated for 16 h. The supernatant was then transferred, and the concentrations of the expected products were analyzed (CYP11B2 product: aldosterone; CYP11B1 product: cortisol). These product concentrations were determined by CisBio HTRF assays or LC-MS / MS. Data in Table 1 were obtained using HTRF assays.

[1338] In cellular enzyme experiments, the inhibitory effect of a compound on the product formation reflects its inhibitory effect on the enzyme. The dose-dependent inhibition of enzyme activity by the compound is calculated by plotting the concentration of the test compound (x-axis) against the measured product level (y-axis). Then, the raw data are fitted to a 4-parameter sigmoid function (Morgan-Mercer-Flodin, MMF model) using the least squares method: y = (AB + Cx) / ( ... D ) / (B+x D )

[1339] Where A is the maximum y-value, B is the EC50 determined using XLFit, C is the minimum y-value, and D is the slope value. The maximum value A corresponds to the amount of product detected without inhibitors, and C corresponds to the amount of product detected in G402 cells expressing the empty vector plasmid.

[1340] EC of the compounds of this invention 50 The values ​​were determined using the G-402 experimental system described above. CYP11B2 enzyme activity was determined under conditions of 1 μM 11-deoxycorticosterone and a variable inhibitor, while CYP11B1 enzyme activity was determined under conditions of 1 μM 11-deoxycortisol and a variable inhibitor.

[1341] Table 1

[1342] Table 2

[1343] Test Example 2: Rat Pharmacokinetic Determination

[1344] 1. Research Objective:

[1345] Using SD rats as test animals, the pharmacokinetic behavior of the compound of this invention in rats (plasma) after oral administration was studied.

[1346] 2. Test Plan

[1347] 2.1 Test Drugs:

[1348] The compound of this invention was prepared in-house.

[1349] 2.2 Experimental animals:

[1350] Three male SD rats were used in each group.

[1351] 2.3 Drug Preparation:

[1352] Oral administration preparation: 0.5% CMC-Na (1% Tween 80)

[1353] Weigh 5g of sodium carboxymethyl cellulose (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.

[1354] Weigh out the compound from the example, dissolve it in the solution, shake well, and sonicate for 15 minutes to obtain a colorless and clear solution with a concentration of 0.5 mg / mL.

[1355] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[1356] Weigh out the compound from the examples, add 5% DMSO according to the total volume ratio of the drug, vortex and sonicate for 2 min to completely dissolve it; then add 10% Solutol HS15, vortex and sonicate for 2 min to completely dissolve it; finally add 85% PBS, vortex and sonicate for 5 min, filter through a 0.22 μm filter membrane to obtain a colorless, transparent, and clear solution with a concentration of 0.2 mg / mL.

[1357] 2.4 Administration:

[1358] Three male SD rats were used in each group. After fasting overnight, they were administered PO at a dose of 5 mg / kg and a volume of 10 mL / kg.

[1359] Three male SD rats were used in each group. After fasting overnight, the rats were administered the drug intravenously at a dose of 1 mg / kg and a volume of 5 mL / kg.

[1360] 2.5 Sample Collection:

[1361] Blood samples of 0.2 mL were collected from the jugular vein of experimental animals before 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 drug administration. The blood samples were placed in EDTA-2K tubes and centrifuged at 8000 rpm for 6 min at 4 °C to separate the plasma. The plasma was then stored at -80 °C. Animals were fed 4 h after drug administration.

[1362] 3. Experimental Results: The final measurement results were obtained using the LCMS / MS method.

[1363] The compounds of this invention exhibit excellent metabolic behavior in rats, with plasma exposure AUC at a PO dose of 5 mg / kg being [missing value]. 0-∞ The plasma exposure AUC of the preferred compound can reach over 15000 ng / mL*h. 0-∞ It can reach over 50,000 ng / mL*h; the bioavailability can reach over 60%, and the bioavailability of preferred compounds can reach over 90%.

[1364] Test Example 3 Ki Measurement

[1365] The G-402 cell line was used as the host cell for the expression (transient or stable) of enzymes from the human CYP11 family. Specifically, G-402 cell lines stably expressing human CYP11B1 and human CYP11B2 were established. To determine the inhibition constants of the test compounds in CYP11B2 and CYP11B1, cells were incubated for 16 h at different substrate concentrations (CYP11B2 cell line: 0.125–4 μM 11-DOC; CYP11B1 cell line: 0.3125–10 μM 11-deoxycortisol) and different inhibitor concentrations (CYP11B2 cell line: 0–100 nM; CYP11B1 cell line: 0–10000 nM). Product levels (CYP11B2 cell line: aldosterone; CYP11B1 cell line: cortisol) were determined using a CisBio uniform time-resolved fluorescence (HTRF) assay. Ki was determined using the fitting algorithm provided by the GraphPad Prism program.

[1366] The compounds of this invention exhibit a better affinity for CYP11B2, with Ki less than 5 nM, and preferably less than 1 nM. Compared to CYP11B2, the compounds of this invention show greater than 200 times selectivity for CYP11B1, preferably greater than 500 times, and more preferably greater than 2000 times.

[1367] Test Example 4: In vivo efficacy determination

[1368] 1. Experimental Objective

[1369] Evaluate the in vivo PD efficacy of the compound in the monkey ACTH Challenge model.

[1370] 2. Experimental Instruments and Reagents

[1371] 2.1 Instruments

[1372] Refrigerator, biosafety cabinet, clean bench, electric pipette aid, constant temperature water bath, ultrasonic cleaner, pure water system, magnetic stirrer, electronic balance, ultrasonic cell disruptor, LC-MS / MS-BT

[1373] 2.2 Reagents

[1374] ACTH, physiological saline, CMC-Na, Tween 80, HP-β-CD, HPMC

[1375] 3. Experimental Operation and Data Processing

[1376] 3.1 Animals

[1377] Crab-eating macaques.

[1378] 3.2 Animal Model

[1379] After the animals reached the barrier system, they were allowed to acclimatize for 14 days and then given an intravenous injection of ACTH.

[1380] 3.3 Grouping and Administration

[1381] a. Grouping is done using a random grouping method.

[1382] b. Based on the grouping results, begin administering the test drug (administration route: oral administration; administration volume: 5 mL / kg; administration frequency: single dose on the same day, dosage is 0, 0.03, 0.1, 1 mpk; solvent: 0.5% CMC-Na + 1% Tween 80; 20% HP-β-CD + 0.25% HPMC K4M).

[1383] c. One hour after administration, ACTH was injected intravenously to establish the monkey ACTH Challenge model (administration route: intravenous injection; administration volume: 1 mL / kg; administration dose: 5 μg / kg; solvent: physiological saline).

[1384] d. Blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, and 4 hours after administration of the test drug to prepare plasma.

[1385] e. The levels of five related hormones in plasma at each time point were detected by LC / MS-MS.

[1386] f. Use software such as Excel and Graphpad Prism 9 to process the data and perform graphical analysis. Observe the trends in hormone changes, determine the time points when each hormone level is at its highest, and select time points for inter-group comparisons.

[1387] 4. Experimental conclusions:

[1388] In the monkey ACTH Challenge experiment, the compound of the present invention effectively reduced aldosterone levels at doses as low as 0.03 mg / kg. At a dose of 0.03 mg / kg, the aldosterone inhibition rate reached more than 40% 1.5 h after administration, and the preferred compound reached more than 50%. At a dose of 0.1 mg / kg, the aldosterone inhibition rate reached more than 80% 1.5 h after administration. Moreover, it did not cause significant changes in hormones such as cortisol.

[1389] V. Pharmacokinetic Evaluation Experiment of Crab-Eating Mammals

[1390] 1. Research Objective:

[1391] Using cynomolgus monkeys as test animals, the pharmacokinetic behavior of the compound of the present invention in cynomolgus monkey plasma after oral administration at a dose of 3 mg / kg was studied.

[1392] 2. Experimental Design:

[1393] 2.1 Experimental reagents:

[1394] The compounds used in this invention embodiment are self-made.

[1395] 2.2 Laboratory animals:

[1396] Each group of crab-eating macaques consists of 3 males.

[1397] 2.3 Formulation:

[1398] Oral administration preparation: 0.5% CMC-Na (1% Tween 80).

[1399] Weigh 0.5g of CMC-Na (viscosity 800-1200) and 1.0g of Tween 80 into a 100ml volumetric flask, vortex, mix, and sonicate to obtain a clear solution.

[1400] Weigh out the compound of the present invention and add it to a 100mL glass bottle. Add the solution, vortex and sonicate to obtain a white suspension with a concentration of 0.6mg / mL.

[1401] 2.4 Administration:

[1402] Three male cynomolgus monkeys were fasted overnight and then administered orally at a dose of 3 mg / kg in a volume of 5 mL / kg.

[1403] 2.5 Sample Collection:

[1404] Blood collection: 0.3 mL of blood was collected from the forelimb veins of cynomolgus monkeys before and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after drug administration. The blood was placed in EDTA-K2 anticoagulant tubes, centrifuged at 6000 rpm for 6 min at 4°C to separate plasma, and stored at -80°C. The monkeys were fed 4 hours after drug administration.

[1405] 2.6 Sample preparation:

[1406] 1) Add 40 μL of plasma sample to 160 μL of acetonitrile to precipitate, mix, and centrifuge at 3500×g for 5–20 minutes.

[1407] 2) Take the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the analyte. LC / MS / MS instrument: AB Sciex API 4000Qtrap.

[1408] 2.7 Liquid phase analysis:

[1409] ●Liquid phase conditions: Shimadzu LC-20AD pump

[1410] ● Column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm) Mobile phase: Solution A is 0.1% formic acid aqueous solution, Solution B is acetonitrile

[1411] ● Flow rate: 0.4 mL / min

[1412] ●Eluting time: 0-4.0 minutes, eluent as follows:

[1413] 3. Experimental conclusions:

[1414] The compounds of this invention exhibit excellent metabolic behavior in cynomolgus monkeys, with plasma exposure AUC of 3 mg / kg at a PO dose. 0-∞ The plasma exposure AUC of the preferred compound can reach over 7000 ng / mL*h. 0-∞ It can reach over 10,000 ng / mL*h.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: It can be a single bond or a double bond; The ring C is selected from the following groups: Z is selected from CR a Or N; M1, M3, and M4 are selected independently from N and NR in different regions. a , or CR a ; M5 and M6 are selected independently from N, C, or CR in different regions. a ; M2 is a bond, N, or CH; R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, or containing 1-3 4-8 membered heterocyclic amino groups selected from N, O, S, SO2 or SONH -(CH2). n C(O)R b -(CH2) n NR a C(O)R b -(CH2) n OR b -(CH2) n NR a R b -(CH2) n SR b -(CH2) n S(O)2R b -(CH2) n S(O)(NH)R b -(CH2) n NR a S(O)2R b -(CH2) n NR a S(O)(NH)R b Or -(CH2) n NS(O)R a R b Optionally, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from C(O), N, O, S, SO2 or SONH, optionally further containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from C(O), N, O, S, SO2 or SONH, and optionally further containing one or more groups selected from R c Substituents; R c Each is independently selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, -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 Optionally, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, optionally further modified by -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 The substituents in it are replaced; R a Or R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, optionally, the C 3-8 Cycloalkyl, containing 1-3 5-8-membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O or S, further by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 heterocyclic or -SO2-C 1-6 Substituents in alkyl groups; R2 or R3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, C 6-10 aryl, containing 1-3 5-6 membered heteroaryl groups selected from N, O, S, or containing 1-3 4-8 membered heterocyclic groups 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 ; p, x, or y are independently selected from 1, 2, 3, or 4 in each location; n is selected from 0, 1, 2 or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is not N-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazo-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide, (R or S)-N-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazo-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, R1 is independently selected from C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C3-8 cycloalkyloxy groups, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, -C(O)(CH2) n R b -NR a C(O)(CH2) n R b -O(CH2) n R b -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 C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, optionally further further containing one or more groups selected from R c Substituents; R c Each is independently selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, -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 Optionally, the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from C(O), N, O or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O or S, optionally further modified by -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 The substituents in it are replaced.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, R1 is independently selected from C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, -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 or -NR a S(O)(NH)R b Optionally, the C 3-10 Cycloalkyl groups, containing 1-3 4-10 membered heterocyclic groups selected from N, O, S, SO2 or SONH, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino, containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, or containing 1-3 4-8 membered heterocyclic hydroxyl groups selected from N, O, S, SO2 or SONH, further surrounded by one or more 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 The substituents in it are replaced; R a Or R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-3 Alkyl, C 3-8 The cycloalkyl group, containing 1-3 5-8-membered heteroaryl groups selected from N, O, or S, or containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O, or S, optionally, the 5-8-membered heteroaryl group containing 1-3 5-8-membered heteroaryl groups selected from N, O, or S, or the 4-8-membered heterocyclic group containing 1-3 4-8-membered heterocyclic groups selected from C(O), N, O, or S, is further surrounded by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups or -SO2-C 1-3 Substituents in alkyl groups.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, R2 or R3 are each independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1- 3-alkoxy group, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyloxy groups.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, further comprising the compound of general formula (I-1) or a pharmaceutically acceptable salt thereof: Ring C is Z is selected from CR a Or N; M2 and M5 are selected from N, C, or CH; R1 is selected from 3-10 membered cycloalkyl groups, 4-10 membered heterocyclic groups containing 1-3 N, O, S, SO2, or SONH groups, 3-8 membered cycloalkyloxy groups, 3-8 membered cycloalkylamino groups, 4-8 membered heterocyclic oxy groups containing 1-3 N, O, S, SO2, or SONH groups, 4-8 membered heterocyclic amino groups containing 1-3 N, O, S, SO2, or SONH groups, and -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 group, the 4-10 membered heterocyclic group containing 1-3 N, O, S, SO2 or SONH, the 3-8 membered cycloalkyloxy group, the 3-8 membered cycloalkylamino group, the 4-8 membered heterocyclic oxy group containing 1-3 N, O, S, SO2 or SONH, or the 4-8 membered heterocyclic amino group containing 1-3 N, O, S, SO2 or SONH, is further surrounded by one or more groups selected from 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 The substituents in it are replaced; R a Or R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-3 Alkyl, 3-8 membered cycloalkyl, containing 1-3 5-8 membered heteroaryl groups selected from N, O, or S, or containing 1-3 4-8 membered heterocyclic groups selected from C(O), N, O, or S; optionally, the 5-8 membered heteroaryl group containing 1-3 membered heteroaryl groups selected from N, O, or S, or the 4-8 membered heterocyclic group containing 1-3 membered heterocyclic groups selected from C(O), N, O, or S, is further surrounded by one or more groups selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, 3-6 membered cycloalkyl or -SO2-C 1-3 Substituents in alkyl groups; R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-Deuterated Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 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, containing 1-3 5-6 membered heteroaryl groups selected from N, O, S, or containing 1-3 4-8 membered heterocyclic groups 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 is selected from hydrogen, deuterium, halogens, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyloxy groups.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, further comprising the compound of general formula (I-3) to general formula (I-10) or a pharmaceutically acceptable salt thereof: in, Z or M2 are each independently selected from N or CH; R1, R2, x are as described in claim 1.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein general formula (I) is further a compound of general formula (I-2-a), (I-2-b), (I-2-c) or (I-2-d) or a pharmaceutically acceptable salt thereof: in, Z is selected from CH or N; Ring E is independently selected from C. 3-8 Cycloalkyl, containing 1-3 5-6 heteroaryl groups selected from N, O, S, or containing 1-3 4-8 heterocyclic groups selected from C(O), N, O, or S; M1, M2, or M3 are each independently selected from N or CR a ; M7 or M8 are each independently selected from N, C or CH; M9 or M 10 Each is independently selected from O, S, NH or CH2; R1, R2, R a As described in claim 1.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6-8, characterized in that, R1 is independently selected from -(CH2). n C(O)R b -(CH2) n OR b -(CH2) n S(O)2R b -(CH2) n NR a C(O)R b Or -(CH2) n NR a R b ; R a Or R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-3 Alkyl, C 3-6 Cycloalkyl, containing 1-3 4-6 membered heterocyclic groups selected from N, O, S, SO2 or SONH, containing 1-3 5-6 membered heteroaryl groups selected from C(O), N, O or S; optionally, the C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups containing 1-3 C(O), N, O, S, SO2 or SONH, or 5-6 membered heteroaryl groups containing 1-3 C(O), N, O or S, further surrounded by one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl or C 3-6 Substituents in cycloalkyl groups; R2 is independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl.

10. The following compounds or their pharmaceutically acceptable salts:

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

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

13. The use of the compound of the general formula shown in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 11, in the preparation of a medicament for treating diseases related to CYP11B2.

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