Aromatic heterocyclic compound, and preparation method therefor and use thereof

Abstract

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Description

Aromatic heterocyclic compounds and their preparation method and application

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202311781771.4 filed with the State Intellectual Property Office of China on December 22, 2023, and Chinese Patent Application No. 202410850958.3 filed with the State Intellectual Property Office of China on June 28, 2024. The contents disclosed in the above applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to the field of medical technology, and in particular to a class of aromatic heterocyclic compounds and a preparation method and use of the compounds. Background Art

[0004] Hypertension is a worldwide chronic non-communicable disease, a major threat to human health, the leading cause of global disease burden, and a major public health issue facing China. The prevalence of hypertension in my country has been increasing annually, from 5.1% in 1959 to 23.2% in 2015 and 27.5% in 2018. Hypertension prevention and treatment face enormous challenges.

[0005] Antihypertensive drugs are a class of medications that control and treat hypertension. They protect patients from damage to target organs such as the heart, brain, and kidneys caused by long-term high blood pressure, and reduce the risk of major cardiovascular and cerebrovascular diseases such as stroke. Based on their mechanism of action, antihypertensive drugs can be divided into: diuretics, α-blockers, β-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and combination preparations.

[0006] In hypertensive patients treated with ACEIs or ARBs for a long time, the phenomenon of "aldosterone escape" causes a rebound in aldosterone levels after an initial decrease, which is associated with end-organ damage. Mineralocorticoid receptor antagonists (MRAs), after suppressing plasma aldosterone levels, can lead to increased aldosterone levels through compensatory mechanisms, thus limiting their efficacy. Furthermore, the adverse effects of steroidal MRAs are often related to impaired renal function or hyperkalemia, which is particularly detrimental for patients with renal impairment, limiting their clinical application.

[0007] As a component of the renin-angiotensin-aldosterone system (RAAS), aldosterone, in addition to its function in regulating fluid and electrolyte homeostasis, is also a key factor in end-organ damage in various cardiovascular and renal diseases. Increased aldosterone is one of the main causes of sodium and water retention, leading to increased blood volume and, ultimately, hypertension. Furthermore, increased aldosterone can further lead to cardiovascular and renal events such as inflammation, organ damage, and fibrosis. Therefore, lowering aldosterone levels may be an effective strategy for refractory hypertension and diseases caused by increased aldosterone.

[0008] Aldosterone synthase (CYP11B2) is a mitochondrial cytochrome P450 enzyme that derives molecular oxygen and electrons from NADPH via (adrenal) cortical ferredoxin reductase (AdR) and (adrenal) cortical ferredoxin (Adx). It catalyzes a three-step oxidation sequence, converting 11-deoxycorticosterone (11-DOC) to aldosterone via the intermediates corticosterone and 18-hydroxycorticosterone. CYP11B2 is a key enzyme in the final three steps of aldosterone biosynthesis. Inhibiting CYP11B2 can prevent aldosterone formation and reduce circulating plasma levels, potentially offering a promising strategy for treating diseases caused by hyperaldosteronism. Therefore, blocking aldosterone biosynthesis with aldosterone synthase inhibitors has been explored as an alternative approach in recent years, and the development of aldosterone synthase inhibitors is of great significance in the treatment of hypertension.

[0009] Currently, the research and development of CYP11B2 inhibitors is in the clinical development stage. For example, baxdrostat, lorundrostat, and BI-690517 have completed Phase II clinical trials, but no CYP11B2 inhibitor has yet been approved for marketing. Therefore, the discovery of effective and safe CYP11B2 inhibitors remains crucial. Summary of the Invention

[0010] The present application provides a class of compounds with novel structures, pharmaceutical compositions containing the same, preparation methods thereof, and uses thereof as aldosterone synthase (CYP11B2) inhibitors.

[0011] In a first aspect, the present application provides a compound as represented by formula (I), its stereoisomers, tautomers, isotopic derivatives (preferably deuterated derivatives) or pharmaceutically acceptable salts:

[0012] in,

[0013] Ring A is a 5-6 membered heterocyclyl, a 5-6 membered heteroaryl or a phenyl group;

[0014] Ring B is phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

[0015] R A is independently selected at each occurrence from deuterium, halogen, oxo, -CN, -NH2, or optionally substituted: C 1-4 Alkyl, C 1-4 Deuterated alkyl (the deuterated alkyl group is substituted with one or more (eg, 2, 3, 4, 5, 6, 7 or 8) deuterium atoms; preferably C 1-3 Deuterated alkyl, for example, -CD3), C 3-4 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 or, when two R A , and the two R A Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 When the alkylthio group is A Together with the carbon atom to which it is attached, it forms C 3-6 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5 or 6) independently selected from deuterium, halogen (e.g., fluorine, chlorine, bromine), C 1-3 Alkyl (e.g., methyl, ethyl, propyl, isopropyl), C 1-3 Substitution with alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy), hydroxy, or oxo;

[0016] R B is independently selected at each occurrence from deuterium, halogen, oxo, -CN, -NH2, or optionally substituted: C 1-4 Alkyl, C 3-4 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 or, when two R B , and the two R B Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 When the alkylthio group is B Together with the carbon atom to which it is attached, it forms C 3-6 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5 or 6) independently selected from deuterium, halogen (e.g., fluorine, chlorine, bromine), C1-3 Alkyl (e.g., methyl, ethyl, propyl, isopropyl), C 1-3 Substitution with alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy), hydroxy, or oxo;

[0017] Ring C is an optionally substituted 4-8 membered heterocyclyl; wherein optionally substituted means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 Haloalkoxy; the heterocyclic group contains 1 N atom, optionally further contains 1, 2 or 3 heteroatoms, the heteroatoms being independently selected from O, N or S;

[0018] X1 is selected from N and CR X1 ;

[0019] X2 is selected from N and CR X2 ;

[0020] X3 selected from N and CR X3 ;

[0021] The condition is that X1, X2 and X3 are not N at the same time;

[0022] R X1 、R X2 、R X3 Each independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkyl and C 1-3 haloalkoxy;

[0023] L is a bond, -O-, -S-, or an optionally substituted group: -C 0-4 Alkylene-N(R1)-, -C 0-4 Alkylene-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-N(R1)-, -C 0-4 Alkylene-N(R1)-S(O)2-, -C 0-4 Alkylene-C(O)-N(R1)-S(O)2-, -C 0-4 Alkylene-C(O)-N(R1)-, -C0-4 Alkylene-S(O)2-N(R1)-, -C 1-4 Alkylene-, -C 3-6 Cycloalkyl-C 0-4 Alkylene-C(O)-N(R1)-, 3-10 membered heterocyclic-C 0-4 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 alkylthio;

[0024] R1 is selected from hydrogen, deuterium, or an optionally substituted group: C 1-3 Alkyl and C 3-6 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl (preferably C 1-3 Alkyl, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C 1-3 Alkoxy, for example, methoxy, ethoxy) and C 1-4 Alkylthio (preferably C1-3 alkylthio, for example, methylthio, ethylthio);

[0025] R is selected from -N(R2)R3, -S(O)2R4, or is optionally replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R w1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, 5-12 membered heteroaryl, C 6-12 Aryl; wherein R w1 is selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, -C(O)-N(R2)R3, or optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R w2 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4Alkylthio, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl; wherein, R w2 is selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3, -S(O)2R4, -C(O)N(R7)R8, -C(O)OR9, or optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R w3 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 6-10 Aryl, 5-12 membered heteroaryl; wherein, R w3 Selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl, C 1-4 Haloalkyl and C1-4 haloalkoxy;

[0026] R2 and R3 are each independently selected from hydrogen, deuterium, or the following groups which are optionally substituted: 1-6 Alkyl, C 3-6 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl (preferably C 1-3 Alkyl, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C 1-3 Alkoxy, for example, methoxy, ethoxy) and C 1-4 Alkylthio (preferably C 1-3 alkylthio, e.g., methylthio, ethylthio);

[0027] R4 is selected from hydrogen, deuterium, or an optionally substituted group: C 1-3 Alkyl and C 3-6 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl (preferably C 1-3Alkyl, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C 1-3 Alkoxy, for example, methoxy, ethoxy) and C 1-4 Alkylthio (preferably C 1- 3-alkylthio, e.g., methylthio, ethylthio);

[0028] R5 is selected from hydrogen, deuterium, or an optionally substituted group: C 1-3 Alkyl and C 3-6 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl (preferably C 1-3 Alkyl, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C 1-3 Alkoxy, for example, methoxy, ethoxy) and C 1-4 Alkylthio (preferably C 1- 3-alkylthio, e.g., methylthio, ethylthio);

[0029] R6 is selected from hydrogen, deuterium, or an optionally substituted group: C 1-3 Alkyl, C 3-6 Cycloalkyl and C 4-6 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl (preferably C 1-3 Alkyl, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C 1-3 Alkoxy, for example, methoxy, ethoxy) and C 1-4 Alkylthio (preferably C 1-3 alkylthio, e.g., methylthio, ethylthio);

[0030] R7 and R8 are each independently selected from hydrogen, deuterium, or the following optionally substituted groups: C 1-3 Alkyl, C 3-6 Cycloalkyl and C 4-6 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C1-4 Alkyl (preferably C 1-3 Alkyl, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C 1-3 Alkoxy, for example, methoxy, ethoxy) and C 1-4 Alkylthio (preferably C 1-3 alkylthio, e.g., methylthio, ethylthio);

[0031] R9 is selected from hydrogen, deuterium, or an optionally substituted group: C 1-6 Alkyl and C 3-6 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl (preferably C 1-3 Alkyl, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C 1-3 Alkoxy, for example, methoxy, ethoxy) and C 1-4 Alkylthio (preferably C 1- 3-alkylthio, e.g., methylthio, ethylthio);

[0032] a is selected from 0, 1, 2, 3 and 4;

[0033] b is selected from 0, 1, 2, 3 and 4;

[0034] Unless otherwise specified, the heteroatoms in the above heterocyclic or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4;

[0035] The prerequisite is that the definitions of the above variables are combined to form a stable chemical structure.

[0036] In some embodiments,

[0037] R A Each occurrence is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 3-4 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 or, when two R A , and the two R A Each independently selected from C 1-4When the two R A Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0038] R B Each occurrence is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 3-4 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 or, when two R B , and the two R B Each independently selected from C 1-4 When the two R B Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0039] L is a bond, -O-, -S-, or an optionally substituted group: -C 0-4 Alkylene-N(R1)-, -C 0-4 Alkylene-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-N(R1)-, -C 0-4 Alkylene-N(R1)-S(O)2-, -C 0-4 Alkylene-C(O)-N(R1)-, -C 0-4 Alkylene-S(O)2-N(R1)-, -C 1-4 Alkylene-, -C 3-6 Cycloalkyl-C 0-4 Alkylene-C(O)-N(R1)-, 3-10 membered heterocyclic-C 0-4 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio.

[0040] In some embodiments,

[0041] Ring A is a 5-6 membered heterocyclyl, a 5-6 membered heteroaryl or a phenyl group;

[0042] Ring B is phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

[0043] R A Each occurrence is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 3-4 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 or, when two R A , and the two R A Each independently selected from C 1-4 When the two R A Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0044] R B Each occurrence is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 3-4 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 or, when two R B , and the two R B Each independently selected from C 1-4 When the two R B Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0045] Ring C is an optionally substituted 4-8 membered heterocyclyl; wherein optionally substituted means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 Haloalkoxy; the heterocyclic group contains 1 N atom, optionally further contains 1, 2 or 3 heteroatoms, the heteroatoms being independently selected from O, N or S;

[0046] X1 is selected from N and CR X1 ;

[0047] X2 is selected from N and CRX2 ;

[0048] X3 selected from N and CR X3 ;

[0049] The condition is that X1, X2 and X3 are not N at the same time;

[0050] R X1 、R X2 、R X3 Each independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkyl and C 1-3 haloalkoxy;

[0051] L is a bond, -O-, -S-, or an optionally substituted group: -C 0-4 Alkylene-N(R1)-, -C 0-4 Alkylene-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-N(R1)-, -C 0-4 Alkylene-N(R1)-S(O)2-, -C 0-4 Alkylene-C(O)-N(R1)-, -C 0-4 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 alkylthio;

[0052] R1 is selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0053] R is selected from -N(R2)R3, -S(O)2R4, or is optionally replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R w1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, 5-12 membered heteroaryl, C 6-12 Aryl; wherein R w1is selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, or optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R w2 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl; wherein, R w2 is selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3, -S(O)2R4, -C(O)N(R7)R8, -C(O)OR9, or optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R w3 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 6-10 Aryl, 5-12 membered heteroaryl; wherein, R w3 Selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl, C 1-4 Haloalkyl and C 1-4 haloalkoxy;

[0054] R2 and R3 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups;

[0055] R4 is selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0056] R5 is selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0057] R6 is selected from hydrogen, deuterium, C 1-3 Alkyl, C 3-6 Cycloalkyl and C 4-6 heterocyclic group;

[0058] R7 and R8 are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 3-6Cycloalkyl and C 4-6 heterocyclic group;

[0059] R9 is selected from hydrogen, deuterium, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0060] a is selected from 0, 1, 2, 3 and 4;

[0061] b is selected from 0, 1, 2, 3 and 4;

[0062] Unless otherwise specified, the heteroatoms in the above heterocyclyl, heterocycloalkyl or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4;

[0063] The prerequisite is that the definitions of the above variables are combined to form a stable chemical structure.

[0064] In some embodiments, the connection between ring A and ring B is fused (or called fusion, i.e., ring A and ring B share two adjacent atoms), bridged (i.e., ring A and ring B share two non-adjacent atoms), or spiro (i.e., ring A and ring B share one atom); preferably, the connection between ring A and ring B is fused.

[0065] In some embodiments, the compound represented by formula (I), wherein the bicyclic ring system composed of ring A and ring B is When b is not 0, Represents Linking site;

[0066] and / or, Ring A and Ring B are not both 6-membered aromatic ring systems, i.e., when Ring A is phenyl or pyridyl, Ring B is not phenyl or pyridyl;

[0067] And / or, the compound represented by formula (I) is not:

[0068] In some embodiments, in the compound represented by formula (I), ring A and ring B are not both 6-membered aromatic ring systems, that is, when ring A is a phenyl group or a 6-membered heteroaryl group, ring B is not a phenyl group or a 6-membered heteroaryl group.

[0069] In some embodiments, Ring A is a 5-membered heterocyclyl, a 6-membered heterocyclyl, or a phenyl group.

[0070] In some embodiments, Ring A is a 6-membered heteroaryl; preferably, pyridyl.

[0071] In some embodiments, Ring A is a 6-membered heterocyclyl or phenyl;

[0072] Preferably, ring A is a 6-membered heterocyclic group or a phenyl group, wherein the heteroatoms in the heterocyclic group are independently selected from N or O, and the number of heteroatoms is 1, 2 or 3;

[0073] Preferably, ring A is a 6-membered heterocyclic group or a phenyl group, wherein the heteroatoms in the heterocyclic group are independently selected from N, and the number of heteroatoms is 1 or 2;

[0074] Preferably, ring A is piperidinyl or phenyl.

[0075] In some embodiments, ring A is a 6-membered heterocyclic group or a phenyl group, wherein the heteroatoms in the heterocyclic group are independently selected from N or O, and the number of heteroatoms is 1 or 2.

[0076] In some embodiments, ring A is piperidinyl, 1,3-azacyclohexanyl, tetrahydropyrimidinyl, morpholinyl, or phenyl.

[0077] In some embodiments, Ring A is a 5-membered heterocyclic group, wherein the heteroatoms in the heterocyclic group are independently selected from N or S, and the number of heteroatoms is 1 or 2.

[0078] In some embodiments, Ring A is pyrrolidinyl or tetrahydrothiazolyl.

[0079] In some embodiments, Ring B is phenyl, 5-6 membered heterocyclyl;

[0080] Preferably, ring B is a 5-6 membered heterocyclic group or a phenyl group, wherein the heteroatoms in the heterocyclic group are independently selected from N or O, and the number of heteroatoms is 1, 2 or 3;

[0081] Preferably, ring B is a 5-6 membered heterocyclic group or a phenyl group, wherein the heteroatoms in the heterocyclic group are independently selected from N, and the number of heteroatoms is 1 or 2;

[0082] Preferably, ring B is phenyl, piperidinyl or tetrahydropyrrolyl.

[0083] In some embodiments, Ring B is phenyl.

[0084] In some embodiments, Ring B is a 5-6 membered heteroaryl group, wherein the heteroatoms in the heteroaryl group are independently selected from N or S, and the number of heteroatoms is 1 or 2.

[0085] In some embodiments, Ring B is pyrazolyl, imidazolyl, thienyl, thiazolyl, pyrimidinyl, or pyridinyl.

[0086] In some embodiments, Ring A is piperidinyl, 1,3-azacyclohexanyl, tetrahydropyrimidinyl, morpholinyl, pyrrolidinyl, or tetrahydrothiazolyl; Ring B is phenyl. In some embodiments, Ring A is piperidinyl, 1,3-azacyclohexanyl, or pyrrolidinyl, and Ring B is phenyl. In some embodiments, Ring A is phenyl, and Ring B is piperidinyl or tetrahydropyrrolyl.

[0087] In some embodiments, the bicyclic ring system formed by Ring A and Ring B is selected from: Preferably, the bicyclic ring system composed of ring A and ring B is selected from: in, Representation and ring connection site.

[0088] In some embodiments, the bicyclic ring system formed by Ring A and Ring B is selected from:

[0089] in, Representation and ring connection site.

[0090] In some embodiments, R A is independently selected at each occurrence from deuterium, halogen, oxo, -CN, -NH2, or optionally substituted: C 1-3 Alkyl (e.g., methyl, ethyl, propyl, isopropyl), C 1-3 Deuterated alkyl (e.g., -CD3), C 3-4 Cycloalkyl (e.g., cyclopropyl, cyclobutyl), C 1-3 Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy), C 1-3 Haloalkyl (e.g., trifluoromethyl) and C 1-3 Haloalkoxy; or, two R A Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl (preferably C 3-5 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl), 3-7 membered heterocyclyl (preferably 4-6 membered heterocyclyl, for example, 4, 5 or 6 membered heterocyclyl), 5-6 membered heteroaryl or phenyl; wherein the optionally substituted refers to being unsubstituted or substituted by one or more (for example, 2, 3, 4, 5 or 6) independently selected from deuterium, halogen (for example, fluorine, chlorine), C 1-3 Alkyl (e.g., methyl, ethyl, propyl, isopropyl), C 1-3 Substitution with alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy), hydroxy, or oxo;

[0091] Or, R AEach occurrence is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 3-4 Cycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 or, when two R A , and the two R A Each independently selected from C 1-3 When the two R A Together with the carbon atom to which it is attached, it forms a C3-6 cycloalkyl group (preferably C 3-5 Cycloalkyl; more preferably C 3-4 cycloalkyl).

[0092] In some embodiments, R A Each occurrence is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-3 Alkyl, C3-4 cycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 or, when two R A , and the two R A Each independently selected from C 1-3 When the two R A Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl;

[0093] Preferably, R A Each occurrence is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 or, when two R A , and the two R A Each independently selected from C 1-3 When the two R A Together with the carbon atom to which it is attached, it forms C 3-4 Cycloalkyl;

[0094] Preferably, R A Each occurrence is independently selected from deuterium, F, Cl, -CN, methyl, methoxy, cyclopropyl and oxo; or, when two RA , and the two R A Each independently selected from C 1-3 When the two R A Together with the carbon atom to which it is attached, it forms a cyclopropyl group;

[0095] Preferably, R A is independently selected at each occurrence from deuterium, F, Cl, -CN, methyl, methoxy, cyclopropyl, and oxo;

[0096] Preferably, R A are independently selected from deuterium, F, Cl, -CN, methyl, cyclopropyl and oxo at each occurrence; or, when two R A , and the two R A Each independently selected from C 1-3 When the two R A Together with the carbon atom to which it is attached, it forms a cyclopropyl group;

[0097] Preferably, R A and - is independently selected at each occurrence from deuterium, F, Cl, -CN, methyl, cyclopropyl, and oxo.

[0098] In some embodiments, R A Each occurrence is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-3 Alkyl, C1-3 deuterated alkyl, C 3-4 Cycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 or, when two R A When the two R A Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl.

[0099] In some embodiments, R A Each occurrence is independently selected from halogen, oxo, -CN, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 3-4 Cycloalkyl and C 1-3 Alkoxy; or, when two R A When the two R A Together with the carbon atom to which it is attached, it forms C 3-4 Cycloalkyl.

[0100] In some embodiments, RA Each occurrence is independently selected from F, Cl, -CN, methyl, deuterated methyl (ie, -CD3), methoxy, cyclopropyl and oxo, or when two R are attached to the same carbon atom of the 5-6 membered heterocyclic group A When the two R A Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

[0101] In some embodiments, R B Each occurrence is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-3 Alkyl, C3-4 cycloalkyl, C 1-3 Haloalkyl and C 1-3 or, when two R B , and the two R B Each independently selected from C 1-3 When the two R B Together with the carbon atom to which it is attached, it forms C 3-4 Cycloalkyl;

[0102] Preferably, R B Each occurrence is independently selected from deuterium, F, Cl, -CN, methyl, cyclopropyl and oxo; or, when two R B , and the two R on the same carbon atom of the 5-6 membered heterocyclic group B Each independently selected from C 1-3 When the two R B Together with the carbon atom to which it is attached, it forms C 3-4 Cycloalkyl (preferably cyclopropyl).

[0103] In some embodiments, R B Each occurrence is independently selected from halogen, oxo or C 1-3 Alkyl; or, when two R B When the two R B Together with the carbon atom to which it is attached, it forms C 3-4 Cycloalkyl.

[0104] In some embodiments, R B Each occurrence is independently selected from F, Cl, methyl and oxo; or, when two R B When the two R B Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

[0105] In some embodiments, Selected from: Preferably, Selected from:

[0106] In some embodiments, Selected from:

[0107] In some embodiments, Selected from:

[0108] In some embodiments, Selected from:

[0109] In some embodiments, Ring C is an optionally substituted 5-8 membered heterocyclyl (e.g., 5-membered, 6-membered, 7-membered, 8-membered); preferably, Ring C is selected from optionally substituted: Preferably, Ring C is selected from optionally substituted: Preferably, Ring C is selected from optionally substituted: in, Representatives and Rings The connection site, Represents the attachment site to L;

[0110] Wherein, the optional substitution refers to being unsubstituted or being substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -NH2, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

[0111] In some embodiments, Ring C is selected from: In some embodiments, Ring C is selected from: In some embodiments, Ring C is in, Representatives and Rings The connection site, Represents the connection site with L.

[0112] In some embodiments, Ring C is an optionally substituted 5-6 membered heterocyclyl;

[0113] Wherein, the optional substitution refers to being unsubstituted or being substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -NH2, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 wherein the heterocyclic group contains 1 N atom and optionally further contains 1, 2 or 3 heteroatoms independently selected from O, N or S; preferably, the optional substitution refers to being unsubstituted or substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -NH2, -OH, methyl, methoxy, methylthio, halomethyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, dichloromethyl, trichloromethyl), halomethoxy (e.g., monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monochloromethoxy, dichloromethoxy and trichloromethoxy); wherein the heterocyclic group contains 1 N atom and optionally further contains 1, 2 or 3 heteroatoms independently selected from O, N or S; preferably, the heterocyclic group contains 1 or 2 N atoms;

[0114] Preferably, ring C is piperidinyl, piperazinyl or tetrahydropyrrolyl.

[0115] In some embodiments, Ring C is in, represents the attachment site to L, Representatives and Rings connection site.

[0116] In some embodiments, X1 is CR X1 ; X2 is CR X2 ; X3 is CR X3 .

[0117] In some embodiments, X1 is CR X1 ; X2 is N; X3 is CR X3 .

[0118] In some embodiments, X1 is CR X1 ; X2 is CR X2 ;X3 is N.

[0119] In some embodiments, X1 is CR X1 ; X2 is N; X3 is N.

[0120] In some embodiments, R X1 、R X2 、R X3are each independently selected from hydrogen, deuterium, F, Cl, Br, -CN and -NH2; preferably, R X1 、R X2 、R X3 are each independently selected from hydrogen.

[0121] In some embodiments, the structural fragment for Preferably, for in, represents the attachment site to ring B, Represents the attachment site to ring C.

[0122] In some embodiments, the structural fragment for Preferably, for in, represents the attachment site to ring B, Represents the attachment site to ring C.

[0123] In some embodiments, L is a bond, -O-, or an optionally substituted group: -C 0-4 Alkylene-N(R1)-, -C 0-4 Alkylene-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-N(R1)-, -C 0-4 Alkylene-C(O)-N(R1)-S(O)2-, -C 0-4 Alkylene-C(O)-N(R1)-, -C 1-4 Alkylene-, -C 3-6 Cycloalkyl-C 0-4 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio.

[0124] In some embodiments, L is a bond, -O-, or an optionally substituted group: -C 0-2 Alkylene-N(R1)-, -C 0-2 Alkylene-C(O)-, -C 0-2 Alkylene-N(R1)-C(O)-, -C 0-2Alkylene-N(R1)-C(O)-N(R1)-, -C 0-2 Alkylene-C(O)-N(R1)-S(O)2-, -C 0-2 Alkylene-C(O)-N(R1)-, -C 1-4 Alkylene-, -C 3-4 Cycloalkyl-C 0-2 wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4) substituents, each of which is independently selected from deuterium, halogen, oxo, and C 1-3 alkyl.

[0125] In some embodiments, L is a bond, -O-, -C(O)-, -N(R1)-C(O)-, -C(O)-N(R1)-, -methylene-C(O)-N(R1)-, -C 1-3 Alkylene-, -N(R1)-C(O)-N(R1)-, -methylene-C(O)-N(R1)-S(O)2-, -methylene-C(O)-, -ethylene-C(O)-N(R1)-, -cyclopropyl-C(O)-N(R1)-, or -ethylene-N(R1)-C(O)-N(R1)-, wherein each R1 is independently H or methyl, and the methylene and ethylene are each independently optionally substituted with 1 or 2 deuterium or methyl groups.

[0126] In some embodiments, L is a bond, -O-, or an optionally substituted group: -C 0-4 Alkylene-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-, -C 0-4 Alkylene-C(O)-N(R1)-, -C 0-4 Alkylene-N(R1)-C(O)-N(R1)-, -C 0-4 Alkylene-N(R1)-S(O)2-, -C 0-4 Alkylene-S(O)2-N(R1)-; wherein the optional substitution refers to being unsubstituted or being substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 substituted by a substituent of an alkylthio group;

[0127] Preferably, L is a bond, -O-, or an optionally substituted group: -C 0-2 Alkylene-C(O)-, -C 0-2 Alkylene-N(R1)-C(O)-, -C 0-2 Alkylene-C(O)-N(R1)-, -C0-2 Alkylene-N(R1)-C(O)-N(R1)-, -C 0-2 Alkylene-N(R1)-S(O)2-, -C 0-2 Alkylene-S(O)2-N(R1)-; wherein the optional substitution refers to being unsubstituted or being substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-3 Alkyl and C 1-3 substituted by an alkoxy substituent;

[0128] Preferably, L is a bond, -O-, -C(O)-, -N(R1)-C(O)-, -C(O)-N(R1)-, or an optionally substituted group consisting of -methylene-C(O)-, -ethylene-C(O)-, -methylene-N(R1)-C(O)-, -ethylene-N(R1)-C(O)-, -methylene-C(O)-N(R1)-, -ethylene-C(O)-N(R1)-, -N(R1) -C(O)-N(R1)-、-N(R1)-S(O)2-、-methylene-N(R1)-C(O)-N(R1)-、-methylene-N(R1)-S(O)2-、-methylene-S(O)2-N(R1)-、-ethylene-S(O)2-N(R1)-;Wherein, the optional substitution means unsubstituted or substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-3 Alkyl (eg, methyl, ethyl) and C 1-3 The alkoxy group (e.g., methoxy) is substituted with a substituent.

[0129] In some embodiments, L is optionally substituted with: -C 1-3 Alkylene-, -C 3-6 Cycloalkyl-C 0-4 Alkylene-C(O)-N(R1)-, 3-10 membered heterocyclic-C 0-4 Alkylene-C(O)-N(R1)-; preferably, L is an optionally substituted group: -C 1-3 Alkylene-, -C 3-6 Cycloalkyl-C 0-2 Alkylene-C(O)-N(R1)-, 3-8 membered heterocyclic-C 0-2 Alkylene-C(O)-N(R1)-; further preferably, L is the following group which is optionally substituted: -C 1-3 Alkylene-, -C 3-4 Cycloalkyl-C(O)-N(R1)-, -C 3-4Cycloalkyl-methylene-C(O)-N(R1)-, 4-8 membered heterocyclyl-C(O)-N(R1)-, 4-8 membered heterocyclyl-methylene-C(O)-N(R1)-; further preferably, L is an optionally substituted group: -methylene-;

[0130] Wherein, the optional substitution refers to being unsubstituted or being substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Preferably, the optional substitution refers to being unsubstituted or being substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-3 Alkyl (eg, methyl, ethyl) and C 1-3 The alkoxy group (e.g., methoxy) is substituted with a substituent.

[0131] In some embodiments, R1 is selected from hydrogen, deuterium, and C 1-3 alkyl;

[0132] Preferably, R1 is selected from hydrogen, deuterium, methyl and ethyl;

[0133] More preferably, R1 is selected from hydrogen.

[0134] In some embodiments, L is a bond, -O-, Methylene, ethylene, propylene, Preferably, among these groups, the left side is connected to ring C.

[0135] In some embodiments, L is a bond, -O-,

[0136] In some embodiments, L is a bond, -O-, Methylene, ethylene, propylene, -C(O)- or -S(O)2-; preferably, in these groups, the left side is connected to the ring C.

[0137] In some embodiments, L is a bond, -O-,

[0138] In some embodiments, L is a bond, Methylene, propylene, -S(O)2-、-C(O)-、

[0139] In some embodiments, L is a bond,

[0140] In some embodiments, R is -N(R2)R3, -S(O)2R4, or is optionally substituted with one or more R w1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, 6-12 membered aryl; wherein, R w1 is selected from deuterium, halogen, oxo, -CN, -OH, -NR2R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, or optionally substituted by one or more R w2 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl; wherein, R w2 is selected from deuterium, halogen, oxo, -CN, -OH, -NR2R3, -S(O)2R4, -C(O)NR7R8, -C(O)OR9, or optionally substituted by one or more R w3 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 6-10 substituted by an aryl group or a 5-12 membered heteroaryl group; R w3 Selected from deuterium, halogen, oxo, -CN, -OH, -NR2R3, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 Halogenated alkoxy.

[0141] In some embodiments, R is -N(R2)R3, -S(O)2R4, or is optionally substituted with one or more R w1 Substituted with the following groups: C 1-4 Alkyl, C 3-8 Cycloalkyl (e.g., 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered), 4-10-membered heterocyclyl (e.g., 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered), 5-10-membered heteroaryl (e.g., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered); wherein R w1 is selected from deuterium, halogen (e.g., F, Cl), oxo, -OH, -N(R2)R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, or optionally substituted by one or more R w2Substituted with the following groups: C 1-4 Alkyl (e.g., 1, 2, 3, 4), C 1-4 Alkoxy (preferably C 1-3 substituted by a substituent of an alkoxy group, for example, a methoxy group, an ethoxy group), a 3-8 membered heterocyclic group (preferably a 4-7 membered heterocyclic group, more preferably a 4-6 membered heterocyclic group, more preferably a 5-6 membered heterocyclic group), a phenyl group, or a 5-6 membered heteroaryl group; R w2 is selected from deuterium, halogen (e.g., F, Cl), oxo, -N(R2)R3, -S(O)2R4, -C(O)N(R7)R8, -C(O)OR9, or optionally substituted by one or more R w3 Substituted with the following groups: C 1-3 Alkyl (e.g., methyl, ethyl), C 1-3 Alkoxy (e.g., methoxy, ethoxy), 5-6 membered heteroaryl substituents; R w3 Selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3 and C 1-3 Alkyl (eg, methyl, ethyl).

[0142] In some embodiments, R2 and R3 are independently selected from hydrogen, deuterium and C 1-4 alkyl.

[0143] In some embodiments, R4 is selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-4 Cycloalkyl.

[0144] In some embodiments, R5 is selected from hydrogen, deuterium, and C 1-3 alkyl.

[0145] In some embodiments, R6 are each independently selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0146] In some embodiments, R7 and R8 are independently selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0147] In some embodiments, R9 is selected from hydrogen, deuterium, and C 1-4 alkyl.

[0148] In some embodiments, R2 and R3 are independently selected from hydrogen, deuterium and C 1-3 alkyl;

[0149] R4 is selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-4 Cycloalkyl;

[0150] R5 is selected from hydrogen, deuterium and C 1-3 alkyl;

[0151] R6 are independently selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0152] R7 and R8 are independently selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0153] R9 is selected from hydrogen, deuterium and C 1-4 alkyl.

[0154] In some embodiments, R is -N(R2)R3, -S(O)2R4, or is optionally substituted with one or more R w1 Substituted with the following groups: C 1-4 Alkyl, C 3-12 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; wherein R w1 is selected from deuterium, halogen, oxo, -OH, -N(R2)R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, or optionally substituted by one or more R w2 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, 3-10 membered heterocyclic group, C 6-10 substituted by an aryl group or a 5-10 membered heteroaryl group; R w2 is selected from deuterium, halogen, oxo, -N(R2)R3, -S(O)2R4, -C(O)N(R7)R8, -C(O)OR9, or optionally substituted by one or more R w3 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, phenyl, 5-6 membered heteroaryl substituents substituted; R w3 Selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 alkylthio;

[0155] R2 and R3 are independently selected from hydrogen, deuterium and C 1-3 alkyl;

[0156] R4 is selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-4 Cycloalkyl;

[0157] R5 is selected from hydrogen, deuterium and C 1-3 alkyl;

[0158] R6 are independently selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0159] R7 and R8 are independently selected from hydrogen, deuterium, C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0160] R9 is selected from hydrogen, deuterium and C 1-4 alkyl.

[0161] In some embodiments, R is -N(R2)R3, -S(O)2R4, or is optionally substituted with one or more R w1 Substituted with the following groups: C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; wherein R w1 is selected from deuterium, halogen, oxo, -OH, -N(R2)R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, or optionally substituted by one or more R w2 Substituted with the following groups: C 1-4 Alkyl, C 1-4 substituted by an alkoxy group, a 3-8 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group; R w2 is selected from deuterium, halogen, oxo, -N(R2)R3, -S(O)2R4, -C(O)N(R7)R8, -C(O)OR9, or optionally substituted by one or more R w3 Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, 5-6 membered heteroaryl substituents; R w3 Selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3 and C 1-3 alkyl;

[0162] R2 and R3 are independently selected from hydrogen, deuterium, methyl, ethyl and isopropyl;

[0163] R4 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl and cyclopropyl;

[0164] R5 is selected from hydrogen, deuterium, methyl and ethyl;

[0165] R6 are each independently selected from hydrogen, deuterium, methyl and ethyl;

[0166] R7 and R8 are independently selected from hydrogen, deuterium, methyl and ethyl;

[0167] R9 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl and tert-butyl.

[0168] In some embodiments, R is -N(R2)R3, -S(O)2C 1-3 Alkyl, or is optionally substituted by one or more (eg, 2 or 3) R w1 Substituted groups: cyclohexyl, pyridyl, piperidyl, n-propyl, isopropyl, pyrazolyl, pyrrolidinyl, methyl, Piperazine, Azetidine, Cyclobutane, Cyclopropyl, Morpholinyl, oxetane, and tert-butyl; wherein R w1 Selected from, optionally with one or more (eg, 2 or 3) R w2 Substituted with the following groups: -NH-C(O)-CH3, -OH, methyl, -N(CH3)2, oxo, morpholinyl, -S(O)2CH3, piperidinyl, -NH-C(O)-CH(CH3)2, methoxy, Ethyl, pyrimidinyl, -NH-C(O)-cyclopropyl, piperazinyl, methoxy, fluoro, -C(O)OC(CH3)3, -S(O)2cyclopropane, -S(O)2C2H5 and -S(O)2CH3; R w2 Selected from fluorine, oxo, methyl, methoxy.

[0169] In some embodiments, R is

[0170] In some embodiments, R is -CH3,

[0171] In some embodiments, R is

[0172] In some embodiments, R is

[0173] In some embodiments, R is

[0174] In some embodiments, R is

[0175] In some embodiments, a is selected from 0, 1, and 2; preferably, a is 2.

[0176] In some embodiments, b is selected from 0, 1, 2, and 3; preferably, b is selected from 0 and 3.

[0177] In some embodiments, the compound represented by formula (I) is a compound represented by formula (II-1) or formula (II-2):

[0178] Among them, ring A, ring B, R A 、R B , X1, X2, X3, L, R, a, and b are as described for the compound of formula (I);

[0179] Y is N, CR Y ;

[0180] R Y Selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Halogenated alkoxy.

[0181] In some embodiments, R Y is selected from hydrogen and deuterium; preferably, R Y For hydrogen.

[0182] In some embodiments, Y is N.

[0183] In some embodiments, Y is CH.

[0184] In some embodiments, the compound represented by formula (I) is a compound represented by formula (II-3) or formula (II-4):

[0185] Among them, ring A, ring B, R A 、R B , X1, X2, X3, L, R, a, and b are as described for the compound of formula (I);

[0186] Y is N, CR Y ;

[0187] R Y Selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Halogenated alkoxy.

[0188] In some embodiments, ring A is a 5-6 membered heterocyclic group, wherein the heteroatoms in the heterocyclic group are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3; preferably, ring A is a 5-6 membered heterocycloalkyl group, wherein the heteroatoms in the heterocycloalkyl group are independently selected from O or N, and the number of heteroatoms is 1 or 2; further preferably, ring A is piperidinyl, 1,3-azacyclohexane or pyrrolidinyl; further preferably, ring A is More preferably, for More preferably, for

[0189] In some embodiments, ring B is a 5-6 membered heterocyclic group, wherein the heteroatoms in the heterocyclic group are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3; preferably, ring B is a 5-6 membered heterocycloalkyl group, wherein the heteroatoms in the heterocycloalkyl group are independently selected from O or N, and the number of heteroatoms is 1 or 2; further preferably, ring B is pyrrolidinyl; further preferably, ring B is More preferably, for More preferably, for

[0190] In some embodiments, the compound represented by formula (I) is a compound represented by formula (III-1), formula (III-2), formula (III-3) or formula (III-4):

[0191] Among them, R A 、R B , X1, X2, X3, L, R, a, b, and Y are as described in the compound represented by formula (I), formula (II-1) or formula (II-2).

[0192] In some embodiments, the compound represented by formula (I) is a compound represented by formula (IV-A), formula (IV-B) or formula (IV-C):

[0193] Among them, R A 、R B , X1, X2, X3, Y, R, a, and b are as described for the compound of formula (I), formula (II-1) or formula (II-2);

[0194] R a 、R b are independently selected from hydrogen, deuterium and C 1-4 alkyl.

[0195] In some embodiments, the compound represented by formula (I) is a compound represented by formula (IV-1), formula (IV-2) or formula (IV-3):

[0196] Among them, R A 、R B , X1, X2, X3, Y, R, a, and b are as described in the compound of formula (I), formula (II-1) or formula (II-2).

[0197] In some embodiments, R is

[0198] In some embodiments, R is

[0199] In some embodiments, R is

[0200] In some embodiments, the compound represented by formula (I) is a compound represented by formula (V):

[0201] Wherein, X3, R, are as described for the compound of formula (I), formula (II-1) or formula (II-2);

[0202] R a 、R b are independently selected from hydrogen, deuterium and C 1-4 alkyl;

[0203] R A Selected from hydrogen, C 1-3 Alkyl (e.g., methyl), deuterated methyl (-CD3), cyclopropyl.

[0204] In some embodiments, the compound represented by formula (I) is a compound represented by formula (A):

[0205] Wherein, X3, R, are as described for the compound of formula (I), formula (II-1) or formula (II-2);

[0206] R a 、R b are independently selected from hydrogen, deuterium and C 1-4 alkyl.

[0207] In some embodiments, Selected from: Ring C is for L is R is

[0208] In a second aspect, the present application provides the following compounds, or stereoisomers, tautomers, isotopic derivatives (preferably deuterated derivatives) or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0209] In a third aspect, the present application provides a method for preparing a compound represented by formula (I):

[0210] These include but are not limited to the following methods:

[0211] General preparation method 1:

[0212] (a) and (b) are reacted by substitution reaction or Buchwald–Hartwig coupling reaction to obtain a compound represented by formula (I), wherein X4 is a halogen, preferably Cl or Br; the definitions of other substituents are as defined for the compound represented by formula (I), formula (II-1) or formula (II-2).

[0213] General preparation method 2:

[0214] (a1) and (b1) are subjected to a Suzuki reaction to obtain an intermediate (c1), wherein X4 and X5 are halogens, preferably Cl and Br; (c1) and (d1) are subjected to a substitution reaction or a Buchwald–Hartwig coupling reaction to obtain a compound represented by formula (III-1), and the definitions of other substituents are as defined for the compounds represented by formula (I), formula (II-1) or formula (II-2).

[0215] General preparation method three:

[0216] (a2) and (b1) are reacted by substitution reaction or metal-catalyzed coupling reaction to obtain intermediate (c2), wherein X4 is halogen or OSO2CF3, and X5 is halogen, preferably Cl or Br; (c2) and (d1) are reacted by substitution reaction or Buchwald–Hartwig coupling reaction to obtain the compound represented by formula (III-2), and the definitions of other substituents are as described above.

[0217] The compounds represented by formula (I) described in the present application can refer to the above general preparation method, and / or be combined with similar preparation methods described in the literature (for example, Liu, Yongfu; et al., Journal of Medicinal Chemistry (2020), 63(13), 6876-6897., WO2013079452A1, etc.).

[0218] In a fourth aspect, the present application provides a pharmaceutical composition comprising the compound described in the first aspect of the present application (Formula (I), Formula (II-1), Formula (II-2), Formula (II-3), Formula (II-4), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-A), Formula (IV-B), Formula (IV-C), Formula (IV-1), Formula (IV-2), Formula (IV-3), Formula (V), a compound shown in Formula (A) or Compound 1-196) or the compound described in the second aspect, or its tautomer, stereoisomer, pharmaceutically acceptable salt, or isotopic derivative (preferably a deuterated derivative) thereof. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0219] In the fifth aspect, the present application provides the compound described in the first aspect of the present application (Formula (I), Formula (II-1), Formula (II-2), Formula (II-3), Formula (II-4), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-A), Formula (IV-B), Formula (IV-C), Formula (IV-1), Formula (IV-2), Formula (IV-3), Formula (V), the compound represented by Formula (A) or Compound 1-196) or the compound described in the second aspect, or its tautomer, stereoisomer, pharmaceutically acceptable salt, isotopic derivative (preferably a deuterated derivative) or the pharmaceutical composition described in the fourth aspect as a drug or in the preparation of Preferably, the drug is a drug used as a CYP11B2 inhibitor; further preferably, the drug is a drug used to prevent and / or treat CYP11B2-mediated diseases; further preferably, the drug is used to treat and / or prevent diseases or conditions caused by increased aldosterone; further preferably, the drug is a drug used to treat and / or prevent cardiovascular and cerebrovascular diseases or kidney disease; further preferably, the drug is a drug used to treat and / or prevent hypertension, hyperaldosteronism, Cushing's disease, heart failure or chronic kidney disease; further preferably, the drug is a drug used to treat and / or prevent refractory hypertension, primary aldosteronism hypertension, primary aldosteronism, heart failure or chronic kidney disease.

[0220] In some embodiments, the compound described in the first aspect (Formula (I), Formula (II-1), Formula (II-2), Formula (II-3), Formula (II-4), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-A), Formula (IV-B), Formula (IV-C), Formula (IV-1), Formula (IV-2), Formula (IV-3), Formula (V), a compound represented by Formula (A) or Compound 1-196) or the compound described in the second aspect, or its tautomer Use of a deuterated isomer, a stereoisomer, a pharmaceutically acceptable salt, an isotopic derivative (preferably a deuterated derivative) thereof, or the pharmaceutical composition according to the fourth aspect in the preparation of a medicament for treating and / or preventing cardiovascular and cerebrovascular diseases or kidney disease; further preferably, the medicament is a medicament for treating and / or preventing hypertension, hyperaldosteronism, Cushing's disease, heart failure or chronic kidney disease; further preferably, the medicament is a medicament for treating and / or preventing refractory hypertension, primary aldosteronism hypertension, primary aldosteronism, Cushing's disease, heart failure or chronic kidney disease.

[0221] In the sixth aspect, the present application provides the compound described in the first aspect (Formula (I), Formula (II-1), Formula (II-2), Formula (II-3), Formula (II-4), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-A), Formula (IV-B), Formula (IV-C), Formula (IV-1), Formula (IV-2), Formula (IV-3), Formula (V), the compound represented by Formula (A) or Compound 1-196) or the compound described in the second aspect, or its tautomer , stereoisomers, pharmaceutically acceptable salts, isotopic derivatives (preferably deuterated derivatives) or the pharmaceutical composition according to the fourth aspect, which are used to prevent and / or treat a disease; preferably, the disease is a CYP11B2-mediated disease; preferably, the disease is a cardiovascular and cerebrovascular disease or a kidney disease; further preferably, the disease is hypertension, aldosteronism, Cushing's disease, heart failure or chronic kidney disease; further preferably, the disease is refractory hypertension, primary aldosteronism hypertension, Cushing's disease, primary aldosteronism, heart failure or chronic kidney disease.

[0222] In some embodiments, the compound of the first aspect (Formula (I), Formula (II-1), Formula (II-2), Formula (II-3), Formula (II-4), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-A), Formula (IV-B), Formula (IV-C), Formula (IV-1), Formula (IV-2), Formula (IV-3), Formula (V), a compound represented by Formula (A) or Compound 1-196) or the compound of the second aspect, or its tautomer, stereoisomer, pharmaceutically acceptable salt, isotopic derivative (preferably a deuterated derivative) or the pharmaceutical composition of the fourth aspect, is used to prevent and / or treat a disease; preferably, the disease is cardiovascular and cerebrovascular disease or kidney disease; further preferably, the disease is hypertension, hyperaldosteronism, Cushing's disease, heart failure or chronic kidney disease; further preferably, the disease is refractory hypertension, primary aldosteronism hypertension, Cushing's disease, primary aldosteronism, heart failure or chronic kidney disease.

[0223] In a seventh aspect, the present application provides a method for treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the first aspect (Formula (I), Formula (II-1), Formula (II-2), Formula (II-3), Formula (II-4), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-A), Formula (IV-B), Formula (IV-C), Formula (IV-1), Formula (IV-2), Formula (IV-3), Formula (V), a compound represented by Formula (A), or Compound 1-196) Or the compound described in the second aspect, or its tautomer, stereoisomer, pharmaceutically acceptable salt, isotope derivative (preferably a deuterated derivative) or the pharmaceutical composition described in the fourth aspect; preferably, the disease is a CYP11B2-mediated disease; further preferably, the disease is a cardiovascular and cerebrovascular disease or a kidney disease; further preferably, the disease is hypertension, aldosteronism, Cushing's disease, heart failure or chronic kidney disease; further preferably, the disease is refractory hypertension, primary aldosteronism hypertension, Cushing's disease, primary aldosteronism, heart failure or chronic kidney disease.

[0224] In some embodiments, the present application provides a method for treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect (Formula (I), Formula (II-1), Formula (II-2), Formula (II-3), Formula (II-4), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-A), Formula (IV-B), Formula (IV-C), Formula (IV-1), Formula (IV-2), Formula (IV-3), Formula (V), Formula (A) or compound 1-196) or the compound described in the second aspect, or its tautomer, stereoisomer, pharmaceutically acceptable salt, isotope derivative (preferably a deuterated derivative) or the pharmaceutical composition described in the fourth aspect; preferably, the disease is cardiovascular and cerebrovascular disease or kidney disease; further preferably, the disease is hypertension, aldosteronism, Cushing's disease, heart failure or chronic kidney disease; further preferably, the disease is refractory hypertension, primary aldosteronism hypertension, Cushing's disease, primary aldosteronism, heart failure or chronic kidney disease.

[0225] definition

[0226] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0227] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0228] When any variable (such as R A ) occurs more than once in the composition or structure of a compound, its definition is independent on each occurrence. Thus, for example, if a group, a site or an atom is represented by two R A is replaced, then each R A There are independent options.

[0229] -N(R1)- in this article refers to in refers to the attachment site; -N(R2)R3 refers to in Refers to the attachment site.

[0230] In this article, -C(O)- refers to in Refers to the attachment site; -C(O)N(R7)R8 herein refers to in Refers to the attachment site; -C(O)OR9 herein refers to in refers to the attachment site; -S(O)- in this article refers to in Refers to the attachment site; -S(O)2- in this article refers to in Refers to the attachment site; -S(O)2R4 herein refers to in Refers to the attachment site.

[0231] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl), more preferably containing 1-6 carbon atoms (ie C 1-6 alkyl), more preferably containing 1 to 4 carbon atoms (i.e., C 1-4 Alkyl), more preferably containing 1-3 carbon atoms (ie C 1-3 Alkyl), such as "C 1- "6-alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0232] Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I; preferably F, Cl, Br; more preferably F, Cl.

[0233] The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms (e.g., 3, 4, 5, 6, 7, 8) or all hydrogen atoms are replaced by halogen, such as C 1-6 Alkyl substituted by halogen means C 1-6 Haloalkyl, for example: CCl3, CH2F, CHF2, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, etc.

[0234] The term "haloalkoxy" refers to an alkoxy group as defined above in which one, two or more hydrogen atoms (e.g., 3, 4, 5, 6, 7, 8) or all hydrogen atoms are substituted with halogen. A haloalkoxy group may be optionally substituted as defined herein for each individual moiety.

[0235] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl, or 3-12 membered cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl), further preferably 3-6 carbon atoms (C 3-6 Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

[0236] Unless otherwise specified, the term "alkoxy" refers to an alkyl residue in which one or more carbon atoms (and their associated hydrogen atoms) are replaced by oxygen, such as "alkoxy." Examples include methoxy, ethoxy, propoxy, and the like.

[0237] Unless otherwise specified, the term "alkylthio" refers to an "alkoxy" group in which the oxygen radical is replaced by sulfur or nitrogen.

[0238] Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon substituent, which is a non-aromatic structure and contains 3-20 ring atoms, of which 1, 2, 3 or more (e.g., 4, 5, 6, 7, 8) ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, it contains 3-14 ring atoms, 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused (or fused) and bridged heterocyclic groups. The heterocyclic group can be attached (e.g., bridged, spiro- or fused (or fused)) to other cyclic groups (including cycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl), but the point of attachment to the parent group must be on a carbon atom or heteroatom of the heterocyclic group. Each heterocyclic group or other cyclic group may be optionally substituted as defined herein for each individual moiety.

[0239] The term "heterocycloalkyl" refers to a saturated "heterocyclyl" as defined above, comprising 3-20 ring atoms, wherein 1, 2, 3 or more (e.g., 4, 5, 6, 7, 8) ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, it comprises 3-14 ring atoms, 3-12 ring atoms, further preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Bicyclic or polycyclic heterocycloalkyls include spirocyclic, fused (or fused) and bridged heterocycloalkyls. The heterocycloalkyl group may be attached (e.g., bridged, spiro, or fused (or juxtaposed)) to other cyclic groups (including cycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl), but the point of attachment to the parent group must be on a carbon atom or heteroatom of the heterocycloalkyl group. Each heterocycloalkyl group or other cyclic group may be optionally substituted as defined herein for each individual moiety.

[0240] Unless otherwise specified, the term "aryl" refers to a monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6-16 carbon atoms (6-16 membered aryl), or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms, and the term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl or pyrenyl, etc. "Aryl" also includes ring systems in which aryl as defined above is fused or combined with one or more cycloalkyl, heterocyclyl or heteroaryl groups, but the point of attachment to the parent must be on a carbon atom of the aryl group. Each aryl or other cyclic group may be optionally substituted as defined herein for each individual moiety.

[0241] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic or polycyclic ring system containing a 5-16 membered structure, or a 5-14 membered structure, a 5-12 membered structure, a 5-10 membered structure, a 5-8 membered structure, or a 5-6 membered structure, wherein 1, 2, 3 or more (e.g., 4, 5, 6, 7 or 8) ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2, 3 or 4; the number of heteroatoms is more preferably 1, 2 or 3. Examples of heteroaryl groups can include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzo [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc. "Heteroaryl" also includes ring systems in which a heteroaryl as defined above is fused or joined to one or more cycloalkyl, heterocyclyl or aryl groups, but the point of attachment to the parent group must be on an atom of the heteroaryl group. Each aryl or other cyclic group may be optionally substituted as defined herein for each individual moiety.

[0242] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with mammalian tissues, particularly human tissues, without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. Such salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting a free base or free acid with a suitable reagent.

[0243] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include optical isomers, enantiomers, diastereomers, conformers (rotamers), geometric isomers (or cis / trans isomers), atropisomers, and the like. Any resulting mixture of stereoisomers can be separated into pure or substantially pure optical isomers, geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0244] Unless otherwise specified, the term "tautomer" refers to structural isomers of different energies that are interconvertible through a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via reorganization of some of the bonding electrons.

[0245] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, individual stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0246] The compounds of the present invention also include their isotopic derivatives. Unless otherwise specified, the term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically labeled or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest atom found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2H), substitution can enhance metabolic stability and prolong half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds. Isotope derivatives are preferably deuterated derivatives.

[0247] Unless otherwise specified, the term "optionally substituted" means that the hydrogen at the substitutable position of the group is not replaced or is replaced by one or more substituents, wherein the substituents are preferably selected from the following groups: halogen, hydroxy, thiol, cyano, nitro, amino, azido, oxo (=O), carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic group, C 6- 14 Aryl or 5-10 membered heteroaromatic ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 The aryl or 5-10 membered heteroaromatic ring group may be optionally selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted by one or more substituents, wherein the oxo group refers to two H groups at the same substitution position being replaced by the same O group to form a double bond. Preferably, the substituent is preferably selected from the following group: halogen, hydroxyl, thiol, cyano, nitro, amino, azido, oxo (=O), carboxyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkylsulfonyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaromatic ring group, wherein the C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkylsulfonyl, 3-7 membered heterocyclic group, C 6-10The aryl or 5-10 membered heteroaromatic ring group may be optionally selected from halogen, hydroxy, amino, cyano, C 1- 4 alkyl or C 1-4 Preferably, the substituent is preferably selected from the group consisting of halogen, hydroxyl, thiol, cyano, nitro, amino, azido, oxo (=O), carboxyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylsulfonyl, 4-6 membered heterocyclic group, phenyl or 5-6 membered heteroaromatic ring group, wherein the C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylsulfonyl, 4-6 membered heterocyclic group, phenyl group or 5-6 membered heteroaromatic ring group can be optionally selected from halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 The alkoxy group is substituted by one or more substituents.

[0248] The term "optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or not.

[0249] The word "comprise" or "include" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0250] The term "object" may also be referred to as "individual" or "subject" and refers to a cell or an animal, including but not limited to mammals, such as laboratory animals or humans.

[0251] An "effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended application, including but not limited to treatment of a disease or alleviation of symptoms. In some embodiments, for example, the amount is a dose that can induce a specific response in cells, or a dose that can exert a therapeutic effect on a disease in a model animal. The specific amount will vary depending on, for example, the specific compound selected, the type of subject and their age / existing health, the dosing regimen followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system used to carry it.

[0252] Some compounds in the present application are optically active. The compounds in the present application may be racemates, optical isomers or mixtures thereof. The synthesis of optical isomers in the compounds in the present application may be prepared from starting materials of optical isomers or by separation of racemates.

[0253] Unless otherwise specified, the term "pharmaceutically acceptable carrier", also known as "pharmaceutically acceptable excipient" or "pharmaceutically acceptable vehicle", refers to a medium generally recognized in the field of delivering biologically active agents to animals (particularly, mammals). Pharmaceutically acceptable carriers are formulated according to many factors that are well within the scope of those of ordinary skill in the art. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. The preparation of the pharmaceutical compositions described herein, including but not limited to, for example, mixing the compound described in the first aspect or the second aspect, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

[0254] The above embodiments represent exemplary embodiments of the present application, but the present application is not limited to the above embodiments. In addition, the various technical features in the above embodiments of the present application can be combined with each other to form one or more new technical solutions, which also fall within the scope of the present application as long as such new technical solutions are technically feasible. DETAILED DESCRIPTION

[0255] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present application only and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present application method. The preferred implementation methods and materials shown in the text are for demonstration purposes only.

[0256] The structures of the compounds of the present application were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or liquid chromatography (HPLC). The NMR measurements were performed using a Bruker 400 MHz and / or a Varian 400 MHz instrument; the LC-MS measurements were performed using an Agilent 1260 Infinity II-6120 / 6125 MSD instrument; and the HPLC measurements were performed using a Waters Acquity UPLC-2 and / or a Shimadzu LC2030 and / or an Agilent 1260 Infinity II instrument. Chiral compound separation was performed using an SFC-150 (Waters) instrument and a DAICEL column. OD; column volume: 20×250 mm (10 μm particle size packing).

[0257] The starting materials in the examples of the present application are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0258] The present application provides a method for preparing the compound. The compound can be prepared by the following steps.

[0259] The abbreviations used in this application have the following meanings:

[0260] PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane; MeOH: methanol; FA: formic acid; MeCN: acetonitrile; THF: tetrahydrofuran; TFA: trifluoroacetic acid.

[0261] The beneficial effects of this application are:

[0262] The compounds of the present application achieve one or more of the following beneficial effects:

[0263] (1) The compounds of the present application have a strong inhibitory effect on CYP11B2;

[0264] (2) The compounds of the present application have good CYP11B2 / CYP11B1 selectivity;

[0265] (3) The compound of the present application has good oral absorption performance in monkeys.

[0266] Preparation Example 1

[0267] Preparation of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one:

[0268] Step 1: Synthesis of 6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one:

[0269] 6-Bromo-3,4-dihydroquinolin-2(1H)-one (10 g, 1.0 eq) was dissolved in N,N-dimethylformamide (180 mL), and 60% sodium hydride (2.54 g) was added portionwise at 0°C. The mixture was slowly warmed to room temperature. After 30 minutes, iodomethane (9.42 g) was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. The reaction mixture was poured into ice water (600 mL) to quench the mixture, and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether (PE):ethyl acetate (EA) = 10:3, volume ratio) to obtain the product (10.5 g). LCMS (ESI) [M+H] + =239.8.

[0270] Step 2:

[0271] The product from the first step (4.5 g, 1.0 eq), pinacol diboronate (5.71 g), potassium acetate (5.52 g), and Pd(dppf)Cl2 (687.58 mg) were added to 1,4-dioxane (100 mL) and reacted at 90°C under nitrogen for 12 hours. The reaction solvent was directly dried and the product was purified by flash chromatography (silica gel, PE:EA = 10:3) to obtain the product (5.3 g). LCMS (ESI) [M+H] + =287.9.

[0272] Preparation Example 2

[0273] Preparation of 6-(5-bromopyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one:

[0274] 3,5-Dibromopyridine (7.93 g, 1.0 eq) was added to N,N-dimethylformamide (80 mL). The sample from Preparation Example 1 (10.57 g), a 1N sodium sulfate aqueous solution (69 mL), and bistriphenylphosphine palladium dichloride (2.35 g) were then added. The mixture was reacted at 110°C for 12 hours. The reaction solution was diluted with ethyl acetate (100 mL) and filtered through celite. The filtrate was extracted with saturated sodium bicarbonate aqueous solution (500 mL) and ethyl acetate (500 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA = 9:1) to obtain the product (1.30 g). LCMS (ESI) [M+H] + =319.2.

[0275] Preparation Example 3

[0276] Preparation of 2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetic acid:

[0277] Step 1: Synthesis of benzyl 4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazine-1-carboxylate:

[0278] The sample from Preparation Example 2 (1.87 g, 1.0 eq) was added to a solution of 1,4-dioxane (13 mL). Benzyl piperazine-1-carboxylate (1.30 g), cesium carbonate (5.77 g), and chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.23 g) were added and reacted at 80°C for 12 hours. The reaction solution was filtered and extracted with aqueous solution (200 mL) and ethyl acetate (200 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA = 1:1) to obtain the product (1.48 g). LCMS (ESI) [M+H] + =457.2.

[0279] Step 2: Synthesis of 1-methyl-6-(5-(piperazin-1-yl)pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one (Intermediate 1):

[0280] The product from the first step (1.00 g, 1.0 eq) was added to isopropanol (40 mL), followed by 10% palladium on carbon (0.1 g). The mixture was reacted at 25°C under a hydrogen atmosphere for 48 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the product (0.74 g, crude product). LCMS (ESI) [M+H] + =323.2. It was used directly in the next reaction without further purification.

[0281] Step 3: Synthesis of ethyl 2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetate:

[0282] A sample of Intermediate 1 (0.74 g, crude product) was added to N,N-dimethylformamide (10 mL), followed by ethyl bromoacetate (0.42 g) and triethylamine (0.58 g). The mixture was allowed to react at 25°C for 12 hours. The reaction solution was extracted with aqueous solution (200 mL) and ethyl acetate (200 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, DCM:MeOH = 10:1) to obtain the product (0.50 g). LCMS (ESI) [M+H] + =409.2.

[0283] Step 4:

[0284] The product obtained in step 3 (0.50 g, 1.0 eq) was added to a mixture of ethanol (2 mL) and water (2 mL), followed by sodium hydroxide (0.42 g) and allowed to react at 25°C for 2 hours. The reaction solution was adjusted to a weak acidity with dilute hydrochloric acid (10 mL), and the reaction solvent was evaporated to obtain the product (1.06 g). LCMS (ESI) [M+H] + =381.2; 1 H NMR (400MHz, DMSO-d6) δ8.42(d,J=1.6Hz,1H),8.35(d,J=2.4Hz,1H),7.79(s,1H),7.73–7.66(m,2H),7. 22–7.15(m,1H),4.10(s,2H),3.70(s,6H),3.29(d,J=5.2Hz,6H),2.96–2.92(m,2H),2.60–2.56(m,2H).

[0285] Preparation Example 4

[0286] Synthesis of 2-(4-(5-bromopyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide

[0287] Step 1: Synthesis of 4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-carboxylic acid benzyl ester:

[0288] 2-(4-((Benzyloxy)carbonyl)piperazin-1-yl)acetic acid (1.2 g, 1 eq), isopropylamine hydrochloride (535.71 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 2.46 g), and N,N-diisopropylethylamine (1.67 g) were added to N,N-dimethylformamide (20 mL) and stirred at room temperature for 3 hours. The reaction solution was poured into water (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 1:4) to obtain the product (900 mg, crude). LCMS (ESI) [M+H] + =320.0.

[0289] Step 2: Synthesis of N-isopropyl-2-(piperazin-1-yl)acetamide:

[0290] The product from the first step (900 mg, 1 eq) was dissolved in methanol (20 mL), and 5% wet palladium on carbon (300 mg) was added. The mixture was stirred at room temperature overnight under a hydrogen atmosphere. Filtered through celite, the filter cake was washed with methanol, and the filtrate was directly concentrated to obtain the product (600 mg, crude product).

[0291] Step 3:

[0292] 3,5-Dibromopyridine (500 mg, 1 eq), the product from the second step (312.84 mg), sodium tert-butoxide (243.4 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos, 61.06 mg), and tris(dibenzylideneacetone)dipalladium (38.66 mg) were added to 1,4-dioxane (15 mL) under nitrogen atmosphere and stirred at 100°C for 5 hours. The reaction solution was concentrated and purified by flash chromatography (silica gel, dichloromethane:methanol = 10:1) to obtain the title compound (400 mg). LCMS (ESI) [M+H] + =341.18. 1 HNMR(400MHz,DMSO-d6)δ8.29(d,J=2.6Hz,1H),8.03(d,J=1.8Hz,1H),7.57-7.48(m,2H),3 .95-3.84(m,1H),3.30-3.26(m,4H),2.94(s,2H),2.58-2.54(m,4H),1.07(d,J=6.6Hz,6H).

[0293] Example 1

[0294] Preparation of N-trans-(4-acetylaminocyclohexyl)-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 1):

[0295] Step 1: Synthesis of 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylic acid benzyl ester:

[0296] Referring to the third step of Preparation Example 3, benzyl piperazine-1-carboxylate (10.00 g, 1.0 eq) and ethyl bromoacetate (8.30 g) were used as raw materials, and tetrahydrofuran (100 mL) was used as solvent. The reaction was carried out at 25°C for 3 hours. Flash chromatography (silica gel, PE:EA = 5:1, volume ratio) was used to obtain the product (1.30 g). LCMS (ESI) [M+H] + =307.0.

[0297] Step 2: Synthesis of 2-(4-((benzyloxy)carbonyl)piperazin-1-yl)acetic acid:

[0298] Refer to the fourth step of Preparation Example 3, using 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylic acid benzyl ester (15.00 g, 1.0 eq) as the starting material, and react at 25°C for 2 hours to obtain the crude intermediate (12.80 g). LCMS (ESI) [M+H] + = 279.2. The crude product was used directly in the next reaction without further purification.

[0299] Step 3: Synthesis of benzyl 4-(2-(((trans-4-((tert-butyloxycarbonyl)amino)cyclohexyl)amino)-2-oxoethyl)piperazine-1-carboxylate

[0300] The product from step 2 (1.00 g, crude) was dissolved in N,N-dimethylformamide (10 mL), and tert-butyl (1R,4R)-4-aminocyclohexyl)carbamate (0.80 g), N,N-diisopropylethylamine (1.40 g), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.60 g) were added. The mixture was reacted at 25°C for 3 hours. Water (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA = 10:1) to obtain the intermediate compound (1.33 g). LCMS (ESI) [M+H] + =475.2.

[0301] Step 4: Synthesis of tert-butyl (trans-4-(2-(piperazin-1-yl)acetylamino)cyclohexyl)carbamate:

[0302] Refer to the second step of the preparation example, use the product obtained in the third step (5.00 g, 1.0 eq) as the starting material, and react at 25°C under a hydrogen atmosphere for 12 hours to obtain the crude intermediate compound (3.51 g). LCMS (ESI) [M+H] + =341.2. The crude product was used directly in the next reaction without further purification.

[0303] Step 5: Synthesis of tert-butyl (trans-4-(2-(4-(5-bromopyridin-3-yl)piperazin-1-yl)acetylamino)cyclohexyl)carbamate:

[0304] The product from step 4 (1.00 g, 1.0 eq, crude) was added to N,N-dimethylformamide (10 mL), followed by 5-bromo-3-iodopyridine (0.80 g), tris(dibenzylideneacetone)palladium (0.10 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.30 g), and cesium carbonate (2.90 g). The mixture was reacted at 100°C for 12 hours. Water (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, DCM:MeOH = 1:1) to obtain the intermediate compound (0.39 g). LCMS (ESI) [M+H] + =496.2.

[0305] Step 6: Synthesis of tert-butyl (trans-4-(2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetylamino)cyclohexyl)carbamate:

[0306] The product obtained in step 5 (387 mg, 1.0 eq) was added to a mixed solution of water (0.5 mL) and dioxane (2.5 mL). The sample from Preparation Example 1 (269 mg), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (57 mg), and cesium carbonate (762 mg) were added and reacted at 100°C for 12 hours. Water (100 mL) was added to the reaction system and extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, DCM:MeOH=8:1) to obtain the intermediate compound (273 mg). LCMS (ESI) [M+H] + =577.4.

[0307] Step 7: Synthesis of N-(trans-4-aminocyclohexyl)-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide:

[0308] The product obtained in step 6 (238 mg, 1.0 eq) was added to hydrochloric acid-dioxane (4 M, 5 mL) and reacted at 25°C for 2 hours. The reaction solution was spin-dried to obtain a crude product (120 mg). LCMS (ESI) [M+H] + =477.4. The crude product was used directly in the next reaction without further purification.

[0309] Step 8:

[0310] The product from step 7 (238 mg, 1.0 eq, crude) was added to dichloromethane (3 mL), followed by triethylamine (202 mg) and acetic anhydride (153 mg). The mixture was reacted at 25°C for 12 hours. The reaction solution was directly concentrated and filtered, and the filtrate was separated and purified by preparative HPLC (C18, 0.1% FA in water, MeCN) to obtain compound 1 (43 mg). LCMS (ESI) [M+H] + =519.3; 1 H NMR (400MHz, DMSO-d6) δ8.28(dd,J=11.2,2.4Hz,2H),7.71(d,J=7.6Hz,1H),7.63(dd,J=4.4,2.4Hz,2H),7.59–7.47(m,2H),7.19–7.1 5(m,1H),3.61–3.43(m,2H),3.33(s,2H),3.29(d,J=2.4Hz,5H),2.99–2.92(m,4H),2.63–2.56(m,6H),1.76(s,7H),1.35–1.14(m,4H).

[0311] Example 2

[0312] Preparation of 2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-N-(pyridin-3-yl)acetamide (Compound 3):

[0313] Step 1: Synthesis of benzyl 4-(2-oxo-2-(pyridin-3-ylamino)ethyl)piperazine-1-carboxylate:

[0314] Referring to the third step of Example 1, 2-(4-((benzyloxy)carbonyl)piperazin-1-yl)acetic acid (1 g, 1.0 eq) was used as the starting material. After stirring at room temperature for 15 minutes, pyridin-3-amine (405.79 mg) was added and stirring was continued for 2 hours. Flash chromatography (silica gel, PE:EA = 10:7) was used to obtain the product (700 mg). LCMS (ESI) [M+H] + =354.9.

[0315] Step 2: Synthesis of 2-(piperazine-1-yl)-N-(pyridin-3-yl)acetamide:

[0316] The product obtained in the first step (400 mg, 1.0 eq) was dissolved in methanol (15 mL), and 5% wet palladium on carbon (100 mg) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated to obtain the product (200 mg, crude product). LCMS (ESI) [M+H] + =220.9.

[0317] Step 3:

[0318] Referring to the first step of the reaction in Preparation Example 3, 6-(5-bromopyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (460.79 mg, 1 eq) and the product obtained in the second step (320 mg, crude product) were used as raw materials. The reaction was carried out at 110°C under nitrogen protection for 12 hours. The reaction solvent was directly dried and separated and purified by flash chromatography (silica gel, DCM:MeOH=10:1). The obtained crude product was dissolved in acetonitrile and separated and purified by preparative HPLC to obtain compound 3 (76.02 mg). LCMS (ESI) [M+H] + =457.0; 1 H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.80(d,J=2.1Hz,1H),8.33–8.25(m,3H),8.0 9(ddd,J=8.4,2.6,1.5Hz,1H),7.63(dq,J=4.5,2.3Hz,2H),7.52(t,J=2.4Hz,1H),7. 35(ddd,J=8.3,4.8,0.8Hz,1H),7.18(d,J=9.1Hz,1H),3.38(t,J=5.1Hz,4H),3.29( s,3H),3.26(s,2H),2.95(t,J=7.4Hz,2H),2.72(t,J=5.0Hz,4H),2.63–2.55(m,2H).

[0319] Example 3

[0320] Preparation of N-(1-((4-methyl-1H-imidazol-5-yl)methyl)piperidin-4-yl)-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 4):

[0321] Step 1: Synthesis of 5-(chloromethyl)-4-methyl-1H-imidazole:

[0322] (4-Methyl-1H-imidazol-5-yl)methanol (500 mg, 1.0 eq) was added to dichloromethane (5 mL), followed by thionyl chloride (5.31 g). The mixture was allowed to react at 25°C for 16 hours. After completion of the reaction, the reaction mixture was directly dried to obtain the product (500 mg, crude product). This product was used directly in the next reaction without further purification.

[0323] Step 2: Synthesis of tert-butyl (1-((4-methyl-1H-imidazol-5-yl)methyl)piperidin-4-yl)carbamate:

[0324] The product from the first step (500 mg, crude) was added to dichloromethane (5 mL). Triethylamine (1.17 g) and tert-butyl piperidin-4-ylcarbamate (700 mg, 1.0 eq) were added at 25°C. The reaction mixture was allowed to react at 25°C for 16 hours. The reaction mixture was directly dried and purified by flash chromatography (silica gel, DCM:MeOH = 15:1) to obtain the product (300 mg). LCMS (ESI) [M+H] + =295.2.

[0325] Step 3: Synthesis of 1-((4-methyl-1H-imidazol-5-yl)methyl)piperidin-4-amine:

[0326] The product from step 2 (150 mg, 1.0 eq) was added to dichloromethane (3 mL), followed by a 4N solution of dioxane hydrochloride (0.6 mL in MeOH) and allowed to react at 25°C for 16 hours. The reaction mixture was directly spin-dried to give the product (120 mg, crude product). This product was used directly in the next step without further purification. LCMS (ESI) [M+H] + =195.2.

[0327] Step 4:

[0328] Referring to the third step of Example 1, the product obtained in the third step (100 mg, crude product) and the sample from Preparation Example 3 (195 mg, 1.0 eq) were used as starting materials and reacted at 25°C for 16 hours. The reaction solvent was directly dried, methanol was added for dissolution, and the product was separated and purified by reverse phase chromatography (15%-25% ACN in water) to obtain compound 4 (23.13 mg). LCMS (ESI) [M+H] + =557.4; 1 H NMR (400MHz, CD3OD) δ8.70(s,1H),8.50(d,J=1.4Hz,1H),8.39(d,J=2.8Hz,1H),8.17(s, 1H),7.75–7.66(m,2H),7.30(d,J=8.4Hz,1H),4.41(s,2H),4.04(s,1H),3.93(s,2H),3.8 0(s,4H),3.57(d,J=12.4Hz,2H),3.48(s,4H),3.41(s,3H),3.19(t,J=10.4Hz,2H),3.08 –3.01(m,2H),2.72–2.66(m,2H),2.42(s,3H),2.19(d,J=13.8Hz,2H),1.92–1.83(m,2H).

[0329] Example 4

[0330] Preparation of 6-(5-(4-(3-hydroxypropyl)piperidin-1-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (Compound 5):

[0331] The sample from Preparation Example 2 (100 mg, 1.0 eq) was added to a 1,4-dioxane / water (volume ratio = 3:1) (4.0 mL) solution, followed by the addition of 3-(piperidin-4-yl)propan-1-ol (46 mg), tris(dibenzylideneacetone)dipalladium (30 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (20 mg), and cesium carbonate (315 mg). The mixture was reacted at 90°C for 2 hours. The mixture was filtered and extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by preparative HPLC (C18, 0.05% ammonia in acetonitrile) to give Compound 5 (8.56 mg). LCMS (ESI) [M+H] + =378.1; 1H NMR (400MHz, CDCl3) δ8.28(d,J=2.8Hz,1H),8.25(d,J=1.8Hz,1H),7.46–7.42(m ,1H),7.37(d,J=1.8Hz,1H),7.32–7.29(m,1H),7.06(d,J=8.4Hz,1H),3.77(d,J= 12.4Hz,2H),3.67(t,J=6.6Hz,2H),3.40(s,3H),3.01–2.96(m,2H),2.80(s,2H), 2.70–2.67(m,2H),1.85(d,J=12.0Hz,2H),1.66–1.60(m,3H),1.43–1.35(m,4H).

[0332] Example 5

[0333] Preparation of N-isopropyl-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 6):

[0334] Step 1: Synthesis of 4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-carboxylic acid benzyl ester:

[0335] Benzyl piperazine-1-carboxylate (500 mg, 1.0 eq), 2-chloro-N-isopropylacetamide (615.56 mg), and sodium carbonate (481.19 mg) were added to acetonitrile (20 mL) and reacted at 50°C under nitrogen for 12 hours. The reaction solvent was directly dried and the product was purified by flash chromatography (silica gel, PE:EA = 1:1) to obtain the product (1 g, crude product). LCMS (ESI) [M+H] + =320.0.

[0336] Step 2: Synthesis of N-isopropyl-2-(piperazin-1-yl)acetamide:

[0337] The product obtained in the first step (500 mg, 1 eq) was dissolved in methanol (20 mL), and 5% wet palladium on carbon (100 mg) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 12 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the product (280 mg). LCMS (ESI) [M+H] + =186.1.

[0338] Step 3:

[0339] Refer to the third step of Example 2, using the sample from Preparation Example 2 (428 mg, 1.0 eq) and the product from the second step (250 mg) as raw materials, and react at 110°C under nitrogen for 12 hours. Compound 6 (169.63 mg) was isolated using the treatment and purification methods of the third step of Example 2. LCMS (ESI) [M+H] + =422.0; 1 H NMR (400MHz, DMSO-d6) δ8.29(d,J=1.8Hz,1H),8.27(d,J=2.7Hz,1H),7.63(dq,J=5.0,2.3Hz,2H),7.55–7.49(m,2H),7.17(d,J=9 .0Hz,1H),3.96–3.85(m,1H),3.34(s,4H),3.29(s,3H),2.98–2.90(m,4H),2.59(dt,J=9.2,6.9Hz,6H),1.09(s,3H),1.07(s,3H).

[0340] Example 6

[0341] Preparation of N-methyl-2-(4-(2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamido)-1H-pyrazol-1-yl)acetamide (Compound 9):

[0342] Step 1: Synthesis of N-methyl-2-(4-nitro-1H-pyrazol-1-yl)acetamide:

[0343] Dissolve 4-nitro-1H-pyrazole (500 mg, 1.0 eq) in acetonitrile (10 mL), then add 2-chloro-N-methylacetamide (375 mg) and potassium carbonate (1.8 g) to the system. React at 80°C under nitrogen for 2 hours. Cool to room temperature and extract with ethyl acetate (30 mL*3). Combine the organic phases and concentrate directly to obtain the product (355 mg, crude product). Use it directly in the next reaction without further purification. LCMS (ESI) [M+H] + =185.2.

[0344] Step 2: Synthesis of 2-(4-amino-1H-pyrazol-1-yl)-N-methylacetamide:

[0345] The product obtained in the first step (200 mg, crude) was dissolved in ethanol / water (5:1) (4.0 mL), and iron powder (300 mg) and ammonium chloride (580 mg) were added. The mixture was reacted at 90°C overnight. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the product (200 mg, crude). The product was used directly in the next step without further purification. LCMS (ESI) [M+H] + =155.2.

[0346] Step 3:

[0347] Referring to the third step of Example 1, the product from the second step (100 mg, crude) and the sample from Preparation Example 3 (205 mg) were used as starting materials and reacted at 25°C for 2 hours. Preparative HPLC separation and purification (C18, 0.05% NH3·H2O in water, MeCN) afforded compound 9 (22.7 mg). LCMS (ESI) [M+H] + =517.4; 1 H NMR(400MHz, CDCl3)δ8.90(s,1H),8.35–8.27(m,2H),8.01(s,1H),7.61(s ,1H),7.45–7.40(m,1H),7.34(d,J=18.0Hz,2H),7.06(d,J=8.4Hz,1H),6. 13(s,1H),4.75(s,2H),3.39(s,3H),3.38–3.34(m,4H),3.24(s,2H),3.00 –2.95(m,2H),2.83–2.79(m,4H),2.77(d,J=4.8Hz,3H),2.71–2.66(m,2H).

[0348] Examples 7-8

[0349] With reference to the third step reaction of Example 1, the sample of Preparation Example 3 (50 mg, 1.0 eq) and the raw materials shown in the table below were used to prepare Compound 15 and Compound 28, respectively.

[0350] Example 9

[0351] Preparation of N-isopropyl-2-(4-(6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)piperazin-1-yl)acetamide (Compound 44):

[0352] Step 1: Synthesis of 2-(4-(6-bromopyrazin-2-yl)piperazin-1-yl)-N-isopropylacetamide:

[0353] 2,6-Dibromopyrazine (320 mg, 1.0 eq), N-isopropyl-2-(piperazin-1-yl)acetamide (260 mg, crude), and cesium carbonate (876.6 mg) were added to dimethyl sulfoxide (6 mL) and reacted at 100°C overnight under nitrogen. The reaction solution was poured into water (20 mL) to quench and extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA = 1:1) to obtain the product (360 mg). LCMS (ESI) [M+H] + =341.9.

[0354] Step 2:

[0355] Referring to the sixth step of Example 1, the sample from Preparation Example 1 (250 mg, 1.0 eq) and the product from the first step (297.94 mg) were used as starting materials. The reaction was carried out at 100°C overnight under nitrogen. The reaction mixture was separated and the organic phase was concentrated. The organic phase was purified by flash chromatography (silica gel, DCM:MeOH = 10:1). The crude product was further purified by reverse phase chromatography (C18, MeCN:H2O = 1:1) to obtain Compound 44 (247.34 mg). LCMS (ESI) [M+H] + =186.1; 1 H NMR (400MHz, Chloroform-d) δ8.34(s,1H),8.07(s,1H),7.90(dd,J=8.5,2.1Hz,1H),7.81(d,J=2.0Hz,1H),7.07(d,J=8.5Hz,1H),6.92(d,J=8.4 Hz,1H),4.20–4.07(m,1H),3.73(t,J=5.1Hz,4H),3.40(s,3H),3.06(s,2 H), 3.03–2.96 (m, 2H), 2.70 (q, J=6.4, 4.9Hz, 6H), 1.20 (d, J=6.6Hz, 6H).

[0356] Example 10

[0357] Preparation of 2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-N-(trans-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)acetamide (Compound 69):

[0358] Step 1: Synthesis of tert-butyl (trans-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)carbamate:

[0359] Tert-butyl (4-oxocyclohexyl)carbamate (1.00 g, 1.0 eq) was added to dichloromethane (10 mL). 1-Methylpiperazin-2-one (535 mg) and sodium triacetylborohydride (3.00 g) were added at 0°C and reacted at 25°C for 16 hours. The reaction solution was quenched with ice water (10 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase chromatography (15% ACN in water) to obtain the product (200 mg). LCMS (ESI) [M+H] + =312.2.

[0360] Step 2: Synthesis of 4-(trans-4-aminocyclohexyl)-1-methylpiperazine-2-one:

[0361] The product from the first step (200 mg, 1.0 eq) was added to dichloromethane (2 mL). A dioxane hydrochloride solution (4 N in MeOH, 0.5 mL) was added at 25°C. The reaction mixture was allowed to react at 25°C for 16 hours. The reaction mixture was directly spin-dried to obtain the product (100.0 mg, crude product). The product was used directly in the next step without further purification. LCMS (ESI) [M+H] + =212.2.

[0362] Step 3:

[0363] Referring to the third step of Example 1, the product from the second step (100 mg, crude) and the sample from Preparation Example 3 (178 mg) were used as starting materials and reacted at 25°C for 16 hours. The reaction solvent was directly dried, dissolved in methanol, and separated and purified by reverse phase chromatography (15%-25% ACN in water) to obtain Compound 69 (64.10 mg). LCMS (ESI) [M+H] + =574.4; 1 H NMR (400MHz, CD3OD) δ8.49(d,J=1.2Hz,1H),8.38(d,J=2.8Hz,1H),8.14(s,1H),7.70(dd,J =8.4, 2.4Hz, 1H), 7.66 (s, 1H), 7.28 (d, J = 8.4Hz, 1H), 3.91 (d, J = 8.4Hz, 4H), 3.76 (d, J = 19. 2Hz,5H),3.69–3.55(m,4H),3.47(d,J=3.2Hz,4H),3.39(s,3H),3.33(d,J=8.8Hz,1H),3.0 6–2.99(m,5H),2.72–2.63(m,2H),2.20–2.13(m,4H),1.73–1.64(m,2H),1.47–1.38(m,2H).

[0364] Example 11

[0365] Preparation of N-isopropyl-2-methyl-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)propanamide (Compound 70):

[0366] Step 1: Prepare 2-methyl-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)propanoic acid (Intermediate 70-1) by referring to the preparation method of Preparation Example 3. LCMS (ESI) [M+H] + =409.4.

[0367] Referring to the third step of Example 1, the product from the first step (70 mg, 1.0 eq) and propan-2-amine (15 mg) were used as starting materials and reacted at 25°C for 2 hours. Preparative HPLC separation and purification (C18, 0.05% NH3·H2O in water, MeCN) afforded compound 70 (29 mg). LCMS (ESI) [M+H] + =450.4; 1 H NMR (400MHz, CDCl3) δ8.32(s,1H),8.28(d,J=2.4Hz,1H),7.52–7.39(m,1H),7.37(d,J=2.0Hz,1H),7.31(t,J=2.0Hz,1H),7.07–7.04 (m,2H),4.10–4.01(m,1H),3.40(s,3H),3.35–3.30(m,4H),3.01–2.95(m,2H),2.72–2.68(m,6H),1.24(s,6H),1.14(d,J=6.4Hz,6H).

[0368] Example 12

[0369] Preparation of N-(3-acetylaminocyclobutyl)-2-methyl-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)propanamide (Compound 71):

[0370] Step 1: Synthesis of tert-butyl 3-(2-methyl-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)propionamido)cyclobutyl)carbamate:

[0371] Referring to the third step of Example 1, intermediate 70-1 (250 mg, 1.0 eq) and tert-butyl (3-aminocyclobutyl)carbamate (136 mg) were used as starting materials and reacted at room temperature for 2 hours. Flash chromatography (silica gel, PE:EA = 2:1) was used to obtain the product (170 mg). LCMS (ESI) [M+H] + =577.2.

[0372] Step 2: Synthesis of N-(3-aminocyclobutyl)-2-methyl-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)propionamide:

[0373] The product obtained in the first step (170 mg, 1.0 eq) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was reacted at 25°C for 30 minutes. The reaction solution was directly spin-dried to obtain the product (120 mg, crude product). The crude product was used directly in the next step without purification. LCMS (ESI) [M+H] + =477.4.

[0374] Step 3:

[0375] The product obtained in the second step (120 mg, crude product) was dissolved in dichloromethane (2.0 mL). Acetic anhydride (77 mg) and triethylamine (75 mg) were added at 0°C, and the mixture was gradually returned to room temperature and allowed to react for 2 hours. The reaction solution was filtered, and the filtrate was directly concentrated and purified by preparative HPLC (C18, 0.5% formic acid in acetonitrile) to obtain compound 71 (49 mg). LCMS (ESI) [M+H] + =519.4; 1 H NMR (400MHz, CDCl3) δ8.33(d,J=1.8Hz,1H),8.31–8.26(m,1H),7.51–7.28(m,4H),7.07(d,J=8.4Hz,1H),5.72(s,1H),4.55–3.86(m, 2H),3.40(s,3H),3.33(s,4H),3.04–2.94(m,2H),2.86–2.60(m,7H),2.37–2.24(m,1H),2.01–1.88(m,4H),1.70(s,1H),1.25(s,6H).

[0376] Examples 13-14

[0377] Referring to the third step reaction of Example 1, intermediate 70-1 (200 mg, 1.0 eq) and Preparation Example 3 (100 mg, 1.0 eq) and the raw materials shown in the table below were used to prepare compounds 72 and 73, respectively.

[0378] Example 15

[0379] Preparation of 6-(5-(4-(3-(1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (Compound 74):

[0380] Step 1: Synthesis of 1-(3-bromopropyl)-1H-1,2,3-triazole:

[0381] Referring to the first step of Example 6, 2H-1,2,3-triazole (1.00 g, 1.0 eq) and 1,3-dibromopropane (2.92 g) were used as raw materials and the reaction was carried out at 80°C for 16 hours. Flash chromatography (silica gel, PE:EA = 3:1) was used to obtain the product (200 mg). LCMS (ESI) [M+H] + =190.0,192.0.

[0382] Step 2:

[0383] Referring to the first step of Example 6, the product from the first step (100 mg, 1.0 eq) and Intermediate 1 (171 mg) were reacted at 80°C for 16 hours. Preparative HPLC separation and purification (C18, 0.5% FA in water, MeCN) afforded Compound 74 (26.38 mg). LCMS (ESI) [M+H] + =432.2; 1 H NMR (400MHz, DMSO-d6) δ8.29(d,J=2.0Hz,1H),8.26(d,J=2.8Hz,1H),8.14(d,J=0. 8Hz,1H),7.72(d,J=0.8Hz,1H),7.64–7.60(m,2H),7.51–7.48(m,1H),7.17(d,J=9 .2Hz,1H),4.44(t,J=7.2Hz,2H),3.28(d,J=5.6Hz,7H),2.97–2.91(m,2H),2.58(d d,J=8.4,6.4Hz,2H),2.55–2.51(m,4H),2.32(t,J=6.8Hz,2H),2.09–1.98(m,2H).

[0384] Examples 16-18

[0385] Referring to the preparation method of Preparation Example 3, intermediate 75-1 was prepared.

[0386] Referring to the third step reaction of Example 1, intermediate 75-1 (290 mg, 1.0 eq), intermediate 70-1 (150 mg, 1.0 eq), the sample of Preparation Example 3 (50 mg, 1.0 eq), and the raw materials shown in the table below were used to prepare compounds 75, 76, and 78, respectively.

[0387] Example 19

[0388] Preparation of 6-(5-(4-(3-(2H-1,2,3-triazol-2-yl)propane)piperazin-1-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (Compound 77):

[0389] The monohydrochloride of Intermediate 1 (50 mg, 1.0 eq) was added to N,N-dimethylformamide (2 mL), followed by triethylamine (42 mg) and 3-(2H-1,2,3-triazol-2-yl)propylmethanesulfonic acid (58 mg). The mixture was reacted at 70°C for 12 hours. The mixture was filtered, the filtrate was concentrated, and then purified by preparative HPLC (C18, 10 mmol / L ammonium bicarbonate in acetonitrile) to afford Compound 77 (10 mg). LCMS (ESI) [M+H] + =432.0; 1 H NMR (400MHz, DMSO-d6) δ8.27(dd,J=12.8,2.2Hz,2H),7.77(d,J=0.8Hz,2H),7.69–7.59(m,2H),7.49(t,J=2.4Hz,1H),7.17(d,J=9.0Hz,1H), 4.48(t,J=6.8Hz,2H), 3.28(d,J=4.9Hz,7H), 2.94(t,J=7.4Hz,2H), 2.58(dd,J=8.6,6.2Hz,6H), 2.33(t,J=7.0Hz,2H), 2.06(p,J=6.9Hz,2H).

[0390] Example 20

[0391] Preparation of 1-methyl-6-(5-(4-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one (Compound 79):

[0392] Referring to the first step of Example 5, the monohydrochloride salt of Intermediate 1 (100 mg, 1.0 eq) and 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole (110 mg) were used as starting materials and reacted at 70°C for 12 hours. The mixture was filtered, the filtrate was concentrated, and then purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 in water, MeCN) to obtain Compound 79 (9.78 mg). LCMS (ESI) [M+H] + =418.0; 1 H NMR(400MHz, DMSO-d6)δ8.38(s,1H),8.26(dd,J=13.5,2.3Hz,2H),7.61(dq,J=4.9,2.3Hz,2H),7.48(t,J=2.3Hz,1H), 7.17(d,J=9.1Hz,1H),3.84(s,3H),3.56(s,2H),3.27(d,J=8.1Hz,7H),2.94(dd,J=8.6,6.2Hz,2H),2.65–2.54(m,6H).

[0393] Example 21

[0394] Preparation of N-(trans-4-acetylaminocyclohexyl)-2-(4-(6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)piperazin-1-yl)acetamide (Compound 80):

[0395] Step 1: Synthesis of benzyl 4-(2-(((trans-4-((tert-butyloxycarbonyl)amino)cyclohexyl)amino)-2-oxoethyl)piperazine-1-carboxylate:

[0396] 2-(4-((Benzyloxy)carbonyl)piperazin-1-yl)acetic acid (3 g, 1.0 eq), tert-butyl (trans-4-aminocyclohexyl)carbamate (2.54 g) and N,N'-diisopropylethylamine (4.18 g) were added to acetonitrile (60°C). The reaction solvent was dried and purified by flash chromatography (silica gel, PE:EA=1:1) to obtain the product (8 g, crude product). It was used directly in the next reaction without further purification. LCMS (ESI) [M+H] + =475.1.

[0397] Step 2: Synthesis of tert-butyl (trans-4-(2-(piperazin-1-yl)acetylamino)cyclohexyl)carbamate:

[0398] Referring to the second step of Example 2, the product from the first step (3 g, crude product) was used, 5% wet palladium on carbon (500 mg) was added, and the mixture was reacted at room temperature under a hydrogen atmosphere for 12 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the product (2.1 g). LCMS (ESI) [M+H] + =341.

[0399] Step 3: Synthesis of tert-butyl (trans-4-(2-(4-(6-bromopyrazin-2-yl)piperazin-1-yl)acetylamino)cyclohexyl)carbamate:

[0400] Referring to the first step of Example 9, tert-butyl (trans-4-(2-(piperazin-1-yl)acetamido)cyclohexyl)carbamate (801.49 mg, 1.0 eq) and 2,6-dibromopyrazine (560 mg) were used as starting materials and reacted at 100°C overnight. Flash chromatography (silica gel, PE:EA = 2:3) was used to obtain the product (380 mg). LCMS (ESI) [M+H] + =496.9.

[0401] Step 4: Synthesis of tert-butyl (trans-4-(2-(4-(6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)piperazin-1-yl)acetylamino)cyclohexyl)carbamate:

[0402] Referring to the sixth step of Example 1, the product from the third step (350 mg, 1.0 eq) and the sample from Preparation Example 1 (242.26 mg) were used as starting materials. The reaction was carried out at 100°C under nitrogen protection overnight. Flash chromatography (silica gel, PE:EA = 1:2) was used to obtain the product (260 mg). LCMS (ESI) [M+H] + =578.1.

[0403] Step 5: Synthesis of N-(trans-4-aminocyclohexyl)-2-(4-(6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)piperazin-1-yl)acetamide:

[0404] Referring to the second step of Example 12, the product obtained in step 4 (240 mg, 1.0 eq) was used as the starting material and the reaction was carried out at room temperature for 12 hours. The reaction solvent was dried and the product was separated and purified by flash chromatography (silica gel, DCM:MeOH = 10:1) to obtain the product (180 mg). LCMS (ESI) [M+H] + =478.1.

[0405] Step 6:

[0406] The product obtained in step 5 (160 mg, 1.0 eq) was dissolved in dichloromethane (5 mL) and triethylamine (101.7 mg) was added. Acetyl chloride (78.89 mg) was added dropwise under ice bath conditions and the mixture was allowed to react at room temperature for 3 hours. The reaction solvent was dried and the crude product was separated and purified by flash chromatography (silica gel, DCM:MeOH=10:1). The product was slurried with acetonitrile, filtered, and the filter cake was dried to obtain compound 80 (45 mg). LCMS (ESI) [M+H] + =520.1; 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.23(s,1H),8.02–7.92(m,2H),7.72(d,J=7.8Hz,1H),7.59(d,J=8.3Hz,1H),7.18(d,J=8.5Hz,1H),3.6 9(t,J=4.9Hz,4H),3.46(s,2H),3.29(s,3H),2.96(dt,J=8.0,3.9Hz,4 H),2.58(dt,J=10.5,5.4Hz,6H),1.87–1.65(m,7H),1.39–1.13(m,4H).

[0407] Example 22

[0408] Preparation of N-isopropyl-N-methyl-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 81):

[0409] Step 1: Synthesis of benzyl 4-(2-(isopropyl(methyl)amino)-2-oxoethyl)piperazine-1-carboxylate:

[0410] Referring to the third step of Example 1, 2-(4-((benzyloxy)carbonyl)piperazin-1-yl)acetic acid (500 mg, 1.0 eq) and N-methyl-2-propylamine (170.83 mg) were used as starting materials and reacted at room temperature for 4 hours. Flash chromatography (silica gel, DCM:MeOH = 10:1) was used to obtain the product (160 mg). LCMS (ESI) [M+H] + =334.

[0411] Compound 81 was prepared by referring to the second and third steps of Example 2. LCMS (ESI) [M+H] + =436.1; 1HNMR(400MHz,Chloroform-d)δ8.30(s,1H),8.28(d,J=2.7Hz,1H),7.46(dd,J=8.4 ,2.2Hz,1H),7.37(s,1H),7.30(d,J=4.7Hz,1H),7.08(s,1H),4.60(dp,J=215.1,6. 7Hz,1H),3.40(s,3H),3.37–3.19(m,6H),3.04–2.94(m,2H),2.85(d,J=39.1Hz,3H ), 2.72 (ddd, J=14.7, 9.6, 6.0Hz, 6H), 1.20 (d, J=6.6Hz, 3H), 1.11 (d, J=6.8Hz, 3H).

[0412] Example 23

[0413] Preparation of 6-(5-(4-(2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (Compound 82):

[0414] Step 1: Synthesis of benzyl 4-(2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl)piperazine-1-carboxylate:

[0415] Referring to the third step of Example 1, 2-(4-((benzyloxy)carbonyl)piperazin-1-yl)acetic acid (400 mg, 1.0 eq) and 3-methoxypyrrolidine (174.46 mg) were used as starting materials and reacted at room temperature for 4 hours. Flash chromatography (silica gel, DCM:MeOH = 10:1) was used to obtain the product (220 mg). LCMS (ESI) [M+H] + =362.

[0416] Compound 82 was prepared by referring to the second and third steps of Example 2. LCMS (ESI) [M+H] + =464; 1H NMR (400MHz, Chloroform-d) δ8.30 (s, 1H), 8.27 (d, J = 2.8Hz, 1H), 7.46 (dd, J = 8. 4,2.2Hz,1H),7.37(s,1H),7.29(t,J=2.3Hz,1H),7.07(d,J=8.4Hz,1H),4.00(d tt,J=26.6,4.4,2.3Hz,1H),3.79–3.43(m,5H),3.40(s,3H),3.34(d,J=7.3Hz,6 H),3.25–3.15(m,2H),3.04–2.92(m,2H),2.82–2.63(m,6H),2.20–1.85(m,2H).

[0417] Example 24

[0418] Preparation of 1-methyl-6-(5-(4-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one (Compound 83):

[0419] A sample of Intermediate 1 (100 mg, 1.0 eq) and 1-methyl-1H-1,2,3-triazole-4-carbaldehyde (34.46 mg) were dissolved in 1,2-dichloroethane (3 mL). After reacting at room temperature for 1 hour, sodium triacetoxyborohydride (65.42 mg) was added and the reaction continued for 1 hour. The mixture was filtered, and the filter cake was rinsed with tetrahydrofuran. The filtrate was concentrated and purified by reverse phase chromatography (0.1% aqueous formic acid, acetonitrile) to obtain Compound 83 (12.22 mg). LCMS (ESI) [M+H] + =417.9; 1 H NMR (400MHz, DMSO-d6) δ8.31–8.27(m,1H),8.27–8.23(m,1H),8.14(s,1H),7.98(s,1H),7.64–7.59(m,2H),7.50–7.46(m ,1H),7.21–7.13(m,1H),4.03(s,3H),3.64(s,2H),3.45–3.32(m,4H),3.26(s,3H),2.97–2.91(m,2H),2.63–2.56(m,6H).

[0420] Examples 25-34

[0421] With reference to the third step reaction of Example 1, the sample of Preparation Example 3 (50 mg, 1.0 eq) and the starting materials shown in the table below were used to prepare compounds 84-93, respectively.

[0422] Example 35

[0423] Preparation of N-isopropyl-1-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)cyclopropane-1-carboxamide (Compound 94):

[0424] Step 1: Synthesis of ethyl 1-(4-benzylpiperazine-1-yl)cyclopropane-1-carboxylate:

[0425] Ethylbis(propan-2-yl)amine (150 mL) was added to N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine (17 g, 1.0 eq) and ethyl 1-aminocyclopropane-1-carboxylate (8.51 g), and the mixture was allowed to react at 100°C for 16 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (200 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA=3:1) to obtain the product (8 g). LCMS (ESI) [M+H] + =289.0; 1 H NMR (400MHz, CDCl3) δ7.34–7.28(m,4H),7.26–7.21(m,1H),4.18–4.08(m,2H),3.49 (s,2H),3.08–2.86(m,4H),2.48–2.21(m,4H),1.28–1.24(m,5H),0.91–0.87(m,2H).

[0426] Step 2: Synthesis of ethyl 1-(piperazine-1-yl)cyclopropane-1-carboxylate:

[0427] Referring to the second step of Example 2, the product obtained in the first step (5 g, 1.0 eq) was used as the starting material and the reaction was carried out at 40°C under hydrogen (balloon pressure) for 16 hours. The reaction solution was filtered through celite and the filtrate was concentrated to obtain the product (3 g, crude product). LCMS (ESI) [M+H] + =199.0; 1 HNMR (400MHz, DMSO-d6) δ4.10–4.01(m,2H),2.90–2.75(m,4H),2.70–2.53(m,4H),1.23–1.12(m,5H),0.93–0.83(m,2H).

[0428] Step 3: Synthesis of ethyl 1-(4-(5-bromopyridin-3-yl)piperazine-1-yl)cyclopropane-1-carboxylate:

[0429] Toluene (50 mL) was added to a mixture of the product from step 2 (3 g, crude), 3,5-dibromopyridine (4.66 g), sodium tert-butoxide (2.18 g), [5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine (525.33 mg), and tris(dibenzylideneacetone)dipalladium (277.13 mg). The mixture was reacted at 100°C under nitrogen for 16 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA = 3:1) to obtain the product (3.3 g). LCMS (ESI) [M+H] + =354.0; 1 H NMR (400MHz, DMSO-d6) δ8.34–8.22(m,1H),8.09–7.98(m,1H),7.55–7.48(m,1H),4.06(q, J=7.1Hz,2H),3.29–3.06(m,4H),3.06–2.96(m,4H),1.25–1.14(m,5H),1.02–0.92(m,2H).

[0430] Step 4: Synthesis of ethyl 1-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)cyclopropane-1-carboxylate:

[0431] Referring to the sixth step of Example 1, the product from the third step (1 g, 1.0 eq) and the sample from Preparation Example 1 (1.22 g) were used and reacted at 80°C under nitrogen for 2 hours. Flash chromatography (silica gel, EA) was used to obtain the product (780 mg). LCMS (ESI) [M+H] + =435.1; 1 HNMR(400MHz, DMSO-d6)δ8.33–8.22(m,2H),7.68–7.59(m,2H),7.54–7.44(m,1H),7.23–7.13(m,1H),4.07(q,J=7.1Hz,2H),3.29(s,3H), 3.28–3.12(m,4H),3.11–3.02(m,4H),2.98–2.90(m,2H),2.63–2.56(m,2H),1.25–1.20(m,2H),1.18(t,J=7.1Hz,3H),1.03–0.95(m,2H).

[0432] Step 5: Synthesis of 1-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)cyclopropane-1-carboxylic acid (Intermediate 35-1):

[0433] The product from step 4 (730 mg, 1.0 eq) was dissolved in methanol (5 mL) and water (5 mL), and lithium hydroxide (120.71 mg) was added. The mixture was reacted at 50°C for 16 hours. The pH of the reaction solution was adjusted to a weakly acidic state with dilute hydrochloric acid and purified by reverse phase chromatography (acetonitrile / 0.1% formic acid = 40%) to obtain the intermediate 35-1 (500 mg). LCMS (ESI) [M+H] + =407.2; 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),8.32–8.21(m,2H),7.67–7.59(m,2H),7.52–7.45(m,1H),7.21–7.14(m,1H),3.29( s,3H),3.28–3.12(m,4H),3.12–3.01(m,4H),2.99–2.92(m,2H),2.63–2.55(m,2H),1.25–1.14(m,2H),0.99–0.88(m,2H).

[0434] Step 6:

[0435] Referring to the third step of Example 1, the intermediate 35-1 (50 mg, 1.0 eq) obtained in the fifth step and isopropylamine (7.27 mg) were used as starting materials and reacted at 25°C for 1 hour. Reverse phase chromatography (0.1% aqueous formic acid, acetonitrile) was used to separate and purify the product to give compound 94 (21.79 mg). LCMS (ESI) [M+H] + =448.2; 1 H NMR (400MHz, DMSO-d6) δ8.34–8.22(m,2H),7.68(d,J=8.1Hz,1H),7.65–7.60(m,2H),7.53–7.47(m,1H),7.21–7.14(m,1H),3.9 3–3.82(m,1H),3.36–3.34(m,4H),3.29(s,3H),2.99–2.90(m,2H),2.61–2.55(m,6H),1.09(d,J=6.6Hz,6H),1.01–0.91(m,4H).

[0436] Example 36

[0437] Preparation of N-(trans-4-acetamidocyclohexyl)-2-(4-(5-(p-tolyl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamide-2,2-d2 (Compound 97):

[0438] Step 1: Synthesis of tert-butyl (trans-4-acetylaminocyclohexyl)carbamate:

[0439] Referring to the eighth step of Example 1, tert-butyl ((1R,4R)-4-aminocyclohexyl)carbamate (200 mg, 1.0 eq) and acetic anhydride (0.29 mL) were used as raw materials and reacted at 25°C for 2 hours. Water (25 mL) was added to the reaction solution for dilution, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the product (200 mg, crude product). 1 H NMR (400MHz, CDCl3) δ5.33–5.27(m,1H),4.45–4.33(m,1H),3.76–3.67(m,1H),3. 44–3.35(m,1H),2.03–1.98(m,4H),1.95(s,3H),1.43(s,9H),1.24–1.18(m,4H).

[0440] Step 2: Synthesis of N-(trans-4-aminocyclohexyl)acetamide:

[0441] Referring to the seventh step of Example 1, the product obtained in the first step (200 mg, crude product) was used as a raw material and the reaction was carried out at 25° C. for 4 hours. The reaction solution was concentrated to obtain the product (110 mg, crude product). 1 H NMR(400MHz, DMSO-d6)δ8.07–7.94(m,3H),7.79(d,J=7.6Hz,1H),3.45–3.40(m,1H),2.98–2.89( m,1H),1.97–1.91(m,2H),1.83–1.78(m,2H),1.77(s,3H),1.41–1.32(m,2H),1.23–1.16(m,2H).

[0442] Step 3: Synthesis of 2-oxo-2-(p-tolyl)acetaldehyde:

[0443] Selenium dioxide (33.08 g) was added to a mixture of 1,4-dioxane (200 mL) and water (20 mL). The mixture was reacted at 70°C for 4 hours until the selenium dioxide was completely dissolved. Under nitrogen, 1-(4-methylphenyl)ethane-1-one (20 g) was slowly added to the reaction mixture and allowed to react at 70°C for 16 hours. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate was extracted with ethyl acetate (300 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Petroleum ether and ethyl acetate (50 mL, 5:1 ratio) were added to the crude product, stirred overnight, filtered, and the filter cake was purified by flash chromatography (silica gel, PE:THF = 3:1 ratio) to obtain the product (21.8 g). 1 H NMR (400MHz, DMSO-d6) δ9.53(s,1H),8.02–7.93(m,2H),7.41–7.30(m,2H),2.41–2.36(m,3H).

[0444] Step 4: Synthesis of 3-(methylthio)-5-(p-tolyl)-1,2,4-triazine:

[0445] The product obtained in step 3 (11 g, 1.0 eq) was dissolved in ethanol (200 mL) and water (40 mL). Methyl hydrazinothioimidate (17.3 g) and sodium bicarbonate (18.71 g) were added and reacted at 100°C for 12 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (80 mL*4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:THF = 17:3 to 1:1) to obtain the product (10.5 g). LCMS (ESI) [M+H] + =218.4; 1 H NMR (400MHz, DMSO-d6) δ9.78 (s, 1H), 8.22 (d, J = 8.2Hz, 2H), 7.42 (d, J = 8.1Hz, 2H), 2.67 (s, 3H), 2.41 (s, 3H).

[0446] Step 5: Synthesis of 3-(methylsulfonyl)-5-(p-tolyl)-1,2,4-triazine:

[0447] The product obtained in step 4 (3 g, 1.0 eq) was dissolved in dichloromethane (35 mL) and 3-chlorobenzene-1-percarbonic acid (7.15 g) was added at -15°C. The mixture was reacted at -15°C for 8 hours. Saturated sodium bicarbonate solution (70 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (35 mL*3). The organic phases were combined, washed with saturated sodium sulfite solution (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:THF = 2:1 to 1:1) to obtain the product (2 g). LCMS (ESI) [M+H] + =250.4; 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),8.35(d,J=8.3Hz,2H),7.49(d,J=8.0Hz,2H),3.58(s,3H),2.44(s,3H).

[0448] Step 6: Synthesis of tert-butyl 4-(5-(p-tolyl)-1,2,4-triazine-3-yl)piperazine-1-carboxylate:

[0449] The product from step 5 (2 g, 1.0 eq), tert-butyl piperazine-1-carboxylate (1.49 g), and sodium carbonate (850.33 mg) were dissolved in acetonitrile (20 mL) and reacted at 25°C for 16 hours. The reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:THF = 4:1) to obtain the product (1.5 g). LCMS (ESI) [M+H] + =356.5; 1 H NMR (400MHz, DMSO-d6) δ9.30(s,1H),8.17(d,J=8.2Hz,2H),7.39(d,J=8.1Hz,2H),3.93–3.85(m,4H),3.50–3.46(m,4H),2.40(s,3H),1.44(s,9H).

[0450] Step 7: Synthesis of 3-(piperazine-1-yl)-5-(p-tolyl)-1,2,4-triazine:

[0451] Refer to the seventh step of Example 1, using the product obtained in the sixth step (1.5 g, 1.0 eq) as the starting material, and react at 25°C for 16 hours. The reaction solution was directly concentrated to obtain the product (900 mg, crude product). LCMS (ESI) [M+H] + =256.5. It was used directly in the next reaction without further purification.

[0452] Step 8: Synthesis of 2-(4-(5-(p-tolyl)-1,2,4-triazine-3-yl)piperazine-1-yl)acetate-d2:

[0453] The product obtained in step 7 (576.57 mg, crude) was dissolved in N,N-dimethylformamide (15 mL), and methyl 2-bromoacetate-d2 (350 mg) and potassium carbonate (937.03 mg) were added. The mixture was reacted at 70°C for 3 hours. Water (40 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (25 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:THF = 20:9) to obtain the product (580 mg). LCMS (ESI) [M+H] + =330.5; 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),8.16(d,J=8.2Hz,2H),7.38(d,J=8.1Hz,2H),3.93–3.86(m,4H),3.63(s,3H),2.67–2.62(m,4H),2.40(s,3H).

[0454] Step 9: Synthesis of 2-(4-(5-(p-tolyl)-1,2,4-triazine-3-yl)piperazine-1-yl)acetic acid-2,2-d2 acid:

[0455] Refer to the fifth step of Example 35, using the product obtained in the eighth step (580 mg, 1.0 eq) as the starting material, the reaction was carried out at 50°C for 2 hours. The reaction solution was adjusted to pH 5-6 with citric acid solution, stirred for 5 minutes, filtered, and the filter cake was dried to obtain the product (460 mg). LCMS (ESI) [MH] - =314.2; 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),8.15(d,J=8.1Hz,2H),7.38(d,J=8.0Hz,2H),3.94–3.89(m,4H),2.72–2.65(m,4H),2.40(s,3H).

[0456] Step 10:

[0457] Referring to the third step of Example 1, the product obtained in step 9 (100 mg, 1.0 eq) and N-(trans-4-aminocyclohexyl)acetamide (59.45 mg) were used as raw materials and reacted at 25°C for 3 hours. Water (20 mL) was added to the reaction solution for dilution, and the mixture was extracted with dichloromethane (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, DCM:MeOH = 10:1) to obtain Compound 97 (57.11 mg). LCMS (ESI) [MH] - =453.9; 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 8.16 (d, J = 8.2Hz, 2H), 7.72 (d, J = 7.7Hz, 1H), 7.61 (d, J = 8.3Hz, 1H), 7.38 (d, J = 8. 1Hz,2H),3.95–3.89(m,4H),3.57–3.45(m,2H),2.58–2.55(m,4H),2.40(s,3H),1.80–1.74(m,7H),1.34–1.18(m,4H).

[0458] Example 37

[0459] Preparation of N-isopropyl-2-(6-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)acetamide (Compound 98):

[0460] Step 1: Synthesis of tert-butyl 6-(2-(isopropylamino)-2-oxoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate:

[0461] Referring to the first step of Example 5, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (50 mg, 1.0 eq) and 2-chloro-N-isopropylacetamide (683.9 mg) were used as raw materials. The reaction was carried out at 35°C under nitrogen for 3 hours. Flash chromatography (silica gel, DCM:MeOH = 10:1) was used to obtain the product (300 mg). LCMS (ESI) [M+H] + =298.

[0462] Step 2: Synthesis of N-isopropyl-2-(2,6-diazaspiro[3.3]heptane-2-yl)acetamide:

[0463] The product from the first step (250 mg, crude) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) was added. The reaction was allowed to react at room temperature for 2 hours. A small amount of sodium carbonate and a small amount of methanol were added to the reaction solution. After bubbling ceased, the solution was filtered and the filtrate was concentrated to obtain the product (120 mg, crude). LCMS (ESI) [M+H] + = 198. It was used directly in the next reaction without further purification.

[0464] Step 3:

[0465] Referring to the third step of Example 2, 6-(5-bromopyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (100 mg, 1.0 eq) and the product from the second step (124.4 mg) were used as starting materials. The reaction was carried out at 100°C overnight under nitrogen. Flash chromatography (silica gel, DCM:MeOH = 10:1) afforded the crude product, which was then purified by reverse phase chromatography (C18, MeCN:H2O = 2:1) to afford Compound 98 (45 mg). LCMS (ESI) [M+H] + =434.1; 1 H NMR(400MHz,Chloroform-d)δ8.23(d,J=1.9Hz,1H),7.83(d,J=2.6Hz,1H),7.45(dd,J=8.4,2.1Hz,1H),7.36(s,1H),7.07(d,J=8.5Hz,1H),6.83(t,J=2.3H z,1H),6.63(s,1H),4.11(d,J=6.6Hz,1H),4.07(s,4H),3.51(s,4H),3.40(s, 3H), 3.11 (s, 2H), 3.02–2.94 (m, 2H), 2.74–2.65 (m, 2H), 1.17 (d, J = 6.5Hz, 6H).

[0466] Example 38

[0467] Preparation of N-cyclopropyl-2-(4-(6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)piperazin-1-yl)acetamide (Compound 99):

[0468] Step 1: Synthesis of 4-(2-(cyclopropylamino)-2-oxoethyl)piperazine-1-carboxylic acid benzyl ester:

[0469] Referring to the first step of Example 21, 2-(4-((benzyloxy)carbonyl)piperazin-1-yl)acetic acid (1 g, 1.0 eq) and cyclopropylamine (246.17 mg) were used as starting materials and reacted at room temperature for 3 hours. Flash chromatography (silica gel, DCM:MeOH = 10:1) afforded the product (500 mg). LCMS (ESI) [M+H] + =318.

[0470] Step 2: Synthesis of N-cyclopropyl-2-(piperazin-1-yl)acetamide:

[0471] Refer to the second step of Example 2, using the product obtained in the first step (500 mg, 1.0 eq) as the starting material, the reaction was carried out at room temperature under a hydrogen atmosphere overnight. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the product (220 mg, crude product). LCMS (ESI) [M+H] + = 184. It was used directly in the next step without further purification.

[0472] Step 3: Synthesis of 2-(4-(6-bromopyrazin-2-yl)piperazin-1-yl)-N-cyclopropylacetamide:

[0473] Referring to the first step of Example 9, 2,6-dibromopyrazine (220 mg, 1.0 eq) and the product from the second step (200 mg, crude product) were used as starting materials. The reaction was carried out at 90°C overnight under nitrogen. Flash chromatography (silica gel, PE:EA = 2:1) was used to obtain the product (300 mg). LCMS (ESI) [M+H] + =339.9.

[0474] Step 4: Synthesis of N-cyclopropyl-2-(4-(6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)piperazin-1-yl)acetamide:

[0475] The sample from Preparation Example 1 (310 mg, 1.0 eq), the product from the third step (367.28 mg), cesium carbonate (703.47 mg), and bis((cyclopenta-1,3-dien-1-yl)diphenylphosphine)palladium iron dichloride (79.21 mg) were added to 1,4-dioxane (8 mL) and water (2 mL), and the mixture was reacted at 100°C overnight under nitrogen. The reaction solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA = 0:1) to obtain the crude product, which was then purified by reverse phase chromatography (C18, MeCN:H2O = 1:1) to obtain Compound 99 (248.32 mg). LCMS (ESI) [M+H] + =421; 1H NMR (400MHz, Chloroform-d) δ8.34(s,1H),8.06(s,1H),7.89(dd,J=8.4,2.1Hz,1H),7.81(d,J=2.1Hz,1H),7.15(s,1H),7.07(d,J=8.5Hz,1H),3.71(t,J =5.1Hz,4H),3.40(s,3H),3.07(s,2H),3.04–2.95(m,2H),2.77(tq,J=7.4,3 .8Hz,1H),2.73–2.63(m,6H),0.83(td,J=7.0,5.4Hz,2H),0.58–0.48(m,2H).

[0476] Example 39

[0477] Preparation of 2-(2,6-dimethyl-4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide (Compound 102):

[0478] Step 1: Synthesis of tert-butyl 4-(5-bromopyridin-3-yl)-2,6-dimethylpiperazine-1-carboxylate:

[0479] 3,5-Dibromopyridine (2.87 g, 1.3 eq), tert-butyl 2,6-dimethylpiperazine-1-carboxylate (2 g), sodium 2-methylpropan-2-ol (1.35 g), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one dipalladium (83.46 mg), and [5-(diphenylphosphino)-9,9-dimethyl-9H-xanthin-4-yl]diphenylphosphine (324.01 mg) were dissolved in toluene (30 mL) and reacted at 100°C under nitrogen for 16 hours. The reaction solution was directly concentrated and purified by flash chromatography (silica gel, PE:EA = 2:1) to obtain the product (1.65 g). LCMS (ESI) [M+H] + =372.3; 1 H NMR (400MHz, DMSO-d6) δ8.32(d,J=2.5Hz,1H),8.03(d,J=1.8Hz,1H),7.56(t,J=2.2Hz,1H),4.13–4. 06(m,2H),3.68(d,J=12.6Hz,2H),2.92(dd,J=12.5,4.4Hz,2H),1.42(s,9H),1.21(d,J=6.8Hz,6H).

[0480] Step 2: Synthesis of tert-butyl 2,6-dimethyl-4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazine-1-carboxylate:

[0481] The product from the first step (1.65 g, 1.0 eq), the sample from Preparation Example 1 (2.05 g), palladium(2+)dichloride bis((cyclopentadien-1-yl)diphenylphosphine)iron (327.24 mg), and tripotassium phosphate (2.84 g) were dissolved in 1,4-dioxane (15 mL) and water (3 mL). The mixture was reacted at 80°C under nitrogen for 3 hours. Water (50 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (25 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA=5:2) to obtain the product (1.6 g). 1 H NMR (400MHz, DMSO-d6) δ8.31–8.28(m,2H),7.64–7.60(m,2H),7.50–7.47(m,1H),7.20–7.16(m,1H),4.15–4.11(m, 2H),3.73–3.69(m,2H),3.29(s,3H),2.98–2.92(m,4H),2.61–2.56(m,2H),1.43(s,9H),1.28(s,3H),1.26(s,3H).

[0482] Step 3: Synthesis of 6-(5-(3,5-dimethylpiperazin-1-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one:

[0483] Refer to the second step reaction of Example 12, use the product obtained in the second step (1.2 g, 1.0 eq) as the starting material, and react at 25°C for 16 hours. The reaction solution is directly concentrated to obtain the product (900 mg). LCMS (ESI) [M+H] + =351.3.

[0484] Steps 4 to 6: Referring to the reactions of Steps 8 to 10 of Example 36, the product obtained in Step 3 (500 mg, 1.0 eq) and ethyl 2-bromoacetate (0.24 ml) were used as starting materials to prepare Compound 102 (71.18 mg). LCMS (ESI) [M+H] + =450.4; 1H NMR (400MHz, DMSO-d6) δ8.28–8.25(m,2H),7.65–7.60(m,2H),7.52–7.46(m,2H),7.20–7.15(m,1H),3.94–3.86(m,1H),3 .80–3.74(m,2H),3.29(s,3H),3.07(s,2H),2.97–2.92(m,2H),2.82–2.75(m,2H),2.61–2.54(m,4H),1.09–1.04(m,12H).

[0485] Examples 40-49

[0486] Referring to the third step of Example 1, the sample of Preparation Example 3 (50 mg, 1.0 eq) and the starting materials shown in the table below were used to prepare compounds 100, 101, 103-107, and 109-110, respectively. Referring to the sixth step of Example 35, intermediate 35-1 (50 mg, 1.0 eq) and the starting materials shown in the table below were used to prepare compound 108.

[0487] Example 50

[0488] Preparation of N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2-(4-(6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)piperazin-1-yl)acetamide (Compound 111):

[0489] Step 1: Synthesis of tert-butyl 4-(6-bromopyrazin-2-yl)piperazine-1-carboxylate:

[0490] Referring to the first step of Example 9, 2,6-dibromopyrazine (15 g, 1.0 eq) and tert-butyl piperazine-1-carboxylate (11.74 g) were used as raw materials. The reaction was carried out at 90°C under nitrogen for 3 hours. Flash chromatography (silica gel, PE:EA = 3:1) was used to obtain the product (19 g). LCMS (ESI) [M+H] + =342.9.

[0491] Step 2: Synthesis of tert-butyl 4-(6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)piperazine-1-carboxylate:

[0492] Referring to the second step of Example 9, the sample from Preparation Example 1 (15.5 g, 1.0 eq) and the product from the first step (18.53 g) were used as starting materials. The reaction was carried out at 100°C overnight under nitrogen. Flash chromatography (silica gel, PE:EA = 1:4) was used to obtain the product (22 g). LCMS (ESI) [M+H] + =424.

[0493] Step 3: Synthesis of 1-methyl-6-(6-(piperazin-1-yl)pyrazin-2-yl)-3,4-dihydroquinolin-2(1H)-one:

[0494] Referring to the second step reaction of Example 12, the product obtained in the second step (22 g, 1.0 eq) was used as the starting material. The reaction was allowed to react at room temperature overnight. The pH of the reaction solution was adjusted to 8 with aqueous sodium bicarbonate. The reaction solution was separated, and the aqueous phase was extracted with dichloromethane (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the product (16 g). LCMS (ESI) [M+H] + =324.

[0495] Step 4: Synthesis of ethyl 2-(4-(6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)piperazin-1-yl)acetate:

[0496] Referring to the first step of Example 6, the product obtained in the third step (10.5 g, 1.0 eq) and ethyl bromoacetate (5.69 g) were used as raw materials and the reaction was carried out at room temperature for 2 hours. The reaction solvent was dried by spin-drying, and water (300 mL) and ethyl acetate (600 mL) were added to the residue. The reaction solution was separated and the organic phase was collected and the solvent was dried by spin-drying to obtain the product (10.5 g). LCMS (ESI) [M+H] + =410.

[0497] Step 5: Synthesis of 2-(4-(6-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)piperazin-1-yl)acetic acid (Intermediate 111-1):

[0498] The product from step 4 (10.5 g, 1.0 eq) and lithium hydroxide (2.46 g) were added to tetrahydrofuran (100 mL) and water (20 mL). The reaction was allowed to proceed overnight at room temperature. The pH of the reaction solution was adjusted to acidic with dilute hydrochloric acid. A yellow solid precipitated, which was filtered and the filter cake dried to obtain the product (9 g). LCMS (ESI) [M+H] + =382.33.

[0499] Step 6:

[0500] Referring to the third step of Example 1, the product obtained in step 5 (50 mg, 1.0 eq) and 3-fluorobicyclo[1.1.1]pentan-1-amine (13.26 mg) were used as starting materials and reacted at room temperature for 1 hour. The reaction solution was separated and purified by reverse phase chromatography (0.1% aqueous ammonia, acetonitrile) to obtain Compound 111 (27.26 mg). LCMS (ESI) [M+H] + =465.3, 1 HNMR(400MHz,DMSO-d6)δ8.48(s,1H),8.44(s,1H),8.23(s,1H),8.01–7.92(m,2H),7.18(d,J=8.5Hz,1H), 3.73–3.63(m,4H),3.29(s,3H),2.99(s,2H),2.98–2.92(m,2H),2.62–2.54(m,6H),2.33(d,J=2.2Hz,6H).

[0501] Example 51

[0502] Preparation of 2-(4-(5-(6-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide (Compound 112):

[0503] Step 1: Synthesis of ethyl 2-(4-(5-(6-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)pyridin-3-yl)piperazin-1-yl)acetate:

[0504] Ethyl 2-(4-(5-bromopyridin-3-yl)piperazin-1-yl)acetate (150 mg, 1.0 eq), 6-chloro-3,4-dihydroisoquinolin-1(2H)-one (124.51 mg), N1,N2-dimethyl-1,2-cyclohexanediamine (65.01 mg), cesium carbonate (297.82 mg), and cuprous iodide (43.52 mg) were dissolved in 1,4-dioxane (10 mL) and reacted at 130°C for 16 hours. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:THF = 5:3) to obtain the product (130 mg). LCMS (ESI) [M+H] + =429.1.

[0505] Step 2: Synthesis of 2-(4-(5-(6-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)pyridin-3-yl)piperazin-1-yl)acetic acid:

[0506] Referring to the fifth step of Example 35, the product from the first step (130 mg, 0.30 mmol, 1.0 eq) was used as starting material and reacted at 50°C for 2 hours. Reverse-phase chromatography (C18, 0.1% NH4HCO3 in H2O / ACN) was used to obtain the title compound (90 mg). LCMS (ESI) [M+H] + =401.1; 1 H NMR (400MHz, DMSO-d6) δ8.18(d,J=2.5Hz,1H),8.06(d,J=1.9Hz,1H),7.93(d,J=8.3Hz,1H),7.53–7.50(m,1H),7.48–7.44( m,1H),7.39–7.34(m,1H),3.96(t,J=6.5Hz,2H),3.27–3.23(m,4H),3.19(s,2H),3.15(t,J=6.4Hz,2H),2.72–2.66(m,4H).

[0507] Step 3: Synthesis of 2-(4-(5-(6-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide:

[0508] Referring to the third step of Example 1, the product from the second step (40 mg, 1.0 eq) and propane-2-amine (5.9 mg) were used as starting materials and reacted at room temperature for 2 hours. Reverse phase chromatography (C18, 0.1% NH4HCO3 in H2O / ACN) was used to obtain compound 112 (37.98 mg). LCMS (ESI) [M+H] + =441.9; 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=2.6Hz,1H),8.06(d,J=1.9Hz,1H),7.93(d,J=8.4Hz,1H),7.55–7.50(m,2H),7.48–7.44(m,1H),7.39–7.36(m ,1H),3.96(t,J=6.5Hz,2H),3.93–3.87(m,1H),3.29–3.24(m,4H),3.15 (t,J=6.4Hz,2H),2.95(s,2H),2.61–2.57(m,4H),1.07(d,J=6.6Hz,6H).

[0509] Examples 52-57

[0510] With reference to the third step reaction of Example 1, compounds 113-118 were prepared respectively using the sample of Preparation Example 3 (50 mg, 1.0 eq) or intermediate 70-1 (50 mg, 1.0 eq) and the starting materials shown in the table below.

[0511] Example 58

[0512] Preparation of 2-(4-(5-(6-chloro-1,1-dimethyl-3-oxoisoindolin-2-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide (Compound 119):

[0513] Step 1: Synthesis of 2-(2-bromo-5-chlorophenyl)propan-2-amine:

[0514] Dissolve 2-bromo-5-chlorobenzonitrile (10 g, 1.0 eq) in tetrahydrofuran (200 mL) and add methylmagnesium bromide (77 mL) dropwise at 0°C under nitrogen protection. After reacting for 2 hours, add tetraisopropyl titanate (13.13 g) and react at room temperature for 16 hours. Add 3M hydrochloric acid to adjust the pH to 3-4 and extract with ethyl acetate (400 mL). Adjust the pH of the aqueous phase to 9-10 with sodium hydroxide solution (1 M) and extract with ethyl acetate (300 mL*3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the product (3 g). LCMS (ESI) [M+H] + =248.0; 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 2.6Hz, 1H), 7.45–7.42 (m, 1H), 7.01–6.96 (m, 1H), 1.85–1.76 (m, 2H), 1.57 (s, 6H).

[0515] Step 2: Synthesis of 5-chloro-3,3-dimethylisoindolin-1-one:

[0516] The product from the first step (2.5 g, 1.0 eq) was dissolved in N,N-dimethylformamide (20 mL), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (369 mg) and ethylbis(propan-2-yl)amine (3.9 mL) were added. The mixture was reacted at 130°C under carbon monoxide (balloon pressure) for 16 hours. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL*4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA=1:1) to obtain the product (600 mg). LCMS (ESI) [M+ACN+H] + =237.1;1 H NMR (400MHz, CDCl3) δ7.73(s,1H),7.45–7.40(m,1H),7.40–7.37(m,1H),7.29–7.24(m,1H),1.56(s,6H).

[0517] Step 3: Synthesis of 2-(5-bromopyridin-3-yl)-5-chloro-3,3-dimethylisoindolin-1-one:

[0518] The product from step 2 (100 mg, 1.0 eq) and 3-bromo-5-iodopyridine (217.65 mg) were dissolved in dioxane (1 mL). Potassium phosphate (216.99 mg), cyclohexane-1,2-diamine (35.02 mg), and cuprous iodide (58.41 mg) were added and reacted at 120°C under nitrogen for 3 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA=4:1) to obtain the product (90 mg). LCMS (ESI) [M+H] + =350.8; 1 HNMR(400MHz,DMSO-d6)δ8.82(d,J=2.1Hz,1H),8.59(d,J=2.0Hz,1H),8.24–8.1 9(m,1H),8.02–8.00(m,1H),7.80–7.77(m,1H),7.63–7.59(m,1H),1.52(s,6H).

[0519] Step 4: Synthesis of 2-(4-(5-(6-chloro-1,1-dimethyl-3-oxoisoindolin-2-yl)pyridin-3-yl)piperazin-1-yl)acetic acid:

[0520] Toluene (2 mL) was added to a mixture of the product obtained in the third step (90 mg), tert-butyl 2-(piperazin-1-yl)acetate (76.89 mg), sodium tert-butoxide (99.95 mg), triethylamine (105.24 mg), [1-(2-diphenylphosphinonaphthalen-1-yl)naphthalen-2-yl]-diphenylphosphine (32.38 mg), and tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (23.81 mg), and the mixture was reacted at 110°C under nitrogen for 16 hours. The reaction solution was directly concentrated and separated and purified by reverse phase chromatography (acetonitrile / 0.1% formic acid aqueous solution = 50%) to obtain the product (30 mg). LCMS (ESI) [M+H] + =415.0.

[0521] Step 5: Synthesis of 2-(4-(5-(6-chloro-1,1-dimethyl-3-oxoisoindolin-2-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide:

[0522] Referring to the third step of Example 1, the product from step 4 (30 mg, 1.0 eq) and propan-2-amine (4.27 mg) were used as starting materials and reacted at room temperature for 1 hour. Reverse phase chromatography (0.1% aqueous ammonia, acetonitrile) was used to separate and purify compound 119 (8.45 mg). LCMS (ESI) [M+H] + =455.8; 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=2.6Hz,1H),7.98(d,J=1.6Hz,1H),7.91(d,J=1.7Hz,1H),7.75(d,J=8.1Hz,1H),7.61–7.57(m,1H),7.52(d ,J=8.1Hz,1H),7.30–7.23(m,1H),3.97–3.84(m,1H),3.31–3.26(m,4H ),2.95(s,2H),2.61–2.55(m,4H),1.49(s,6H),1.07(d,J=6.6Hz,6H).

[0523] Examples 59-68

[0524] With reference to the third step reaction of Example 1, compounds 120-129 were prepared respectively using the sample of Preparation Example 3 (50 mg, 1.0 eq) or intermediate 111-1 (100 mg, 1.0 eq) and the starting materials shown in the table below.

[0525] Example 69

[0526] Preparation of 2-(4-(5-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide (Compound 130):

[0527] Step 1: Synthesis of 3-chloro-N-(3-fluorophenyl)propionamide:

[0528] Under nitrogen protection at 0°C, pyridine (14.24g) and 3-fluoroaniline (10g, 1.0eq) were dissolved in acetone (240mL). 3-chloropropionyl chloride (12.57g) was slowly added to the system. After the addition was complete, the reaction was allowed to react at 50°C for 16 hours. The reaction solution was cooled to room temperature, concentrated, diluted with water (100mL), adjusted to pH 7 with 1M hydrochloric acid, and extracted with ethyl acetate (80mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the product (15g). LCMS (ESI) [M+H] + =202.0, 1 H NMR (400MHz, CDCl3) δ7.56–7.40(m,2H),7.30–7.24(m,1H),7.19–7.11(m,1H ), 6.83(td,J=8.2,1.9Hz,1H), 3.88(t,J=6.4Hz,2H), 2.82(t,J=6.4Hz,2H).

[0529] Step 2: Synthesis of 5-fluoro-3,4-dihydroquinolin-2(1H)-one (P1) and 7-fluoro-3,4-dihydroquinolin-2(1H)-one (P2):

[0530] Aluminum trichloride (3306 mg) was added to the product obtained in the first step (5 g, 1.0 eq) and reacted at 125°C for 5 hours. The reaction solution was cooled to room temperature and slowly added with ice water (50 mL) at 0°C to quench the reaction. The mixture was extracted with dichloromethane (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a mixture of intermediate compounds P1 and P2 (4.0 g). LCMS (ESI) (M+H) + =166.1.

[0531] Step 3: Synthesis of 5-fluoro-1-methyl-3,4-dihydroquinolin-2(1H)-one (P1-1) and 7-fluoro-1-methyl-3,4-dihydroquinolin-2(1H)-one (P2-1):

[0532] A solution of a mixture of intermediate compound P1 (1.83 g) and intermediate compound P2 (9.17 g, 1.0 eq) in dimethylformamide (200 mL) was added to a solution of sodium hydride (2.55 g) in dimethylformamide (200 mL) at 0°C and allowed to react for 10 minutes. Iodomethane (10.25 g) was slowly added to the system and allowed to react at room temperature for 1 hour. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (300 mL), diluted with water (300 mL), and extracted with ethyl acetate (300 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA = 87:13) to obtain a mixture of products P1-1 and P2-1 (12.19 g, crude product). NMR analysis showed a ratio of P1-1 / P2-1 of 1 / 5. LCMS (ESI) [M+H] + =180.0.

[0533] Step 4: Synthesis of 6-bromo-5-fluoro-1-methyl-3,4-dihydroquinolin-2(1H)-one (P1-2) and 6-bromo-7-fluoro-1-methyl-3,4-dihydroquinolin-2(1H)-one (P2-2):

[0534] 1-Bromopyrrolidine-2,5-dione (15.27 g) was added to a solution of a mixture of P1-1 (1.71 g, crude) and P2-1 (10.25 g, crude) in dimethylformamide (200 mL) and allowed to react at 25°C for 16 hours. Water (500 mL) was added to the reaction solution and extracted with ethyl acetate (300 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA=4:1) to obtain a mixture of products P1-2 and P2-2 (15.66 g). NMR showed a ratio of P1-2 / P2-2=1 / 7. 1 g of the mixture was subjected to SFC (supercritical fluid chromatography) to obtain P1-2 (90 mg) and P2-2 (860 mg). Compound P1-2: LCMS (ESI) [M+H] + =259.9. 1 H NMR (400 MHz, CDCl3) δ 7.44–7.38 (m, 1H), 6.68 (dd, J = 8.8, 0.9 Hz, 1H), 3.34 (s, 3H), 3.00–2.94 (m, 2H), 2.69–2.62 (m, 2H). Compound P2-2: LCMS (ESI) [M+H] + =259.9. 1H NMR (400MHz, CDCl3) δ7.32 (d, J = 7.3Hz, 1H), 6.76 (d, J = 10.2Hz, 1H), 3.31 (s, 3H), 2.90–2.85 (m, 2H), 2.65 (dd, J = 8.5, 6.2Hz, 2H).

[0535] Step 5: Synthesis of 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one:

[0536] Bis((cyclopenta-1,3-dien-1-yl)diphenylphosphine)palladium iron dichloride (114 mg) was added to a solution of compound P2-2 (400 mg, 1.0 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (787 mg), and potassium acetate (456 mg) in 1,4-dioxane (10 mL). The mixture was reacted at 90°C under nitrogen for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase chromatography (C18, 0.1% ammonia in water / acetonitrile = 80% / 20%) to obtain the product (90 mg). LCMS (ESI) [M+H] + =305.1; LCMS (ESI) (boronic acid) [M+H] + =224.1.

[0537] Step 6: Synthesis of 2-(4-(5-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide:

[0538] Under a nitrogen atmosphere, bis((cyclopenta-1,3-dien-1-yl)diphenylphosphine)palladium iron dichloride (15 mg) was added to a solution of 2-(4-(5-bromopyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide (70 mg, 1.0 eq), the product from step 5 (75 mg), and potassium phosphate (131 mg) in 1,4-dioxane (5 mL) and water (1 mL). The mixture was reacted at 80°C for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative HPLC (C18, 0.1% NH3.H2O in H2O / ACN) to give compound 130 (47.03 mg). LCMS (ESI) [M+H] + =439.9; 1H NMR (400MHz, DMSO-d6) δ8.30(d,J=2.7Hz,1H),8.15(t,J=1.8Hz,1H),7.50(dd,J=17.8,8.3Hz,2H),7.42–7.39(m,1H),7.11(d,J=12.8H z,1H),3.95–3.86(m,1H),3.32–3.28(m,4H),3.27(s,3H),2.96(s,2H),2.91(t,J=7.4Hz,2H),2.62–2.56(m,6H),1.08(d,J=6.6Hz,6H).

[0539] Examples 70-73

[0540] With reference to the third step reaction of Example 1, compounds 131-134 were prepared respectively using the sample of Preparation Example 3 (50 mg, 1.0 eq) or intermediate 111-1 (100 mg, 1.0 eq) and the starting materials shown in the table below.

[0541] Example 74

[0542] Preparation of 2-(4-(5-(5-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide (Compound 135):

[0543] Step 1: Synthesis of 5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one:

[0544] 6-Bromo-5-fluoro-1-methyl-3,4-dihydroquinolin-2(1H)-one (60 mg, 1.0 eq), bispinacol boronate (118.07 mg), potassium acetate (68.45 mg), and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (17.06 mg) were dissolved in 1,4-dioxane (3 mL) and reacted at 90°C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled, and water (10 mL) was added. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude target compound was obtained by flash chromatography (silica gel, PE:EA = 7:1). This was then purified by reverse phase chromatography (0.1% aqueous ammonia / acetonitrile) to afford the product (40 mg). LCMS (ESI) (M+H) + =224.1.(boric acid molecular weight).

[0545] Step 2:

[0546] Referring to the sixth step of Example 69, the product from the first step (30 mg, 1.0 eq) and 2-(4-(5-bromopyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide (33.55 mg) were used as starting materials. The reaction was carried out at 80°C under a nitrogen atmosphere for 2 hours. The product was separated and purified by preparative HPLC (0.1% NH3·H2O in water / ACN) to give Compound 135 (6.34 mg). LCMS (ESI) (M+H) + =440.3; 1 H NMR (400MHz, MeOD-d4) δ8.23(d,J=2.4Hz,1H),8.13(s,1H),7.51(s,1H),7.44(t,J=8.5Hz,1H),7.07(d,J=8.5Hz,1H),4.1 0–3.96(m,1H),3.39(s,3H),3.38–3.34(m,4H),3.07(s,2H),3.05–2.99(m,2H),2.73–2.65(m,6H),1.17(d,J=6.6Hz,6H).

[0547] Example 75

[0548] Preparation of N-isopropyl-2-(4-(5-(6-methoxy-1,1-dimethyl-3-oxoisoindolin-2-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 136):

[0549] Step 1: Synthesis of 2-(2-bromo-5-methoxyphenyl)propan-2-amine:

[0550] Refer to the first step of Example 58, using 2-bromo-5-methoxybenzonitrile (5 g, 1.0 eq) as the starting material, and react at room temperature for 16 hours. The treatment method of the first step of Example 58 was used to obtain the product (2 g, crude product). LCMS (ESI) [M+H] + =244.0; 1 HNMR (400MHz, CDCl3) δ7.48(d,J=8.7Hz,1H),7.16(d,J=3.0Hz,1H),6.62(dd,J=8.7,3.0Hz,1H),3.79(s,3H),2.07–1.92(m,2H),1.64(s,6H).

[0551] Referring to the second to fifth steps of Example 58, compound 136 (8.63 mg) was prepared using the product obtained in the first step (2 g, crude product) as the starting material. LCMS (ESI) [M+H] + =452.1;1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=2.5Hz,1H),7.89(d,J=1.5Hz,1H),7.64(d,J=8.4Hz,1H),7.52(d,J=8.1Hz,1H),7.33(d,J=2.1Hz,1H),7.29–7. 22(m,1H),7.06(dd,J=8.4,2.2Hz,1H),3.95–3.86(m,4H),3.30–3.27(m, 4H), 2.95 (s, 2H), 2.63–2.54 (m, 4H), 1.47 (s, 6H), 1.07 (d, J = 6.6Hz, 6H).

[0552] Second step product (5-methoxy-3,3-dimethylisoindolin-1-one): LCMS (ESI) [M+H] + =192.1; 1 H NMR (400MHz, CDCl3) δ7.73(d,J=8.4Hz,1H),6.96(M,1H),6.89(s,1H),6.85(d,J=2.1Hz,1H),3.89(s,3H),1.54(s,6H).

[0553] The third step product (2-(5-bromopyridin-3-yl)-5-methoxy-3,3-dimethylisoindolin-1-one): LCMS (ESI) [M+H] + =348.9; 1 HNMR(400MHz, CDCl3)δ8.70(d,J=2.1Hz,1H),8.52(d,J=2.1Hz,1H),7.86–7.8 2(m,2H),7.04–7.00(m,1H),6.92(d,J=2.1Hz,1H),3.92(s,3H),1.55(s,6H).

[0554] The fourth step product (2-(4-(5-(6-methoxy-1,1-dimethyl-3-oxoisoindolin-2-yl)pyridin-3-yl)piperazin-1-yl)acetic acid): LCMS (ESI) [M+H] + =411.2; 1H NMR (400MHz, DMSO-d6) δ8.34(d,J=2.6Hz,1H),7.96–7.86(m,1H),7.70–7.62(m,1H),7.34(d,J=2.1Hz,1H),7.29–7. 23(m,1H),7.06(dd,J=8.4,2.2Hz,1H),3.89(s,3H),3.35–3.24(m,4H),3.17(s,2H),2.84–2.61(m,4H),1.47(s,6H).

[0555] Example 76

[0556] Preparation of N-isopropyl-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamide (Compound 137):

[0557] Step 1: Synthesis of 3-(methylthio)-1,2,4-triazine-5(4H)-one:

[0558] Sodium hydride (4 g, 1.29 eq) was added to water (100 mL, 100.0%) under ice-cooling and stirred until dissolved. 3-Mercapto-1,2,4-triazine-5(4H)-one (10 g) and iodomethane (7.23 mL) were added and reacted at room temperature for 12 hours. Filter and dry the filter cake to obtain the product (4.7 g). LCMS (ESI) [M+H] + =144.04.

[0559] Step 2: Synthesis of tert-butyl 4-(5-oxo-4,5-dihydro-1,2,4-triazine-3-yl)piperazine-1-carboxylate:

[0560] The product from the first step (4.6 g, 1.0 eq) and tert-butyl piperazine-1-carboxylate (6.58 g) were added to N-methylpyrrolidone (40 mL) and reacted at 150°C for 2 hours. The reaction solution was poured into methyl tert-butyl ether and filtered to obtain the product (8.26 g). LCMS (ESI) [M+H] + =282.17.

[0561] Step 3: Synthesis of tert-butyl 4-(5-chloro-1,2,4-triazine-3-yl)piperazine-1-carboxylate:

[0562] Dissolve triphenylphosphine (10.07 g) in 1,4-dioxane (60 mL) and add 1-chloropyrrolidine-2,5-dione (5.04 g). After stirring at 25°C for 30 minutes, add the product from step 2 (3.6 g, 1.0 eq) and react at 125°C for 1 hour. Cool the reaction mixture, add N,N-diisopropylethylamine (4 mL), filter, and concentrate the filtrate. Purify by flash chromatography (silica gel, PE:EA = 6:1) to obtain the product (700 mg). LCMS (ESI) [M+H] + =300.4.

[0563] Step 4: Synthesis of tert-butyl 4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,4-triazine-3-yl)piperazine-1-carboxylate:

[0564] Referring to the second step of Example 39, the product obtained in the third step (700 mg, 1.0 eq) and the sample from Preparation Example 1 (1.07 g) were used as starting materials. The reaction was carried out at 80°C under nitrogen for 1 hour. Flash chromatography (silica gel, PE:THF = 1:1) was used to obtain the product (850 mg). LCMS (ESI) [M+H] + =425.2; 1 H NMR (400MHz, DMSO-d6) δ9.31 (s, 1H), 8.21–8.15 (m, 2H), 7.25 (d, J = 8.5Hz, 1H), 3.92–3.87 ( m,4H),3.51–3.47(m,4H),3.31(s,3H),3.02–2.96(m,2H),2.64–2.60(m,2H),1.44(s,9H).

[0565] Step 5: Synthesis of 1-methyl-6-(3-(piperazin-1-yl)-1,2,4-triazin-5-yl)-3,4-dihydroquinolin-2(1H)-one:

[0566] Referring to the third step reaction of Example 50, the product obtained in the fourth step (1.6 g, 1.0 eq) was used as the starting material and the reaction was carried out at room temperature for 3 hours. After treatment, the product (1.4 g, crude product) was obtained. LCMS (ESI) [M+H] + = 325. It was used directly in the next step without further purification.

[0567] Step 6:

[0568] Referring to the first step of Example 5, the product from Step 5 (80 mg, crude) and 2-chloro-N-(propan-2-yl)acetamide (43.47 mg) were used as starting materials. The reaction was carried out at 35°C under nitrogen for 3 hours. Preparative HPLC separation and purification (C18, 10 mmol / L NH4HCO3 in water, MeCN) afforded Compound 137 (45.18 mg). LCMS (ESI) [M+H] + =424.41; 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),8.22–8.13(m,2H),7.57(d,J=8.1Hz,1H),7.25(d,J=8.5Hz,1H ),3.97–3.85(m,5H),3.31(s,3H),2.98(d,J=7.1Hz,4H),2.65–2.54(m,6H),1.09(d,J=6.6Hz,6H).

[0569] Example 77

[0570] Preparation of 2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-N-(3-morpholinocyclobutyl)acetamide (Compound 138):

[0571] Step 1: Synthesis of 3-((tert-Butyloxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate:

[0572] Dissolve tert-butyl (3-hydroxycyclobutyl)carbamate (900 mg, 1.0 eq) in dichloromethane (20 mL), add N,N-dimethylpyridin-4-amine (1.17 g) and triethylamine (972.77 mg). After stirring, add 4-methylbenzene-1-sulfonyl chloride (916.39 mg) dropwise and react at 45°C for 2 hours. Extract with dichloromethane (10 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and purified by flash chromatography (silica gel, PE:EA = 1:4) to obtain the product (1.1 g). LCMS (ESI) [M+H-Boc] + =242.14.

[0573] Step 2: Synthesis of tert-butyl (3-morpholinocyclobutyl)carbamate:

[0574] The product from the first step (500 mg, 1.0 eq) and morpholine (1.28 g) were dissolved in N,N-dimethylpyridin-4-amine (17.89 mg) and reacted at 100°C overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA = 1:1) to obtain the product (300 mg).

[0575] Step 3: Synthesis of 3-morpholinocyclobutane-1-amine:

[0576] Referring to the second step reaction of Example 37, the product obtained in the second step (300 mg, 1.0 eq) was used as the starting material, and the reaction was carried out at room temperature for 3 hours. After treatment and separation, the product (150 mg) was obtained. LCMS (ESI) [M+H] + =157.1. It was used directly in the next reaction without further purification.

[0577] Step 4:

[0578] Referring to the third step of Example 1, the sample from Preparation Example 3 (100 mg, 1.0 eq) and the product from the third step (100 mg, crude) were used as starting materials and reacted at room temperature for 2 hours. Preparative HPLC separation and purification (C18, 10 mmol / L NH4HCO3 in water, MeCN) afforded Compound 138 (25.17 mg). LCMS (ESI) [M+H] + =519.1; 1 H NMR (400MHz, DMSO-d6) δ8.28 (dd, J=10.4, 2.2Hz, 2H), 8.00 (dd, J=34.6, 7.9Hz, 1H), 7.63 (dq, J=4 .8,2.3Hz,2H),7.50(d,J=2.4Hz,1H),7.17(d,J=9.0Hz,1H),4.19(q,J=7.0Hz,1H),3.56(dt,J=1 0.8, 4.5Hz, 4H), 3.29 (s, 3H), 2.95 (dd, J=11.7, 8.4Hz, 4H), 2.75 (q, J=7.2, 6.2Hz, 1H), 2.59 (dt, J=9.4,6.5Hz,6H),2.43–2.12(m,7H),1.98(dt,J=12.7,7.2Hz,1H),1.77(q,J=10.2,8.3Hz,1H).

[0579] Example 78

[0580] Preparation of 2-(4-(5-(6'-chloro-3'-oxospiro[cyclopropane-1,1'-isoindoline]-2'-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide (Compound 139):

[0581] Step 1: Synthesis of 6'-chlorospiro[cyclopropane-1,1'-isoindolin]-3'-one:

[0582] Methyl 4-chloro-2-cyanobenzoate (600 mg, 1.0 eq) was dissolved in diethyl ether (10 mL), and tetraisopropyl titanate (959.02 mg) was added. Ethylmagnesium bromide (2.04 mL, 3 M) was added dropwise to the reaction mixture at 0°C under nitrogen protection. After completion of the addition, the mixture was allowed to react at room temperature for 3 hours. The reaction mixture was quenched with hydrochloric acid (1 M, 10 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE:EA = 1:1) to obtain the product (140 mg). LCMS (ESI) [M+H] + =194.1; 1 HNMR(400MHz,DMSO-d6)δ8.80(s,1H),7.71–7.62(m,1H),7.55–7.40(m,2H),1.60–1.36(m,4H).

[0583] Step 2: Synthesis of 2'-(5-bromopyridin-3-yl)-6'-chlorospiro[cyclopropane-1,1'-isoindoline]-3'-one:

[0584] Referring to the third step of Example 58, the product from the first step (140 mg, 1.0 eq) and 3-bromo-5-iodopyridine (307.89 mg) were used as starting materials. The reaction was carried out at 120°C under nitrogen for 3 hours. Flash chromatography (silica gel, PE:EA = 2:1) was used to obtain the product (120 mg). LCMS (ESI) [M+H] + =350.9; 1 H NMR(400MHz, DMSO-d6)δ8.82(d,J=2.1Hz,1H),8.55(d,J=2.0Hz,1H),8.24–8.19(m,1H),7.85 –7.82(m,1H),7.64–7.63(m,1H),7.60–7.57(m,1H),1.58(d,J=2.1Hz,2H),1.37–1.32(m,2H).

[0585] Referring to the fourth and fifth steps of Example 58, the product obtained in the second step was used as the starting material (120 mg, 1.0 eq) to obtain compound 139 (26.46 mg). LCMS (ESI) [M+H] + =454.0; 1 HNMR(400MHz,DMSO-d6)δ8.37(d,J=2.7Hz,1H),7.85(d,J=1.8Hz,1H),7.83 –7.78(m,1H),7.64–7.60(m,1H),7.60–7.55(m,1H),7.52(d,J=8.2Hz,1H), 7.28–7.23(m,1H),3.95–3.85(m,1H),3.31–3.26(m,4H),2.94(s,2H),2.60 –2.54(m,4H),1.60–1.49(m,2H),1.34–1.25(m,2H),1.07(d,J=6.6Hz,6H).

[0586] The third step product (2-(4-(5-(6'-chloro-3'-oxospiro[cyclopropane-1,1'-isoindoline]-2'-yl)pyridin-3-yl)piperazin-1-yl)acetic acid): LCMS (ESI) [M+H] + =413.1.

[0587] Examples 79-85

[0588] Referring to the third step reaction of Example 1, the sample of Preparation Example 3 (50 mg, 1.0 eq) and the starting materials shown in the table below were used to prepare compounds 140-145 and 148, respectively.

[0589] Example 86

[0590] Preparation of N-(trans-4-acetylaminocyclohexyl)-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamide (Compound 146):

[0591] Step 1: Synthesis of ethyl 2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,4-triazine-3-yl)piperazin-1-yl)acetate:

[0592] Referring to the fourth step of Example 50, 1-methyl-6-(3-(piperazin-1-yl)-1,2,4-triazin-5-yl)-3,4-dihydroquinolin-2(1H)-one (1.1 g, 1.0 eq) and ethyl 2-bromoacetate (594.63 mg) were used as starting materials and reacted at room temperature for 2 hours. The reaction solution was directly concentrated and purified by flash chromatography (silica gel, PE:EA = 3:1) to obtain the product (1.1 g). LCMS (ESI) [M+H] + =411.1.

[0593] Step 2: Synthesis of 2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,4-triazine-3-yl)piperazin-1-yl)acetic acid:

[0594] Referring to the fifth step of Example 50, the product obtained in the first step (1 g, 1.0 eq) was used and reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to acidic with 1 M hydrochloric acid, and solid precipitated. The product (1 g, crude) was obtained by filtration and drying. LCMS (ESI) [M+H] + = 383. It was used directly in the next step without further purification.

[0595] Step 3: Synthesis of tert-butyl (trans-4-(2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamido)cyclohexyl)carbamate:

[0596] Referring to the third step of Example 1, the product from the second step (200 mg, crude) and tert-butyl (trans-4-aminocyclohexyl)carbamate (224.15 mg) were used as starting materials and reacted at room temperature for 2 hours. Flash chromatography (silica gel, PE:EA = 2:1) was used to obtain the product (300 mg). LCMS (ESI) [M+H] + =579.1.

[0597] Step 4: Synthesis of N-((1R, 4R)-4-aminocyclohexyl)-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,4-triazine-3-yl)piperazin-1-yl)acetamide:

[0598] Referring to the fifth step reaction of Example 76, the product obtained in the third step (200 mg, 1.0 eq) was used and reacted at room temperature for 2 hours to obtain the product (150 mg, crude product). LCMS (ESI) [M+H] + =479.1. It was used directly in the next step without further purification.

[0599] Step 5:

[0600] Referring to the sixth step of Example 21, the product from step 4 (150 mg, crude) and acetyl chloride (29.52 mg) were used as starting materials and reacted at room temperature for 2 hours. Preparative HPLC separation and purification (C18, 10 mmol / L NH4HCO3 in water, MeCN) afforded Compound 146 (12.12 mg). LCMS (ESI) [M+H] + =521.1; 1 H NMR (400MHz, DMSO-d6) δ9.28(s,1H),8.22–8.13(m,2H),7.72(d,J=7.8Hz,1H),7.61(d,J=8.2Hz,1H),7.25(d,J=8.6Hz,1H),3.93(t,J=5.0Hz,4H),3 .46(tt,J=7.6,3.8Hz,2H),3.31(s,3H),2.98(d,J=3.2Hz,4H),2.59(dq,J =16.0,5.5Hz,6H),1.78(d,J=5.7Hz,4H),1.76(s,3H),1.38–1.14(m,4H).

[0601] Example 87

[0602] Preparation of N-isopropyl-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide-2,2-d2 (Compound 147):

[0603] Step 1: Synthesis of methyl 2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetate-d2:

[0604] Referring to the eighth step of Example 36, intermediate 1 (700 mg, crude product) and methyl 2-bromoacetate-d2 (336.52 mg) were used as starting materials and the reaction was carried out at 25°C for 2 hours. Preparative HPLC separation and purification (C18, 0.1% NH4HCO3 in H2O / ACN) afforded the product (390 mg). LCMS (ESI) [M+H] + =397.5,397.4; 1H NMR(400MHz,DMSO-d6)δ8.30–8.25(m,2H),7.65–7.60(m,2H),7.49(s,1H),7.19–7.15(m,1H ),3.64(s,3H),3.30–3.27(m,7H),2.97–2.91(m,2H),2.71–2.66(m,4H),2.61–2.56(m,2H).

[0605] Step 2: Synthesis of 2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetic acid-2,2-d2 acid:

[0606] Refer to the ninth step of Example 36, using the product from the first step (390 mg, 1.0 eq) as starting material, and stirring at 50°C for 2 hours. The reaction solution was directly concentrated, and dilute hydrochloric acid (1 M) was added dropwise to the residue to adjust the pH to 6-7. After the solid precipitated, it was filtered and the filter cake was dried to obtain the product (300 mg). LCMS (ESI) [M+H] + =383.4.

[0607] Step 3:

[0608] Referring to the third step of Example 1, the product from the second step (50 mg, 1.0 eq) and isopropylamine (7.73 mg) were used as starting materials and reacted at 25°C for 2 hours. Preparative HPLC separation and purification (C18, 0.1% NH3H2O ​​in H2O / ACN) afforded compound 147 (4.69 mg). LCMS (ESI) [M+H] + =424.4; 1 H NMR(400MHz,MeOD-d4)δ8.24–8.18(m,2H),7.59–7.56(m,2H),7.54(s,1H),7.23(d,J=8.4Hz,1H),4.07–3.9 9(m,1H),3.40–3.36(m,7H),3.03–2.98(m,2H),2.74–2.69(m,4H),2.68–2.63(m,2H),1.17(d,J=6.6Hz,6H).

[0609] Example 88

[0610] Preparation of N-(1-(2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetyl)azetidin-3-yl)acetamide (Compound 149):

[0611] Step 1: Synthesis of tert-butyl 3-acetamidoazetidine-1-carboxylate:

[0612] Dissolve tert-butyl 3-aminoazetidine-1-carboxylate (500 mg, 1 eq) in dichloromethane (10 mL), add acetyl chloride (273.49 mg) at 0°C, and react at room temperature for 2 hours. The reaction solution was quenched with water (20 mL) and extracted with dichloromethane (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the product (260 mg, crude product). LCMS (ESI) [M+H] + =215.2; 1 HNMR (400MHz, CDCl3) δ6.13-5.92(m,1H),4.70-4.51(m,1H),4.37-4.17(m,2H),3.81-3.62(m,2H),2.01(s,3H),1.44(s,9H).

[0613] Step 2: Synthesis of N-(azetidin-3-yl)acetamide trifluoroacetate:

[0614] The first step product (260 mg, crude product, 1 eq) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 16 hours. The reaction solution was directly concentrated to obtain the product (110 mg, crude product). LCMS (ESI) [M+H] + =115.1.

[0615] Step 3: Synthesis of compound 149:

[0616] The product from Preparation Example 3 (50 mg, 1 eq) was dissolved in N,N-dimethylformamide (1 mL). N,N-diisopropylethylamine (0.07 mL), HATU (74.96 mg), and the product from the second step (29.99 mg) were added and reacted at room temperature for 1 hour. The mixture was separated and purified by reverse phase chromatography (0.1% aqueous ammonia, acetonitrile) to obtain the title compound (8.16 mg, 13% yield). LCMS (ESI) [M+H] + =477.3; 1HNMR(400MHz,DMSO-d6)δ8.50(d,J=6.4Hz,1H),8.29(d,J=1.7Hz,1H),8.26(d, J=2.7Hz,1H),7.66-7.60(m,2H),7.52-7.47(m,1H),7.20-7.15(m,1H),4.50-4 .37(m,2H),4.18-4.05(m,1H),4.05-3.95(m,1H),3.74-3.64(m,1H),3.30-3.2 7(m,7H),3.11-2.99(m,2H),2.98-2.91(m,2H),2.62-2.56(m,6H),1.82(s,3H).

[0617] Example 89

[0618] Preparation of N-(3-acetylaminocyclobutyl)-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 150):

[0619] Step 1: Synthesis of tert-butyl (3-acetamidocyclobutyl)carbamate:

[0620] Referring to the first step of Example 88, tert-butyl (3-aminocyclobutyl)carbamate (200 mg, 1 eq) was used as the starting material to obtain the product (115 mg, crude product). LCMS (ESI) [M+H-56] + =173.6.

[0621] Step 2: Synthesis of N-(3-aminocyclobutyl)acetamide trifluoroacetate:

[0622] Referring to the second step of Example 88, tert-butyl (3-acetamidocyclobutyl)carbamate (115 mg, 1 eq) was used as the starting material to obtain the product (60 mg, crude product). LCMS (ESI) [M+H] + =129.6.

[0623] Step 3: Synthesis of compound 150:

[0624] Referring to the third step of Example 88, the product from Preparation Example 3 (80 mg, 1 eq) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (0.09 mL), HATU (95.95 mg), and the product from the second step (58.57 mg) were added and reacted at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and then purified by reverse-phase chromatography (C18, 0.1% NH3H2O ​​in H2O / ACN) to obtain the title compound (41.45 mg). LCMS [ESI] [M+H] + =491.3; 1 H NMR (400MHz, MeOD-d4) δ8.26-8.17(m,2H),7.60-7.55(m,2H),7.53(s,1H),7.22(d,J=8.4Hz,1H),4.42-4.27(m,1H),4.11 -3.91(m,1H),3.41-3.37(m,7H),3.10-3.06(m,2H),3.03-2.97(m,2H),2.75 -2.63(m,7H),2.38-2.30(m,2H),1.99-1.93(m,1H),1.93-1.88(m,3H).

[0625] Example 90

[0626] Preparation of N-methyl-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-N-(3-(N-methylacetamido)cyclobutyl)acetamide (Compound 151):

[0627] Step 1: Synthesis of tert-butyl (methyl (3- (N-methylacetylamino) cyclobutyl) carbamate:

[0628] Dissolve tert-butyl (3-acetamidocyclobutyl)carbamate (300 mg, 1 eq) in NN-dimethylformamide (6 mL). Add sodium hydride (90.63 mg) under nitrogen in an ice bath. After stirring for 30 minutes, add iodomethane (0.25 mL) and continue the reaction at room temperature for 2 hours. The reaction solution is quenched with water (45 mL) and extracted with ethyl acetate (25 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and purified by flash chromatography (silica gel, petroleum ether:tetrahydrofuran = 3:1) to obtain the product (80 mg). LCMS (ESI) [M+H] + =257.5.

[0629] Step 2: Synthesis of N-methyl-N-(3-(methylamino)cyclobutyl)acetamide trifluoroacetate:

[0630] Referring to the second step reaction of Example 88, the product (110 mg, 1 eq) of the first step of Example 90 was used as the starting material to obtain the product (60 mg). LCMS (ESI) [M+H] + =157.6.

[0631] Step 3: Synthesis of compound 151:

[0632] The product from Preparation Example 3 (80 mg, 1 eq) and HATU (95.95 mg) were dissolved in N,N-dimethylformamide (2 mL). Triethylamine (0.09 ml) and the product from the second step (56.83 mg) were added sequentially under an ice bath. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was purified by reverse-phase chromatography (C18, 0.1% NH3H2O ​​in H2O / ACN) to obtain the title compound (32.27 mg). LCMS (ESI) [M+H] + =519.3; 1 H NMR(400MHz,DMSO-d6)δ8.27(dd,J=12.2,2.0Hz,2H),7.64-7.60(m,2H),7.51-7.47(m,1H),7.19-7.15(m,1H),5.00-4.04(m,2H),3.3 0-3.27(m,7H),3.26-3.21(m,2H),3.02-2.91(m,5H),2.90-2.80(m,3H),2.64-2.55(m,6H),2.45-2.17(m,4H),1.99(d,J=10.9Hz,3H).

[0633] Example 91

[0634] Preparation of 2-(4-(5-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide (Compound 152):

[0635] Step 1: Synthesis of 3-chloro-N-(2-fluorophenyl)propionamide:

[0636] 2-Fluoroaniline (5 g, 1 eq) and pyridine (3.92 g) were added to 1,2-dichloroethane (100 mL). 3-Chloropropionyl chloride (6.28 g) was added dropwise in an ice bath and allowed to react at room temperature for 2 hours. The mixture was washed with water and 2N hydrochloric acid solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the product (8.8 g). LCMS (ESI) [M+H] + =201.8.

[0637] Step 2: Synthesis of 8-fluoro-3,4-dihydroquinolin-2(1H)-one:

[0638] The first step product (4g, 1eq) and aluminum trichloride (13.23g) were added to a reaction flask, heated to 150°C, and stirred for 1.5 hours. After the reaction temperature dropped below 100°C, water was slowly added dropwise to quench the reaction. After the system cooled to room temperature, the pH of the system was adjusted to neutral with aqueous sodium hydroxide solution. Extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 4:1) to obtain the product (2.1g). LCMS (ESI) [M+H] + =166.0.

[0639] Step 3: Synthesis of 6-bromo-8-fluoro-3,4-dihydroquinolin-2(1H)-one:

[0640] The product from step 2 (2 g, 1 eq) was dissolved in DMF (40 mL). N-bromosuccinimide (2.37 g) was added in portions under ice-cooling conditions. The mixture was stirred and reacted overnight at room temperature. The reaction solution was poured into water (200 mL), filtered, and the filter cake was dried to obtain the product (2.2 g). LCMS (ESI) [M+H] + =243.7.

[0641] Step 4: Synthesis of 6-bromo-8-fluoro-1-methyl-3,4-dihydroquinolin-2(1H)-one:

[0642] The product from step 3 (2.8 g, 1 eq) was dissolved in DMF (60 mL). Potassium tert-butoxide (2.57 g) was added under ice-cooling conditions and the reaction was stirred at this temperature for 0.5 hours. Methyl iodide (2.44 g) was then added and the reaction was stirred at room temperature for 2 hours. The reaction solution was poured into water (300 mL) for quenching and extracted with ethyl acetate (150 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to obtain the product (1.8 g). LCMS (ESI) [M+H] + =257.9.

[0643] Step 5: Synthesis of 8-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one:

[0644] The product from step 4 (500 mg, 1 eq), pinacol diboron (737.94 mg), potassium acetate (570.38 mg), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (142.14 mg) were added to 1,4-dioxane (20 mL) under nitrogen atmosphere and stirred at 100°C for 2 hours. The reaction solution was directly concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to obtain the product (400 mg). LCMS (ESI) [M+H] + =305.9.

[0645] Step 6: Synthesis of compound 152:

[0646] The product from Step 5 (100 mg, 1 eq), the product from Preparation Example 4 (111.83 mg), cesium carbonate (213.55 mg), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (24.04 mg) were added to 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen, the mixture was heated to 100°C and stirred for 5 hours. The reaction solution was directly concentrated and purified by flash chromatography (silica gel, ethyl acetate) to obtain the crude target compound. The crude product was dissolved in acetonitrile, filtered, and the filtrate was concentrated and purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 in water, MeCN) to obtain the target compound (69.86 mg). LCMS (ESI) [M+H] + =440.1; 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=1.8Hz,1H),8.29(d,J=2.7Hz,1H),7.61(dd,J=14.4,2.0Hz,1H),7.57-7.47(m,3H),3.91 (dp,J=8.0,6.5Hz,1H),3.35(d,J=2.7Hz,3H),3.33(s,4H),2.95(d,J=4.5Hz,4H),2.64-2.53(m,6H),1.08(d,J=6.6Hz,6H).

[0647] Example 92

[0648] Preparation of 2-(4-(5-(6-cyano-1,1-dimethyl-3-oxoisoindolin-2-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide (Compound 153):

[0649] Step 1: Synthesis of methyl 2-(bromomethyl)-4-cyanobenzoate:

[0650] Methyl 4-cyano-2-methylbenzoate (200 mg, 1 eq) was dissolved in carbon tetrachloride (8 mL), and N-bromosuccinimide (243.84 mg) and azobisisobutyronitrile (93.74 mg) were added. The mixture was heated to 80°C and stirred overnight. The reaction solvent was directly dried and the product was isolated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the product (100 mg). 1 H NMR (400MHz, Chloroform-d) δ8.05(d,J=8.1Hz,1H),7.78(d,J=1.7Hz,1H),7.66(dd,J=8.1,1.7Hz,1H),4.92(s,2H),3.98(s,3H).

[0651] Step 2: Synthesis of 2-(4-methoxybenzyl)-1-oxoisoindoline-5-carbonitrile:

[0652] The first step product (5.5g, 1eq) was dissolved in tetrahydrofuran (60mL), 1-(4-methoxyphenyl)methylamine (7.42g) was added under ice bath conditions, and the reaction was stirred at room temperature for 3 hours. The reaction solution was filtered, the filtrate was dried, and the residue was dissolved in ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether: ethyl acetate = 3:1) to obtain the product (3.3g). LCMS (ESI) [M+H] + =278.9.

[0653] Step 3: Synthesis of 2-(4-methoxybenzyl)-3,3-dimethyl-1-oxoisoindoline-5-carbonitrile:

[0654] The product from step 2 (3.3 g, 1 eq) was dissolved in tetrahydrofuran (60 mL) and 60% sodium hydride (2.27 g) was added. After stirring at room temperature for 1 hour, iodomethane (10.1 g) was added and the temperature was raised to 70°C and stirred for 2 hours. The mixture was cooled to room temperature and quenched by adding saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 2:1) to obtain the product (4 g, crude product). LCMS (ESI) [M+H] + =307.

[0655] Step 4: Synthesis of 3,3-dimethyl-1-oxoisoindoline-5-carbonitrile:

[0656] The product from step 3 (4 g, 1 eq) was dissolved in acetonitrile (80 mL). An aqueous solution of cerium nitrate (8.62 g, 30 mL) was added under ice-cooling conditions and the reaction was stirred for 1 hour. The reaction solution was poured into water (200 mL) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to obtain the product (1.3 g). LCMS (ESI) [M+H] + =187.

[0657] Step 5: Synthesis of compound 153:

[0658] The product from Step 4 (100 mg, 1 eq), the product from Preparation Example 4 (74.89 mg), potassium phosphate (227.99 mg), cuprous iodide (30.68 mg), and cyclohexane-1,2-diamine (36.79 mg) were added to 1,4-dioxane (5 mL) and heated under reflux for 5 hours. The reaction mixture was dried and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 0:1) to obtain the crude target compound. The crude product was dissolved in acetonitrile and filtered. The filtrate was purified by preparative HPLC (C18, 10 mmol / L NH4HCO3 in water, MeCN) to obtain the target compound (18.06 mg). LCMS (ESI) [M+H] + =447.0; 1 H NMR (400MHz, DMSO-d6) δ8.42(t,J=1.1Hz,1H),8.38(d,J=2.7Hz,1H),8.01(dd,J=7.8,1.3Hz,1H),7.95-7.89(m,2H),7.52(d,J=8.1Hz,1H),7. 30(t,J=2.3Hz,1H),3.90(dp,J=8.0,6.5Hz,1H),3.30(d,J=5.3Hz,4H),2.95(s,2H),2.59(t,J=5.1Hz,4H),1.51(s,6H),1.07(d,J=6.6Hz,6H).

[0659] Example 93

[0660] Preparation of N-(3-acetylaminobicyclo[1.1.1]pentan-1-yl)-2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 154):

[0661] Step 1: Synthesis of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate:

[0662] Referring to the first step of Example 88, tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (530 mg, 1 eq) was used as the starting material to obtain the product (290 mg). LCMS (ESI) [M+H-56] + =185.5.

[0663] Step 2: Synthesis of N-(3-aminobicyclo[1.1.1]pentan-1-yl)acetamide trifluoroacetate:

[0664] Referring to the second step reaction of Example 88, the product of the first step of Example 93 (290 mg) was used as the starting material to obtain the product (150 mg). LCMS (ESI) [M+H] + =141.6.

[0665] Step 3: Synthesis of compound 154:

[0666] Referring to the third step of Example 90, the product of Preparation Example 3 (60 mg, 1 eq) and the product of the second step (40.09 mg) were used as starting materials and reacted at room temperature for 2 hours. Flash chromatography (C18, 0.1% NH3H2O ​​in H2O / ACN) afforded the title compound (37.38 mg). LCMS (ESI) [M+H] + =503.3; 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.30-8.25(m,3H),7.65-7.60(m,2H),7.52-7.48(m,1H),7.19-7.15(m,1H),3 .37-3.34(m,2H),3.31-3.30(m,2H),3.29(s,3H),2.97-2.91(m,4H),2.62-2.55(m,6H),2.18(s,6H),1.75(s,3H).

[0667] Example 94

[0668] Preparation of N-isopropyl-2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide-2,2-d2 (Compound 155):

[0669] Step 1: Synthesis of tert-butyl 4-(5-bromopyridin-3-yl)piperazine-1-carboxylate:

[0670] Toluene (400 mL) was added to a mixture of tert-butyl piperazine-1-carboxylate (30 g, 1 eq), 3,5-dibromopyridine (49.6 g), sodium tert-butoxide (23.22 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANT PHOS, 5.59 g), and tris(dibenzylideneacetone)dipalladium (2.95 g). The mixture was reacted at 100°C under nitrogen for 16 hours. Water (500 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 4:1) to obtain the product (42 g). LCMS (ESI) [M+H] + =341.9; 1 HNMR (400MHz, CDCl3) δ8.21(d,J=2.6Hz,1H),8.15(d,J=1.8Hz,1H),7.32-7.29(m,1H),3.61-3.57(m,4H),3.21-3.16(m,4H),1.49(s,9H).

[0671] Step 2: Synthesis of 6-bromo-1-(methyl-d3)-3,4-dihydroquinolin-2(1H)-one:

[0672] 6-Bromo-3,4-dihydroquinolin-2(1H)-one (4g, 1eq) was dissolved in N,N-dimethylformamide (40mL). Sodium hydride (813.55mg) was slowly added under ice-cooling. After stirring at 0°C for 30 minutes, deuterated iodomethane (3.01g) was added dropwise. After the addition was complete, the reaction was continued at room temperature for 3 hours. Water (120mL) was added to quench the reaction solution and the product was extracted with ethyl acetate (70mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 2:1) to obtain the product (3.5g). LCMS [ESI] [M+H] + =245.4 (isotope peak); 1 H NMR (400MHz, CDCl3) δ7.36 (dd, J=8.6, 2.3Hz, 1H), 7.31-7.28 (m, 1H), 6.83 (d, J=8.6Hz, 1H), 2.91-2.86 (m, 2H), 2.66-2.62 (m, 2H).

[0673] Step 3: Synthesis of 1-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one:

[0674] The product from step 2 (4 g, 1 eq), pinacol diboron (8.36 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.21 g), and potassium acetate (4.84 g) were dissolved in 1,4-dioxane (60 mL) and reacted at 90°C under nitrogen for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and then purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 2:1) to obtain the product (3.5 g). LCMS [ESI] [M+H] + =291.3 (isotope peak).

[0675] Step 4: Synthesis of tert-butyl 4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazine-1-carboxylate:

[0676] The product from the first step (1.5 g, 1 eq), the product from the third step (1.91 g), potassium carbonate (1.82 g), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (321.37 mg) were dissolved in 1,4-dioxane (30 mL) and water (6 mL) and reacted at 80°C for 2 hours under nitrogen. The reaction solution was diluted with water (70 mL) and extracted with ethyl acetate (45 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:tetrahydrofuran = 2:1) to obtain the product (1 g). LCMS (ESI) [M+H] + =426.5; 1 HNMR (400MHz, CDCl3) δ8.33(d,J=1.6Hz,1H),8.28(d,J=2.6Hz,1H),7.46(dd,J=8.4,2.0Hz,1H),7.38-7.36(m,1H),7.31(t,J =2.1Hz,1H),7.06(d,J=8.4Hz,1H),3.65-3.61(m,4H),3.27-3.22(m,4H),3.01-2.96(m,2H),2.73-2.68(m,2H),1.49(s,9H).

[0677] Step 5: Synthesis of 1-(methyl-d3)-6-(5-(piperazin-1-yl)pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one:

[0678] The product from step 4 (1 g, 1 eq) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the mixture was allowed to react at room temperature for 16 hours. The reaction mixture was concentrated to give the product (750 mg). LCMS (ESI) [M+H] + =326.5.

[0679] Step 6: Synthesis of methyl 2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetate-d2:

[0680] The product from step 5 (750 mg, 1 eq) was dissolved in N,N-dimethylformamide (10 mL), and methyl 2-bromoacetate-d2 (0.43 mL) and potassium carbonate (955.6 mg) were added. The mixture was allowed to react at room temperature for 2 hours. Water (55 mL) was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (35 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:tetrahydrofuran = 1:4) to obtain the product (660 mg). 1 H NMR (400MHz, DMSO-d6) δ8.27 (dd, J=11.8, 2.2Hz, 2H), 7.65-7.59 (m, 2H), 7.51-7.47 (m, 1H), 7.19-7. 14(m,1H),3.64(s,3H),3.31-3.27(m,4H),2.98-2.91(m,2H),2.70-2.65(m,4H),2.61-2.56(m,2H).

[0681] Step 7: Synthesis of 2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetic acid-2,2-d2:

[0682] The product from step 6 (660 mg, 1 eq) was dissolved in methanol (8 mL) and water (8 mL). Lithium hydroxide (197.83 mg) was added and the mixture was reacted at 50°C for 2 hours. Dilute hydrochloric acid (3 M) was added dropwise to the reaction solution to adjust the pH to 5-6. After the solid precipitated, it was filtered and the filter cake was dried to obtain the product (600 mg). LCMS (ESI) [M+H] + =386.5.

[0683] Step 8: Synthesis of compound 155:

[0684] The product from step 7 (300 mg, 1 eq) and HATU (355.11 mg) were dissolved in N,N-dimethylformamide (5 mL). Triethylamine (236.26 mg) and isopropylamine (55.2 mg) were added sequentially under an ice bath, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated and purified by flash chromatography (C18, 0.1% NH4HCO3 in H2O / ACN) to obtain the title compound (114.5 mg). LCMS (ESI) [M+H] +=427.5; 1 H NMR (400MHz, DMSO-d6) δ8.30-8.25(m,2H),7.65-7.60(m,2H),7.56-7.48(m,2H),7.18-7.14(m,1H),3.95-3. 85(m,1H),3.35-3.33(m,2H),3.31-3.29(m,2H),2.97-2.92(m,2H),2.63-2.56(m,6H),1.08(d,J=6.6Hz,6H).

[0685] Example 95

[0686] Preparation of N-isopropyl-2-(3-((5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)amino)azetidin-1-yl)acetamide (Compound 156):

[0687] Step 1: Synthesis of tert-butyl 3-((5-bromopyridin-3-yl)amino)azetidine-1-carboxylate:

[0688] 3-Bromo-5-iodopyridine (5 g, 1 eq) was dissolved in N,N-dimethylformamide (50 mL). 3-Aminoazetidine-1-carboxylic acid tert-butyl ester (3.94 g), cuprous bromide (505.3 mg), potassium phosphate (7.48 g), and [1,1'-binaphthyl]-2,2'-diol (1.01 g) were added and reacted at 85°C for 3 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting mixture was then purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the desired product (2 g). LCMS (ESI) [M+H] + =330.1 (isotope peak); 1 HNMR (400MHz, CDCl3) δ8.07(d,J=1.7Hz,1H),7.88(d,J=2.3Hz,1H),6.91(t,J=2.2Hz,1H) ,4.36-4.29(m,2H),4.29-4.23(m,1H),4.21-4.13(m,1H),3.78-3.70(m,2H),1.45(s,9H).

[0689] Step 2: Synthesis of tert-butyl 3-((5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)amino)azetidine-1-carboxylate:

[0690] To a mixture of tert-butyl 3-((5-bromopyridin-3-yl)amino)azetidine-1-carboxylate (1.5 g, 4.57 mmol, 1 eq), the product of Preparation Example 1 (1.71 g), potassium carbonate (1.9 g) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (335.34 mg) was added dioxane (20 mL) and water (4 mL), and the mixture was reacted at 80 ° C under nitrogen protection for 3 hours. Water (60 mL) was added to the reaction solution and extracted with ethyl acetate (60 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, petroleum ether: tetrahydrofuran = 1:4) to obtain the product (1.7 g). LCMS (ESI) [M+H] + =409.4; 1 HNMR (400MHz, CDCl3) δ8.24(d,J=1.5Hz,1H),7.94(d,J=2.6Hz,1H),7.47-7.41(m,1H),7.39-7.32(m,1H),7.07(d,J=8.4Hz,1 H),6.95-6.88(m,1H),4.37-4.20(m,4H),3.88-3.72(m,2H),3.40(s,3H),3.03-2.93(m,2H),2.75-2.65(m,2H),1.45(s,9H).

[0691] Step 3: Synthesis of 6-(5-(azetidin-3-ylamino)pyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one:

[0692] Referring to the second step reaction of Example 88, the second product (1.7 g) was used as the starting material and separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous ammonia system, 25% yield of product) to obtain the product (1.2 g). LCMS (ESI) [M+H] + =309.2.

[0693] Step 4: Synthesis of ethyl 2-(3-(((5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)amino)azetidin-1-yl)acetate:

[0694] Referring to the sixth step reaction of Example 94, the product of the fifth step (800 mg, 1 eq) was used as the starting material and separated and purified by reverse phase chromatography (acetonitrile / 0.1% trifluoroacetic acid aqueous solution system) to obtain the product (600 mg). LCMS (ESI) [M+H] + =395.2.

[0695] Step 5: Synthesis of 2-(3-((5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)amino)azetidin-1-yl)acetic acid:

[0696] Referring to the reaction of step 7 of Example 94, the product of step 4 (200 mg, 1 eq) was used as the starting material and separated and purified by reverse phase chromatography (acetonitrile / pure water system) to obtain the product (100 mg). LCMS (ESI) [M+H] + =367.2; 1 HNMR(400MHz,DMSO-d6)δ8.12(s,1H),7.89(d,J=2.3Hz,1H),7.62-7.50(m,2H),7.17(d,J=8.5Hz,1H),7.12-7.01(m,1H),6.53 (d,J=7.1Hz,1H),4.37-4.24(m,1H),4.09-4.02(m,2H),3.37-3.35(m,4H),3.28(s,3H),2.98-2.92(m,2H),2.62-2.55(m,2H).

[0697] Step 6: Synthesis of compound 156:

[0698] Referring to the third step of Example 88, the product from the fifth step (50 mg, 1 eq) and propan-2-amine (8.07 mg) were used as starting materials and separated and purified by reverse phase chromatography (0.1% aqueous ammonia solution, acetonitrile) to obtain the title compound (21.27 mg). LCMS (ESI) [M+H] + =408.0; 1 HNMR(400MHz,DMSO-d6)δ8.09(d,J=1.6Hz,1H),7.88(d,J=2.5Hz,1H),7.58-7. 50(m,2H),7.39(d,J=8.1Hz,1H),7.21-7.13(m,1H),7.07-6.99(m,1H),6.41(d, J=7.0Hz,1H),4.18-4.09(m,1H),3.91-3.82(m,1H),3.80-3.73(m,2H),3.28(s ,3H),3.02(s,2H),3.00-2.91(m,4H),2.61-2.55(m,2H),1.06(d,J=6.6Hz,6H).

[0699] Example 96

[0700] Preparation of N-methyl-2-(4-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)acetamide (Compound 157):

[0701] Step 1: Synthesis of ethyl 2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)acetate:

[0702] Sodium vitamin C (460 mg) was added to a solution of ethyl 2-azidoacetate (3 g, 1 eq), prop-2-yn-1-ol (1.95 g), and copper sulfate pentahydrate (58 mg) in tert-butanol (30 mL) and water (30 mL). The mixture was reacted at room temperature for 16 hours. Water (50 mL) was then added and the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the product (1.4 g). LCMS (ESI) [M+H] + =186.1; 1 H NMR (400MHz, CDCl3) δ7.69 (s, 1H), 5.16 (s, 2H), 4.80 (s, 2H), 4.26 (dd, J = 8.3, 5.9Hz, 2H), 1.31 (t, J = 7.1Hz, 3H).

[0703] Step 2: Synthesis of ethyl 2-(4-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)acetate:

[0704] Methanesulfonyl chloride (1.73 g) was added to a solution of ethyl 2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)acetate (1.4 g, 1 eq) and triethylamine (2.3 g) in dichloromethane (20 mL) at 0°C. The mixture was allowed to react for 1 hour at room temperature. The reaction mixture was concentrated to obtain the product (1.78 g, crude product). LCMS (ESI) [M+H] + =264.1.

[0705] Step 3: Synthesis of 2-(4-((4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)acetic acid:

[0706] Potassium carbonate (578 mg) was added to a solution of Intermediate 1 (0.9 g, 1 eq) and the second-step product (1.47 g) in acetonitrile (10 mL) and allowed to react at 80°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by reverse-phase chromatography (C18, 0.1% NH4HCO3 in water / MeCN = 80% / 20%) to give the product (200 mg). LCMS (ESI) [M+H] + =462.3.

[0707] Step 4: Synthesis of compound 157:

[0708] Referring to the third step of Example 88, the product from the third step (160 mg, 1 eq) and methylamine hydrochloride (47 mg) were used as starting materials and reacted at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using prep-HPLC (C18, 0.1% NH3.H2O in water / MeCN) to obtain the title compound (16.23 mg). LCMS (ESI) [M+H] + =475.2; 1 H NMR(400MHz,DMSO-d6)δ8.30-8.19(m,3H),7.97(s,1H),7.65-7.59(m,2H),7.49(s,1H),7.19-7.14(m,1H) ,5.05(s,2H),3.64(s,2H),3.30-3.25(m,7H),2.97-2.91(m,2H),2.64(d,J=4.6Hz,3H),2.61-2.55(m,6H).

[0709] Example 97

[0710] Preparation of 3-(4-(5-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)pyridin-3-yl)piperazin-1-yl)propan-1-ol (Compound 158):

[0711] Step 1: Synthesis of 6-bromo-3,4-dihydroquinoline-2(1H)-thione:

[0712] Dissolve 6-bromo-3,4-dihydroquinolin-2(1H)-one (5 g, 1 eq) and Lawesson's reagent (13.42 g) in toluene (100 mL) and reflux at 120°C for 3 hours. Filter the reaction mixture and wash with dichloromethane. The filter cake is purified by flash chromatography (silica gel, petroleum ether:tetrahydrofuran = 1:1) to obtain the product (3.5 g). LCMS (ESI) [M+H]+ =244.3.

[0713] Step 2: Synthesis of 7-bromo-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline:

[0714] The first step product (3.5 g, 1 eq) and acetic acid hydrazide (1.5 g) were dissolved in cyclohexanol (60 mL) and reacted at 170°C for 6 hours. The reaction solution was concentrated and purified by flash chromatography (silica gel, petroleum ether:tetrahydrofuran = 1:1) to obtain the product (1.5 g). LCMS (ESI) [M+H] + =264.3; 1 H NMR (400MHz, DMSO-d6) δ7.74-7.71(m,1H),7.61-7.59(m,2H),3.00-2.96(m,4H),2.65(s,3H).

[0715] Step 3: Synthesis of 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline:

[0716] The product from step 2 (300 mg, 1 eq), pinacol diboronate (432.66 mg), 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (83.34 mg), and potassium acetate (334.42 mg) were dissolved in 1,4-dioxane (10 mL) and reacted at 90°C under nitrogen for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and then purified by flash chromatography (silica gel, petroleum ether:tetrahydrofuran = 1:2) to obtain the product (330 mg). LCMS (ESI) [M+H] + =312.3.

[0717] Step 4: Synthesis of 4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)piperazine-1-carboxylic acid benzyl ester:

[0718] Benzyl piperazine-1-carboxylate (6 g, 1 eq) and potassium carbonate (11.29 g) were dissolved in acetone (60 mL). A solution of 2-(3-bromopropoxy)tetrahydro-2H-pyran (6.08 g) in acetone (20 mL) was added dropwise under an ice bath and allowed to react at room temperature for 16 hours. The reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the product (5 g). LCMS (ESI) [M+H] + =363.5.

[0719] Step 5: Synthesis of 1-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)piperazine:

[0720] The product from step 4 (4.6 g, 1 eq) was dissolved in methanol (80 mL), palladium on carbon (13.51 g) was added, and the mixture was ventilated three times with a hydrogen balloon and allowed to react at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain the product (2.4 g). LCMS (ESI) [M+H] + =229.5; 1 H NMR (400MHz, CDCl3) δ4.60-4.55(m,1H),3.89-3.74(m,2H),3.52-3.40(m,2H), 2.92(t,J=4.9Hz,4H),2.51-2.40(m,6H),1.83-1.68(m,4H),1.60-1.49(m,4H).

[0721] Step 6: Synthesis of 1-(5-bromopyridin-3-yl)-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)piperazine:

[0722] 3,5-Dibromopyridine (2.18 g), the product from step 5 (2.1 g, 1 eq), sodium tert-butoxide (2.65 g), tris(dibenzylideneacetone)dipalladium (842.21 mg), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP) (1.15 g) were dissolved in toluene (50 mL) and reacted at 100°C under nitrogen for 16 hours. The reaction solution was filtered and washed with tetrahydrofuran. The filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:tetrahydrofuran = 2:1) to obtain the product (620 mg). LCMS (ESI) [M+H] + =386.1; 1 H NMR (400MHz, DMSO-d6) δ8.30-8.27(m,1H),8.05-8.00(m,1H),7.54-7.50(m,1H),4.56-4.52(m,1H),3.77-3.64(m,2H),3.44-3 .36(m,2H),3.25-3.21(m,4H),2.49-2.45(m,4H),2.40-2.36(m,2H),1.75-1.68(m,3H),1.63-1.57(m,1H),1.50-1.41(m,4H).

[0723] Step 7: Synthesis of 1-methyl-7-(5-(4-(3-(tetrahydro-2H-pyran-2-yl)oxy)propyl)piperazin-1-yl)pyridin-3-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline:

[0724] The product from step 6 (300 mg, 1 eq), the product from step 3 (364.38 mg), potassium phosphate (497.11 mg), and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (50.88 mg) were dissolved in 1,4-dioxane (5 mL) and water (1 mL) and reacted at 80°C for 4 hours under nitrogen. Water (50 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (25 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, dichloromethane:methanol = 10:1) to obtain the product (150 mg). LCMS (ESI) [M+H] + =489.4; 1 H NMR (400MHz, DMSO-d6) δ8.35-8.29(m,2H),7.88-7.85(m,1H),7.78-7.72(m,2H),7.57-7.53(m,1H),4.57-4.53(m,1H),3.79-3.65(m,2H),3.4 5-3.38(m,2H),3.30-3.27(m,4H),3.07-3.02(m,4H),2.71(s,3H),2.56 -2.53(m,4H),2.43-2.39(m,2H),1.76-1.64(m,4H),1.50-1.43(m,4H).

[0725] Step 8: Synthesis of 3-(4-(5-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)pyridin-3-yl)piperazin-1-yl)propan-1-ol:

[0726] To the product from step 7 (150 mg, 1 eq) was added a hydrochloric acid-dioxane solution (10 mL, 4 M) and allowed to react at room temperature for 3 hours. The reaction mixture was adjusted to pH 6-7 with a 3 M sodium hydroxide solution, filtered, and the filtrate concentrated. The product was then purified by flash chromatography (C18, 0.1% NH3H2O ​​in H2O / ACN) to yield the title compound (43.66 mg). LCMS (ESI) [M+H] + =405.3; 1H NMR(400MHz,DMSO-d6)δ8.34-8.30(m,2H),7.87(s,1H),7.78-7.72(m,2H),7.56-7.53(m,1H),4.47(s,1H),3.47-3 .45(m,2H),3.31-3.28(m,4H),3.04(s,4H),2.70(s,3H),2.55--2.52(m,4H),2.42-2.37(m,2H),1.66-1.59(m,2H).

[0727] Example 98

[0728] Preparation of N-isopropyl-2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 159):

[0729] Step 1: Synthesis of ethyl 2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetate:

[0730] Referring to the sixth step of Example 94, 1-(methyl-d3)-6-(5-(piperazin-1-yl)pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one (2 g, 1 eq) and ethyl 2-bromoacetate (923.73 mg) were used to separate and purify the product by reverse phase chromatography (C18; acetonitrile / pure water system) to obtain the product (1 g). LCMS (ESI) [M+H] + =412.3; 1 HNMR(400MHz,DMSO-d6)δ8.33-8.22(m,2H),7.66-7.58(m,2H),7.53-7.46(m,1H),7.19-7.13(m,1H),4.17-4. 05(m,2H),3.32-3.25(m,6H),3.00-2.89(m,2H),2.72-2.66(m,4H),2.62-2.55(m,2H),1.21(t,J=7.1Hz,3H).

[0731] Step 2: Synthesis of 2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetic acid:

[0732] Referring to the seventh step of Example 94, the product from the first step (1 g, 1 eq) was used as the starting material and separated and purified by reverse phase chromatography (acetonitrile / 0.1% formic acid aqueous solution = 25%) to obtain the product (900 mg, yield 96%). LCMS (ESI) [M+H] + =384.2; 1 HNMR(400MHz, DMSO-d6)δ8.29(d,J=1.7Hz,1H),8.26(d,J=2.7Hz,1H),7.67-7.59(m,2H),7.55-7.46(m,1H), 7.20-7.12(m,1H),3.34-3.30(m,4H),3.23(s,2H),2.97-2.91(m,2H),2.78-2.71(m,4H),2.61-2.55(m,2H).

[0733] Step 3: Synthesis of compound 159:

[0734] Referring to the third step of Example 88, the product from the second step (800 mg, 1 eq) and isopropylamine (123.32 mg) were used as starting materials. The product was separated and purified by reverse phase chromatography (C18; acetonitrile / 0.1% aqueous ammonia system) to obtain the title compound (393.15 mg). LCMS (ESI) [M+H] + =425.4; 1 HNMR(400MHz, DMSO-d6)δ8.29(d,J=1.7Hz,1H),8.27(d,J=2.7Hz,1H),7.67-7.60(m,2H),7.58-7.46(m,2H),7.21-7.1 3(m,1H),3.91(tt,J=13.2,6.6Hz,1H),3.33-3.29(m,4H),3.00-2.88(m,4H),2.66-2.54(m,6H),1.08(d,J=6.6Hz,6H).

[0735] Example 99

[0736] Preparation of 1-isopropyl-3-(2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)ethyl)urea (Compound 160):

[0737] Step 1: Synthesis of tert-butyl 2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)ethyl)carbamate:

[0738] Intermediate 1 (200 mg, 1 eq) was dissolved in acetonitrile (3 mL), potassium carbonate (171.38 mg) and tert-butyl (2-bromoethyl)carbamate (166.73 mg) were added, and the mixture was reacted at 50°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and then purified by flash chromatography (silica gel, petroleum ether:tetrahydrofuran = 1:4) to obtain the product (200 mg). LCMS (ESI) [M+H] + =466.4; 1 HNMR (400MHz, CDCl3) δ8.30(d,J=1.8Hz,1H),8.27(d,J=2.7Hz,1H),7.46(dd,J=8.4,2.1Hz,1H),7.40-7.35(m,1H),7.34-7.29(m,1H),7.07(d,J= 8.4Hz,1H),4.98(s,1H),3.40(s,3H),3.36-3.24(m,6H),3.05-2.91(m,2 H),2.75-2.68(m,2H),2.68-2.62(m,4H),2.59-2.48(m,2H),1.46(s,9H).

[0739] Step 2: Synthesis of 6-(5-(4-(2-aminoethyl)piperazin-1-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one hydrochloride:

[0740] The first step product (200 mg, 1 eq) was dissolved in dioxane (3 mL), and a dioxane hydrochloride solution (3 mL, 4 M) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated to obtain the product (150 mg, crude product). LCMS (ESI) [M+H] + =366.3.

[0741] Step 3: Synthesis of 1-isopropyl-3-(2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)ethyl)urea:

[0742] The product from step 2 (150 mg, 1 eq) was dissolved in acetonitrile (3 mL), and triethylamine (75.53 mg) and isopropyl isocyanate (0.05 mL) were added. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was separated and purified by reverse phase chromatography (0.1% aqueous ammonia solution / acetonitrile) to obtain the title compound (121.74 mg). LCMS (ESI) [M+H] + =451.0; 1HNMR(400MHz,DMSO-d6)δ8.29(d,J=1.8Hz,1H),8.26(d,J=2.7Hz,1H),7.65-7 .58(m,2H),7.52-7.47(m,1H),7.20-7.13(m,1H),5.85(d,J=7.6Hz,1H),5.63( t,J=5.4Hz,1H),3.71-3.59(m,1H),3.32-3.24(m,7H),3.19-3.10(m,2H),2.98 -2.90(m,2H),2.62-2.53(m,6H),2.38(t,J=6.4Hz,2H),1.02(d,J=6.5Hz,6H).

[0743] Example 100

[0744] Preparation of 2-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-N-(spiro[2.2]pentan-1-yl)acetamide (Compound 161):

[0745] Referring to the third step of Example 88, the product of Preparation Example 3 (50 mg, 1 eq) and spiro[2.2]pentan-1-amine (10.93 mg) were used as starting materials. The title compound (13.15 mg) was obtained by reverse phase chromatography (0.1% aqueous ammonia solution, acetonitrile). LCMS (ESI) [M+H] + =446.2; 1 HNMR (400MHz, DMSO-d6) δ8.29(d,J=1.7Hz,1H),8.26(d,J=2.6Hz,1H),7.77(d,J=4.1Hz,1H),7.66-7.60(m,2H),7.53-7.48(m,1H),7.20-7.15(m, 1H),3.32-3.29(m,4H),3.29(s,3H),2.99(s,2H),2.99-2.90(m,3H),2.6 5-2.54(m,6H),1.21-1.15(m,1H),0.94-0.85(m,2H),0.85-0.69(m,3H).

[0746] Example 101

[0747] Preparation of 6-(5-(4-(1-ethyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (Compound 162):

[0748] Referring to the third step of Example 90, 1-ethyl-1H-pyrazole-4-carboxylic acid (100 mg, 1 eq) and Intermediate 1 (230.06 mg) were used as starting materials. The product was separated and purified by flash chromatography (C18, 0.1% NH3H2O ​​in H2O / ACN) to obtain the title compound (100.93 mg). LCMS (ESI) [M+H] + =445.2; 1 H NMR(400MHz,DMSO-d6)δ8.35-8.26(m,2H),8.15(s,1H),7.72(s,1H),7.66-7.61(m,2H),7.56-7.52(m,1H),7.20-7.16(m,1H),4.1 6(q,J=7.3Hz,2H),3.83-3.73(m,4H),3.37-3.33(m,4H),3.29(s,3H),2.97-2.92(m,2H),2.62-2.56(m,2H),1.39(t,J=7.3Hz,3H).

[0749] Example 102

[0750] Preparation of N-isopropyl-2-(4-(5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 163):

[0751] To a mixture of the product of Preparation Example 4 (200 mg, 1 eq), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (160.08 mg), potassium carbonate (243.01 mg), and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (43 mg) were added dioxane (5 mL) and water (1 mL), and the mixture was reacted at 80°C for 3 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase chromatography (0.1% aqueous ammonia solution / acetonitrile system) to obtain the title compound (112.72 mg). LCMS (ESI) [M+H] + =408.0; 1HNMR (400MHz, DMSO-d6) δ10.17(s,1H),8.24(d,J=3.4Hz,2H),7.59-7.55(m,1H),7.55-7.48(m,2H),7.48-7.44(m,1H),6.94(d,J= 8.2Hz,1H),3.98-3.84(m,1H),3.31-3.26(m,4H),2.98-2.91(m,4H),2.63-2.57(m,4H),2.49-2.46(m,2H),1.08(d,J=6.6Hz,6H).

[0752] Example 103

[0753] Preparation of N-isopropyl-2-(4-(5-(1-methyl-2-oxoindolin-5-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 164):

[0754] Referring to the reaction of Example 102, the product of Preparation Example 4 (50 mg, 1 eq) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-2-one (40.02 mg) were used as starting materials. The title compound (38.6 mg) was obtained by separation and purification by reverse phase chromatography (0.1% aqueous ammonia solution / acetonitrile system). LCMS (ESI) [M+H] + =408.0; 1 HNMR (400MHz, DMSO-d6) δ8.31-8.22(m,2H),7.68-7.62(m,2H),7.52(d,J=8.1Hz,1H),7.49-7.45(m,1H),7.10-7.05(m,1H ),3.96-3.85(m,1H),3.61(s,2H),3.32-3.29(m,4H),3.16(s,3H),2.96(s,2H),2.64-2.56(m,4H),1.08(d,J=6.6Hz,6H).

[0755] Example 104

[0756] Preparation of 1-methyl-6-(5-(4-(2-oxopyrrolidin-3-yl)piperazin-1-yl)pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one (Compound 165):

[0757] Step 1: Synthesis of tert-butyl 3-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-2-oxopyrrolidine-1-carboxylate:

[0758] Intermediate 1 (60 mg, 1 eq) and potassium carbonate (77.16 mg) were dissolved in acetonitrile (5 mL), and tert-butyl 3-bromo-2-oxopyrrolidine-1-carboxylate (49.15 mg) was added. The mixture was allowed to react at 40°C for 16 hours. The reaction mixture was concentrated and purified by reverse phase chromatography (C18, 0.1% TFA in H2O / ACN) to obtain the product (50 mg). LCMS (ESI) [M+H] + =506.3.

[0759] Step 2: Synthesis of compound 165:

[0760] The first-stage product (50 mg, 1 eq) was dissolved in dichloromethane (3 mL). After adding a hydrochloric acid solution in dioxane (3 mL, 4 M), the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in a small amount of tetrahydrofuran (1 mL). The pH was adjusted to neutral with aqueous sodium hydroxide (3 M) and filtered. The filtrate was concentrated and purified by reverse-phase chromatography (C18, 0.1% NH3H2O ​​in H2O / ACN) to obtain the title compound (21.09 mg). LCMS (ESI) [M+H] + =406.2; 1 H NMR(400MHz,DMSO-d6)δ8.29-8.24(m,2H),7.74(s,1H),7.64-7.60(m,2H),7.50-7.46(m,1H),7.20-7.15(m,1H), 3.30-3.25(m,8H),3.19-3.08(m,2H),3.00-2.91(m,4H),2.64-2.56(m,4H),2.17-2.08(m,1H),2.03-1.92(m,1H).

[0761] Example 105

[0762] Preparation of 1-methyl-6-(5-(4-((1-methyl-2-oxopyrrolidin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one formate (Compound 166):

[0763] Step 1: Synthesis of (1-methyl-2-oxopyrrolidin-3-yl)methyl methanesulfonate:

[0764] Refer to the second step of Example 96, using 3-(hydroxymethyl)-1-methylpyrrolidin-2-one (150 mg, 1 eq) as the starting material. After completion of the reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the product (200 mg, crude product). LCMS (ESI) [M+H] + =208.2.

[0765] Step 2: Synthesis of compound 166:

[0766] Referring to the third step of Example 96, intermediate 1 (200 mg, 1 eq) and the product from the first step (192.74 mg) were used as starting materials. The product was separated and purified by reverse phase chromatography (0.1% aqueous ammonia solution / acetonitrile system) and then by preparative HPLC (0.1% formic acid solution / acetonitrile system) to obtain the title compound (44.82 mg). LCMS (ESI) [M+H] + =434.3; 1 H NMR(400MHz,DMSO-d6)δ8.34-8.23(m,2H),8.18(s,1H),7.67-7.57(m,2H),7.54-7.45(m,1H),7.21-7.14(m,1H),3.33-3.28(m,5H ),3.28-3.22(m,4H),2.98-2.91(m,2H),2.73(s,3H),2.68-2.54(m,6H),2.50-2.35(m,3H),2.22-2.09(m,1H),1.89-1.73(m,1H).

[0767] Example 106

[0768] Preparation of N-isopropyl-2-(4-(5-(1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Example 167):

[0769] Step 1: Synthesis of 6-bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one:

[0770] Referring to the first step of Preparation Example 1, 6-bromo-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (200 mg, 1 eq) was used as the starting material and the product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to obtain the product (200 mg). LCMS (ESI) [M+H] +=244.1 (isotope peak); 1 H NMR (400MHz, DMSO-d6) δ7.55(dd,J=8.6,2.3Hz,1H),7.52-7.48(m,1H),7.05(d,J=8.6Hz,1H),5.24(s,2H),3.25(s,3H).

[0771] Step 2: Synthesis of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one:

[0772] Refer to the second step of Preparation Example 1 and use the product obtained in the first step (200 mg, 1 eq) as the starting material to obtain the target compound (200 mg, crude product). LCMS (ESI) [M+H] + =290.1.

[0773] Step 3: Synthesis of compound 167:

[0774] Referring to the preparation of Example 102, the product of Preparation Example 4 (150 mg, 1 eq) and the product of the second step (152.51 mg, 1.2 eq) were used as starting materials. Flash chromatography (silica gel, petroleum ether:tetrahydrofuran = 1:4) was used for separation and purification, followed by reverse phase chromatography (0.1% aqueous ammonia solution / acetonitrile system) to obtain the title compound (111.58 mg). LCMS (ESI) [M+H] + =424.3; 1 HNMR (400MHz, DMSO-d6) δ8.33-8.25(m,2H),7.80-7.72(m,1H),7.71-7.64(m,1H),7.58-7.46(m,2H),7.18(d,J=8. 5Hz,1H),5.31(s,2H),3.98-3.84(m,1H),3.34-3.28(m,7H),2.96(s,2H),2.69-2.56(m,4H),1.08(d,J=6.6Hz,6H).

[0775] Example 107

[0776] Preparation of N-isopropyl-2-(4-(5-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 168):

[0777] Step 1: Synthesis of 5'-bromo-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one:

[0778] Referring to the first step of Preparation Example 1, 5'-bromospiro[cyclopropane-1,3'-indolin]-2'-one (400 mg, 1 eq) was used as the starting material and the product was isolated and purified by flash chromatography (silica gel, petroleum ether:tetrahydrofuran = 1:1) to obtain the product (400 mg). LCMS (ESI) [M+H] + =254.0 (isotope peak); 1 H NMR (400MHz, DMSO-d6) δ7.43(dd,J=8.3,2.0Hz,1H),7.28(d,J=2.0Hz,1H),7.03(d,J=8.3Hz,1H),3.19(s,3H),1.72-1.66(m,2H),1.54-1.50(m,2H).

[0779] Step 2: Synthesis of 1'-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indoline]-2'-one:

[0780] Referring to the second step reaction of Preparation Example 1, the product of the first step (200 mg, 1 eq) was used as the raw material and separated and purified by flash chromatography (silica gel, petroleum ether:tetrahydrofuran = 5:1) to obtain the product (200 mg). LCMS (ESI) [M+H] + =300.1.

[0781] Step 3: Synthesis of compound 168:

[0782] Referring to the preparation of Example 102, the product of Preparation Example 4 (70 mg, 1 eq), the product of the second step (92.05 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (13.37 mg), and potassium phosphate (130.63 mg) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL). The mixture was reacted at 80°C under nitrogen for 2 hours. Water (30 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase chromatography (C18, 0.1% NH3H2O ​​in H2O / ACN) to obtain the title compound (40.12 mg). LCMS (ESI) [M+H] + =434.2; 1H NMR (400MHz, DMSO-d6) δ8.29(d,J=1.7Hz,1H),8.24(d,J=2.7Hz,1H),7.62(dd, J=8.1,1.8Hz,1H),7.55-7.48(m,2H),7.42(d,J=1.6Hz,1H),7.15(d,J=8.2Hz, 1H),3.94-3.87(m,1H),3.31-3.28(m,4H),3.25(s,3H),2.96(s,2H),2.63-2.5 9(m,4H),1.75(z,J=7.7,3.8Hz,2H),1.57-1.52(m,2H),1.08(d,J=6.6Hz,6H).

[0783] Example 108

[0784] Preparation of N-isopropyl-2-(4-(5-(1,3,3-trimethyl-2-oxoindolin-5-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 169):

[0785] Step 1: Synthesis of 5-bromo-1,3,3-trimethylindolin-2-one:

[0786] 5-Bromoindolin-2-one (500 mg, 2.36 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL) and the mixture was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to obtain 200 mg of cahanweinu. LCMS (ESI) [M+H+41] + =295.2; 1 H NMR (400MHz, CDCl3) δ7.42-7.35(m,1H),7.31(d,J=2.0Hz,1H),6.72(d,J=8.2Hz,1H),3.20(s,3H),1.37(s,6H).

[0787] Step 2: Synthesis of 1,3,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-2-one:

[0788] Referring to the second step of Preparation Example 1, 5-bromo-1,3,3-trimethylindolin-2-one (260 mg, 1 eq) was used to obtain the product (250 mg, crude product). LCMS (ESI) [M+H] + =302.4.

[0789] Step 3: Synthesis of compound 169:

[0790] Referring to the preparation of Example 102, the product of Preparation Example 4 (200 mg, 1 eq) and the product of the second step (211.83 mg) were used as starting materials. The mixture was separated and purified by flash chromatography (silica gel, ethyl acetate) and then by reverse phase chromatography (0.1% aqueous ammonia solution / acetonitrile system) to obtain the title compound (95.07 mg). LCMS (ESI) [M+H] + =436.3; 1 HNMR(400MHz,DMSO-d6)δ8.30(d,J=1.6Hz,1H),8.26(d,J=2.6Hz,1H),7.77(d,J=1.6Hz,1H),7.64(dd,J=8.1,1.7Hz,1H),7.60-7.43(m,2H), 7.10(d,J=8.1Hz,1H),3.99-3.82(m,1H),3.37-3.33(m,4H),3.18(s,3 H),2.97(s,2H),2.68-2.55(m,4H),1.33(s,6H),1.08(d,J=6.6Hz,6H).

[0791] Example 109

[0792] Preparation of N-isopropyl-2-(4-(5-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 170):

[0793] Referring to the preparation of Example 102, the third step reaction of Example 97 (60 mg, 1 eq) and the product of Preparation Example 4 (52.64 mg) were used as starting materials. The product was separated and purified by reverse phase chromatography (C18, 0.1% NH3H2O ​​in H2O / ACN) to obtain the title compound (18 mg). LCMS (ESI) [M+H] + =446.2; 1 H NMR (400MHz, DMSO-d6) δ8.35-8.31(m,2H),7.88-7.86(m,1H),7.78-7.72(m,2H),7.57-7.55(m,1H),7.55-7.50(m,1H),3.94-3.8 6(m,1H),3.36-3.35(m,2H),3.30-3.28(m,2H),3.04(s,4H),2.96(s,2H),2.71(s,3H),2.63-2.59(m,4H),1.08(d,J=6.6Hz,6H).

[0794] Example 110

[0795] Preparation of 1-methyl-6-(5-(4-(1-propionylazetidin-3-yl)piperazin-1-yl)pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one (Compound 171):

[0796] Step 1: Synthesis of tert-butyl 3-(4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)azetidine-1-carboxylate:

[0797] Intermediate 1 (400 mg, 1 eq) was dissolved in acetonitrile (5 mL), and potassium carbonate (342.95 mg), potassium iodide (41.19 mg), and tert-butyl 3-bromoazetidine-1-carboxylate (585.88 mg) were added. The mixture was reacted at 100°C for 48 hours. The reaction solution was filtered, the filtrate was concentrated, and then purified by flash chromatography (silica gel, ethyl acetate) to obtain the product (170 mg). LCMS (ESI) [M+H] + =478.3; 1 HNMR(400MHz, DMSO-d6)δ8.29(d,J=1.7Hz,1H),8.26(d,J=2.7Hz,1H),7.67-7.58(m,2H),7.54-7.45(m,1H),7.20-7.14(m,1H),3.97-3.7 9(m,2H),3.78-3.64(m,2H),3.32-3.27(m,7H),3.15-3.04(m,1H),2.99-2.87(m,2H),2.62-2.55(m,2H),2.49-2.42(m,4H),1.39(s,9H).

[0798] Step 2: Synthesis of 6-(5-(4-(azetidin-3-yl)piperazin-1-yl)pyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one hydrochloride:

[0799] Referring to the second step reaction of Example 99, the product from the first step was used as a starting material (150 mg) to obtain the product (120 mg, crude product). LCMS (ESI) [M+H] + =378.2.

[0800] Step 3: Synthesis of compound 171:

[0801] The product from step 2 (120 mg, 1 eq) was dissolved in dichloromethane (3 mL). Triethylamine (58.55 mg) and propionyl chloride (40.23 mg) were added at 0°C and allowed to react at room temperature for 1 hour. The reaction solution was concentrated and purified by reverse phase chromatography (0.1% aqueous ammonia solution / acetonitrile) to obtain the title compound (69.09 mg). LCMS (ESI) [M+H] + =434.2; 1 H NMR(400MHz,DMSO-d6)δ8.30(d,J=1.7Hz,1H),8.27(d,J=2.7Hz,1H),7.66-7.60(m,2H ),7.53-7.47(m,1H),7.20-7.14(m,1H),4.14(t,J=7.9Hz,1H),4.03-3.93(m,1H),3.91 -3.83(m,1H),3.74-3.65(m,1H),3.32-3.26(m,7H),3.20-3.10(m,1H),2.98-2.90(m,2 H),2.62-2.56(m,2H),2.50-2.44(m,4H),2.06(q,J=7.5Hz,2H),0.96(t,J=7.5Hz,3H).

[0802] Example 111

[0803] Preparation of N-isopropyl-2-(4-(5-(3-methyl-5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)pyridin-3-yl)piperazin-1-yl)acetamide (Compound 173):

[0804] Step 1: Synthesis of (5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)pyridin-3-yl)boronic acid:

[0805] The product of Preparation Example 4 (100 mg, 1 eq) was dissolved in dioxane (3 mL), and diboronic acid pinacol ester (148.83 mg), potassium acetate (86.28 mg), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (21.5 mg) were added. The mixture was reacted at 100°C under nitrogen for 16 hours. The reaction solution was concentrated to obtain the product (85 mg, crude product). LCMS (ESI) [M+H] + =307.1.

[0806] Step 2: Synthesis of 3-bromo-4-methyl-5-nitro-1H-pyrazole:

[0807] 4-Methyl-5-nitro-1H-pyrazole (4.5 g, 1 eq) was dissolved in N,N-dimethylformamide (50 mL). Liquid bromine (3.63 mL) was added dropwise at 0°C. After complete addition, the mixture was allowed to react at 40°C for 16 hours. The reaction solution was cooled to room temperature and quenched with saturated sodium thiosulfate aqueous solution. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 2:1) to obtain the product (4.5 g). 1 HNMR(400MHz,DMSO-d6)δ14.73(s,1H),2.22(s,3H).

[0808] Step 3: Synthesis of 3-bromo-4-methyl-1H-pyrazol-5-amine:

[0809] The product from step 2 (1.5 g, 1 eq) was dissolved in ethanol (20 mL) and water (4 mL), and iron powder (2.03 g) and ammonium chloride (778.98 mg) were added. The mixture was reacted at 90°C for 1 hour. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the product (1.2 g). LCMS (ESI) [M+H] + =176.1; 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),5.01(s,2H),1.74(s,3H).

[0810] Step 4: Synthesis of 2-bromo-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-5(4H)-one:

[0811] The product from step 3 (1 g, 1 eq) was dissolved in pyridine (10 mL) and water (1 mL). Ethyl acrylate (0.85 mL) was added and the mixture was sealed and reacted at 130°C for 16 hours. The reaction solution was added to a solution of petroleum ether and ethyl acetate (5:1 by volume, 80 mL). After solid precipitated, it was filtered and the filter cake was collected to obtain the product (500 mg). LCMS (ESI) [M+H] + =231.9 (isotope peak); 1 HNMR (400MHz, DMSO-d6) δ10.84(s,1H),4.18(t,J=7.0Hz,2H),2.77(t,J=7.0Hz,2H),1.84(s,3H).

[0812] Step 5: Synthesis of compound 173:

[0813] To a mixture of the product from step 4 (40 mg, 1 eq), (5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)pyridin-3-yl)boronic acid (79.85 mg), potassium carbonate (72.09 mg), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (12.76 mg) were added dioxane (2.5 mL) and water (0.5 mL). The mixture was reacted at 80°C under nitrogen for 3 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase chromatography (0.1% NH3H2O ​​in H2O / ACN) to yield the title compound (36.19 mg). LCMS (ESI) [M+H] + =412.2; 1 HNMR (400MHz, DMSO-d6) δ10.75(s,1H),8.27(d,J=2.7Hz,1H),8.22(d,J=1.0Hz,1H),7.52(d,J=8.1Hz,1H),7.45-7.38(m,1H),4.26(t,J=7 .0Hz,2H),3.96-3.83(m,1H),3.30-3.21(m,4H),2.95(s,2H),2.80(t,J=7.0Hz,2H),2.63-2.57(m,4H),2.07(s,3H),1.08(d,J=6.6Hz,6H).

[0814] Example 112

[0815] Preparation of 1-methyl-6-(5-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one (Compound 175):

[0816] Intermediate 1 (100 mg, 1 eq) was dissolved in dichloromethane (5 mL). Triethylamine (94.16 mg) and methanesulfonyl chloride (71.06 mg) were added sequentially under an ice bath, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse-phase chromatography (C18, 0.1% NH3H2O ​​in H2O / ACN) to obtain the title compound (61.59 mg). LCMS (ESI) [M+H] + =401.0; 1H NMR(400MHz,DMSO-d6)δ8.36-8.29(m,2H),7.66-7.62(m,2H),7.58-7.54(m,1H),7.20-7 .16(m,1H),3.44-3.40(m,4H),3.29-3.25(m,7H),2.95-2.93(m,4H),2.61-2.57(m,3H).

[0817] Example 113

[0818] Preparation of N-(cis-3-methoxycyclobutyl)-2-(6-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)acetamide (Compound 187):

[0819] Step 1: Synthesis of tert-butyl 6-(5-bromopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate:

[0820] Referring to the third step of Preparation Example 4, 3,5-dibromopyridine (5 g, 1 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (5.24 g) were used and reacted at 100°C under nitrogen for 16 hours. Water (100 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain the product (3.2 g). LCMS (ESI) [M+H] + =356.0 (isotope peak); 1 HNMR (400MHz, CDCl3) δ8.06(d,J=1.7Hz,1H),7.75(d,J=2.4Hz,1H),6.85(t,J=2.1Hz,1H),4.11(s,4H),4.04(s,4H),1.45(s,9H).

[0821] Referring to the fourth to eighth steps of Example 94, the following intermediates and target compounds were prepared respectively:

[0822] Example 114

[0823] Preparation of N-(trans-3-methoxycyclobutyl)-2-(6-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)acetamide (Compound 188):

[0824] Referring to the eighth step of Example 94, the product from the fifth step of Example 113 (50 mg, 1 eq) and trans-3-methoxycyclobutylamine hydrochloride (17.53 mg) were used as starting materials. The product was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous ammonia system) to obtain the title compound (4.83 mg). LCMS (ESI) [M+H] + =476.3; 1 HNMR(400MHz,MeOD)δ8.13(d,J=1.5Hz,1H),7.72(d,J=2.4Hz,1H),7.55(dd,J=8.4, 2.1Hz,1H),7.53-7.49(m,1H),7.22(d,J=8.4Hz,1H),7.09-7.05(m,1H),4.37-4.29( m,1H),4.09(s,4H),4.06-3.98(m,1H),3.67(s,4H),3.39(s,3H),3.24(s,2H),3.23 (s,3H),3.03-2.97(m,2H),2.69-2.63(m,2H),2.36-2.28(m,2H),2.25-2.17(m,2H).

[0825] Example 115 (Compound 177)

[0826] Preparation of N-(3-acetamidocyclobutyl)-2-(6-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)acetamide:

[0827] Referring to the third step of Example 88, using 2-(6-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)acetic acid (70 mg, 1 eq) and N-(3-aminocyclobutyl)acetamide hydrochloride (32.3 mg) as starting materials, the product was separated and purified by reverse phase chromatography (0.1% NH3H2O ​​in H2O / ACN) and then by flash chromatography (silica gel, dichloromethane:methanol = 10:1) to obtain the title compound (8.56 mg). LCMS (ESI) [M+H] + =503.4; 1HNMR(400MHz,MeOD)δ8.13(d,J=1.7Hz,1H),7.72(d,J=2.5Hz,1H),7.55(dd,J= 8.4,2.1Hz,1H),7.52-7.49(m,1H),7.22(d,J=8.4Hz,1H),7.08-7.05(m,1H),4 .39-4.23(m,2H),4.08(s,4H),3.67-3.64(m,4H),3.38(s,3H),3.25-3.21(m,2 H),3.02-2.97(m,2H),2.68-2.64(m,2H),2.41-2.18(m,4H),1.94-1.91(m,3H).

[0828] Example 116 (Compound 178)

[0829] Preparation of 2-(6-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-N-(oxetane-3-yl)acetamide:

[0830] Referring to the third step of Example 88, using 2-(6-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)acetic acid (100 mg, 1 eq) and 3-aminooxetane (20.49 mg) as starting materials, the product was separated and purified by reverse phase chromatography (0.1% NH3H2O ​​in H2O / ACN) followed by flash chromatography (silica gel, dichloromethane:methanol = 10:1) to obtain the title compound (6.76 mg). LCMS (ESI) [M+H] + =448.3; 1 HNMR (400MHz, MeOD) δ8.12(d,J=1.8Hz,1H),7.72(d,J=2.6Hz,1H),7.55(dd,J=8. 4,2.1Hz,1H),7.52-7.48(m,1H),7.21(d,J=8.4Hz,1H),7.09-7.03(m,1H),4.98-4 .90(m,1H),4.88-4.86(m,1H),4.85-4.82(m,1H),4.58(t,J=6.5Hz,2H),4.08(s, 4H),3.61(s,4H),3.38(s,3H),3.23(s,2H),3.03-2.96(m,2H),2.71-2.62(m,2H).

[0831] Example 117 (Compound 172)

[0832] Preparation of 2-(4-(5-(1-cyclopropyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide:

[0833] Step 1: Synthesis of 6-bromo-1-cyclopropyl-3,4-dihydroquinolin-2(1H)-one:

[0834] Dissolve 6-bromo-3,4-dihydroquinolin-2(1H)-one (2 g, 1 eq) in dichloromethane (30 mL). Add cyclopropylboronic acid (1.52 g), copper acetate monohydrate (3.18 g), and triethylamine (2.69 g). Stir at room temperature under oxygen for 24 hours. The reaction mixture is filtered, the filtrate is concentrated, and then purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to obtain the product (400 mg). LCMS (ESI) [M+H] + =268.0 (isotope peak); 1 H NMR (400MHz, CDCl3) δ7.36 (dd, J=8.6, 2.3Hz, 1H), 7.28-7.26 (m, 1H), 7.17 (d, J=8.6Hz, 1H), 2 .82-2.76(m,2H),2.75-2.69(m,1H),2.64-2.56(m,2H),1.18-1.10(m,2H),0.66-0.62(m,2H).

[0835] Step 2: Synthesis of 1-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one:

[0836] Refer to the second step reaction of Preparation Example 1, use the first step product (150 mg, 1 eq) as the raw material, filter the reaction solution, and concentrate the filtrate to obtain the product (170 mg, crude product). LCMS (ESI) [M+H] + =314.2.

[0837] Step 3: Synthesis of compound 172:

[0838] Referring to the method of Example 102, the product of Preparation Example 4 (120 mg, 1 eq) and the product of the second step (143.18 mg) were used as starting materials and separated and purified by reverse phase chromatography (0.1% NH3H2O ​​in H2O / ACN) to obtain the title compound (46.87 mg). LCMS (ESI) [M+H] + =448.3; 1HNMR(400MHz,DMSO-d6)δ8.29(d,J=1.6Hz,1H),8.26(d,J=2.6Hz,1H),7.63(dd,J= 8.4,2.1Hz,1H),7.61-7.57(m,1H),7.56-7.47(m,2H),7.38(d,J=8.4Hz,1H),3.95 -3.86(m,1H),3.33-3.30(m,4H),2.96(s,2H),2.85(t,J=7.1Hz,2H),2.78-2.71(m ,1H),2.65-2.57(m,4H),2.56-2.51(m,2H),1.13-1.05(m,8H),0.58-0.48(m,2H).

[0839] Example 118 (Compound 186)

[0840] Preparation of N-isopropyl-2-(4-(5-(1-isopropyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide:

[0841] Step 1: Synthesis of 6-bromo-1-isopropyl-3,4-dihydroquinolin-2(1H)-one:

[0842] Referring to the first step of Preparation Example 1, 6-bromo-3,4-dihydroquinolin-2(1H)-one (200 mg, 1 eq) and iodoisopropyl (451.16 mg) were used as raw materials and separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to obtain the product (120 mg). LCMS (ESI) [M+H] + =268.0; 1 HNMR(400MHz, CDCl3)δ7.32(dd,J=8.6,2.3Hz,1H),7.30-7.27(m,1H),6.99(d,J=8.6H z,1H),4.71-4.60(m,1H),2.83-2.74(m,2H),2.58-2.51(m,2H),1.50(d,J=7.0Hz,6H).

[0843] Step 2: Synthesis of 1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one:

[0844] Referring to the second step reaction of Preparation Example 1, the product of the first step reaction (120 mg, 1 eq) was used as the starting material to obtain the product (130 mg, crude product). LCMS (ESI) [M+H] +=316.1.

[0845] Step 3: Synthesis of compound 186:

[0846] Referring to the method of Example 102, using Preparation Example 4 (80 mg, 1 eq) and the product of the second step (96.06 mg) as starting materials, the title compound (30.43 mg) was obtained by reverse phase chromatography (0.1% NH3H2O ​​in H2O / ACN). LCMS (ESI) [M+H] + =450.3; 1 HNMR(400MHz,DMSO-d6)δ8.38-8.15(m,2H),7.64-7.60(m,1H),7.58(dd,J=8.4,2 .1Hz,1H),7.56-7.51(m,1H),7.50-7.47(m,1H),7.28(d,J=8.5Hz,1H),4.68-4.5 8(m,1H),3.95-3.86(m,1H),3.32-3.28(m,4H),2.96(s,2H),2.89-2.83(m,2H),2 .63-2.57(m,4H),2.49-2.45(m,2H),1.46(d,J=6.9Hz,6H),1.08(d,J=6.6Hz,6H).

[0847] Example 119 (Compound 182)

[0848] Preparation of 2-(4-(5-(5-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide:

[0849] Step 1: Synthesis of 7-bromo-5-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one:

[0850] 2-Amino-5-bromo-3-fluorophenol (500 mg, 1 eq) was dissolved in N,N-dimethylformamide (10 mL), and chloroacetyl chloride (274.11 mg) and potassium carbonate (670.89 mg) were added. The mixture was stirred at 80°C for 2 hours. Water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL*3). The organic phase was washed with saturated brine (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 2:1) to obtain the product (400 mg). LCMS (ESI) [M+H] + =246.0; 1HNMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 7.22 (dd, J = 9.8, 1.9Hz, 1H), 7.17-6.96 (m, 1H), 4.65 (s, 2H).

[0851] Step 2: Synthesis of 7-bromo-5-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one:

[0852] Referring to the first step of the reaction in Preparation Example 1, the product from the first step (400 mg, 1 eq) and iodomethane (0.15 ml) were used as raw materials and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 2:1) to obtain the product (300 mg). LCMS (ESI) [M+H] + =260.0; 1 HNMR (400 MHz, CDCl 3) δ7.09-6.90(m,2H),4.55(s,2H),3.46(d,J=6.0Hz,3H).

[0853] Step 3: Synthesis of 5-fluoro-4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one:

[0854] Referring to the second step reaction of Preparation Example 1, the product of the second step (150 mg, 1 eq) was used as the starting material to obtain the product (170 mg, crude product). LCMS (ESI) [M+H] + =308.1.

[0855] Step 4: Synthesis of compound 182:

[0856] Referring to the method of Example 102, the product of Preparation Example 1 (80 mg, 1 eq) and the product of the third step reaction (144 mg) were used as starting materials and separated and purified by reverse phase chromatography (0.1% NH3H2O ​​in H2O / ACN) to obtain the title compound (67.97 mg). LCMS (ESI) [M+H] + =442.2; 1HNMR (400MHz, DMSO-d6) δ8.32(d,J=1.8Hz,1H),8.30(d,J=2.7Hz,1H),7.57-7.51(m,2H),7.49(dd,J=14.1,2.0Hz,1H),7.39-7.35(m, 1H),4.70(s,2H),3.96-3.86(m,1H),3.40(d,J=6.0Hz,3H),3.35-3.32(m,4H),2.96(s,2H),2.64-2.54(m,4H),1.08(d,J=6.6Hz,6H).

[0857] With reference to the preparation method of the above examples, the following compounds were prepared, and their structures and characterization data are as follows:

[0858] Biological Examples

[0859] Experimental Example 1: Human Aldosterone Synthase (CYP11B2) Inhibitory Activity Detection

[0860] Experimental reagents and instruments: Aldosterone kit (Cisbio, Cat#64ALDPEG); Envision microplate reader (PerkinElmer)

[0861] Principle and Methods: In humans, aldosterone synthase (CYP11B2) converts 11-deoxycorticosterone (11-DOC) to aldosterone through a series of metabolic processes. In this study, a G402-human CYP11B2 over-expressing cell line was constructed in vitro (reference: Valentín-Goyco J, et al. Selectivity of osilodrostat as an inhibitor of human steroidogenic cytochromes P450. J Steroid Biochem Mol Biol. 2023, 231:106316). 11-Deoxycorticosterone (11-DOC) was used as a substrate, and the test compound was added. After incubation, the supernatant was collected. The aldosterone content in the supernatant was determined by HTRF, and the inhibitory effect of the compound on CYP11B2 was calculated.

[0862] Experimental Procedure: 11-Deoxycorticosterone (11-DOC) was added to a well plate (10,000 cells / well) that had been plated one day in advance. Compounds were then added to the corresponding wells in various dilutions and mixed thoroughly. Control wells were also set up with a final DMSO concentration of 0.1%. The cells were incubated in a 37°C / 5% CO2 incubator for 24 hours. The collected supernatant was added to a 384-well plate at 10 μL / well. 5 μL of the receptor working solution and 5 μL of the donor antibody were added, respectively. The plates were centrifuged at 1000 rpm for 1 minute. The cells were incubated at room temperature for 60-120 minutes. The fluorescence signal ratio at 665 nm / 615 nm was read using an Envision microplate reader (PerkinElmer).

[0863] Experimental data processing method: GraphPad Prism 5 software was used for test data processing and analysis. First, the average reaction signal of the high-signal control well and the low-signal control well was calculated respectively. Then, the reaction inhibition rate of each compound well was calculated according to the formula "single-well inhibition rate % = 100-(high-signal control group average value - single-well signal value) / (high-signal control group average value - low-signal control group average value)". Then, the concentration and corresponding inhibition rate data were imported into Prism 5 software, and the inhibition rate-concentration curve was fitted using the log (inhibitor) vs. response-Variable slop method in the software, and the IC of the compound was calculated. 50 value.

[0864] The compounds of the present application have good CYP11B2 inhibitory activity. The activity data of exemplary compounds are shown in the table below.

[0865] Table 1 Human aldosterone synthase (CYP11B2) inhibitory activity assay

[0866] IC of CYP11B2 enzyme inhibition 50 Value: A++≤3nM, 3nM <A+≤10nM,10nM<A≤20nM.

[0867] Experimental Example 2: Human Aldosterone Synthase (CYP11B1) Inhibitory Activity Detection

[0868] Experimental reagents and instruments: Cortisol kit (Cisbio, Cat#62ALDPEG); Envision microplate reader (PerkinElmer)

[0869] Principle and Methods: In humans, 11β-hydroxylase (CYP11B1) is a key enzyme responsible for cortisol biosynthesis. This experiment involved constructing a G402-human CYP11B1 over-expression cell line in vitro. 11-Deoxycortisol was used as a substrate, and the test compound was added. Following incubation, the supernatant was collected. The cortisol content in the supernatant was determined using HTRF, and the inhibitory effect of the compound on 11β-hydroxylase (CYP11B1) was calculated.

[0870] Experimental Procedure: 11-Deoxycortisol was added to a well plate (10,000 cells / well) that had been plated one day in advance. Compounds diluted in various gradients were then added to the corresponding wells and mixed thoroughly. Control wells were also set up with a final DMSO concentration of 0.1%. The cells were incubated in a 37°C / 5% CO2 incubator for 24 hours. The collected supernatant was added to a 384-well plate at 10 μL / well. 5 μL of Acceptor working solution and 5 μL of Donor Antibody were added, respectively. The plates were centrifuged at 1000 rpm for 1 minute. The cells were incubated at room temperature for 60-120 minutes. The fluorescence signal ratio at 665 nm / 615 nm was read using an Envision microplate reader (PerkinElmer).

[0871] Experimental data processing method: GraphPad Prism 5 software was used for test data processing and analysis. First, the average reaction signal of the high signal control well and the low signal control well was calculated respectively. Then, the reaction inhibition rate of each compound well was calculated according to the formula "single well inhibition rate % = 100-(high signal control group average value-single well signal value) / (high signal control group average value-low signal control group average value)". Then, the concentration and corresponding inhibition rate data were imported into Prism 5 software, and the inhibition rate-concentration curve was fitted using the log (inhibitor) vs. response-Variable slop method in the software, and the IC of the compound was calculated. 50 value.

[0872] The compounds of the present application have good CYP11B2 / CYP11B1 selectivity. The selectivity data of exemplary compounds are shown in the table below.

[0873] Table 2 CYP11B2 / CYP11B1 selectivity results

[0874] Ratio of CYP11B1 IC50 to CYP11B2 IC50: A>500; 500≥B>200; 200≥C>100; D≤100

[0875] The structure of control compound 1 is

[0876] Experimental Example 3: Cassette PK study in cynomolgus monkeys

[0877] Test animals: healthy adult males Cynomolgus macaques, 6 animals, 40-65 months.

[0878] Drug preparation: 5% DMSO + 10% Solutol + 85% Saline (1 / 2 / 17, v / v / v). Weigh an appropriate amount of test compound and add it to a centrifuge tube. Add an appropriate volume of DMSO and vortex to dissolve to obtain a clear solution. Add Solutol and vortex again to mix thoroughly. Add Saline and vortex to mix thoroughly to obtain a clear solution. Mix equal volumes of the two preparations to obtain 0.1 mg / mL for intravenous administration and 0.2 mg / mL for PO administration, respectively. Prepare immediately before use.

[0879] Dosing: Intravenous (IV) and oral (PO) dosing groups, with three male cynomolgus monkeys per group, were fasted overnight prior to dosing. Food was resumed 4 hours after dosing, with free access to water. The IV dose was 0.2 mg / kg in a 2 mL / kg dosing volume. The oral dose was 1 mg / kg in a 5 mL / kg dosing volume.

[0880] Sample Collection: Plasma samples were collected from the intravenous group at 5, 15, 30, 1, 2, 4, and 8 hours after dosing. Plasma samples were collected from the oral group at 15, 30, 1, 2, 4, 8, and 24 hours after dosing. At the designated time points, 500 μL of blood was collected in anticoagulant tubes containing EDTA-K2 anticoagulant and centrifuged within 30 minutes to obtain plasma. Whole blood samples were placed on wet ice before centrifugation. All collected plasma samples were stored on dry ice or in an ultra-low temperature freezer until analysis.

[0881] Sample Preparation: Dilution of test samples: Transfer 3.0 μL of each test plasma sample into an EP tube pre-added with 27 μL of blank plasma and vortex to mix. Extraction of standard curve, quality control, blank, and test samples: Transfer 7.0 μL of each of blank, standard curve, quality control, and diluted test sample into a 96-well plate. Add 70.0 μL of internal standard working solution. Place the 96-well plate on a mixer and mix at 500 rpm for 10 minutes at room temperature. After mixing, centrifuge at 4000 rpm for 10 minutes at 4°C. Transfer 50.0 μL of the supernatant into a 96-well plate pre-added with 50.0 μL of ultrapure water. Place the 96-well plate on a mixer and mix at 500 rpm for 10 minutes at room temperature to complete the extraction of the standard curve, quality control, blank, and test samples. Plasma samples were analyzed by LC-MS / MS to obtain the concentration of the test compound. LC / MS / MS analysis instrument: Triple Quad 6500

[0882] Data analysis: The raw data of biological analysis were collected and calculated by AB Sciex mass spectrometer software Analyst 1.7.2. 8.2 Processing Software The main pharmacokinetic parameters were calculated by fitting a non-compartmental model. The data were processed and graphed using a computer program (Microsoft Office Excel, Microsoft, USA).

[0883] Experimental results:

[0884] The compounds of the present application have lower clearance rates and good oral absorption properties. The results of exemplary compounds are shown in the table below:

[0885] Experimental Example 4: Concomitant PK study in cynomolgus monkeys

[0886] Experimental animals: healthy adult males Cynomolgus macaques, 40-65 months.

[0887] Drug preparation: 5% DMSO + 10% Solutol + 85% Saline (1 / 2 / 17, V / V / V). Weigh an appropriate amount of test compound into a centrifuge tube. Add an appropriate volume of DMSO and vortex to dissolve to obtain a clear solution. Add Solutol and vortex again to mix thoroughly. Add Saline and vortex to mix thoroughly to obtain a clear solution.

[0888] Animal Model: After 7 days of acclimation, animals were injected intramuscularly with ACTH (ACTH challenge model). Plasma samples were collected before and 1 hour after intramuscular injection for PD markers. Animals with a greater than 2-fold change in PD markers compared to pre-injection values ​​were selected for PD efficacy testing.

[0889] Grouping and dosing:

[0890] (1) Administration: Oral administration (po); Dosage: 1 mg / kg; Dosage volume: 5 mL / kg; Frequency of administration: 1 single dose per day.

[0891] (2) ACTH injection method: intramuscular injection; injection time: 1 hour after po administration; dose: 14.5 μg / kg; injection volume: 0.1 ml / kg.

[0892] Sample collection: Blood was collected before po administration and 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration to prepare plasma.

[0893] About 0.3 mL of blood was collected from a limb vein and placed in an EDTA-K2 tube. The tube was gently shaken to mix thoroughly and then placed in an ice-water bath. The tube was centrifuged within 30 minutes (4°C, 2000 g, 10 minutes) to separate the plasma. The plasma sample was stored in a -80°C freezer until testing. The separated blood was frozen in a refrigerator until testing. The sample was kept in an ice-water bath throughout the entire process.

[0894] Data Analysis: Pharmacokinetic parameters in cynomolgus monkeys were calculated using a non-compartmental model using Phoenix WinNonlin software. Plasma concentration-time data and curves for each animal are presented, along with the mean, standard deviation, and curve for each dose group. Data were processed and graphed using Microsoft Office Excel (Microsoft, USA).

[0895] Experimental results:

[0896] The compounds of the present invention have good oral absorption properties. The results of exemplary compounds are shown in the following table:

[0897] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound, a stereoisomer, a tautomer, an isotopic derivative or a pharmaceutically acceptable salt thereof, wherein: The compound is as shown in formula (I), in, Ring A is a 5-6 membered heterocyclyl, a 5-6 membered heteroaryl or a phenyl group; Ring B is phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl; R A is independently selected at each occurrence from deuterium, halogen, oxo, -CN, -NH2, or optionally substituted with: C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 3-4 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 or, when two R A , and the two R A Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 When the two R A Together with the carbon atom to which it is attached, it forms C 3-6 wherein the optional substitution refers to being unsubstituted or substituted by one or more independently selected from deuterium, halogen, C 1-3 Alkyl, C 1-3 Substitution of alkoxy, hydroxy, and oxo groups; R B is independently selected at each occurrence from deuterium, halogen, oxo, -CN, -NH2, or optionally substituted with: C 1-4 Alkyl, C 3-4 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 or, when two R B , and the two R B Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 When the two R B Together with the carbon atom to which it is attached, it forms C 3-6 wherein the optional substitution refers to being unsubstituted or substituted by one or more independently selected from deuterium, halogen, C 1-3 Alkyl, C 1-3 Substitution of alkoxy, hydroxy, and oxo groups; Ring C is an optionally substituted 4-8 membered heterocyclic group; wherein optionally substituted means unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 Haloalkoxy; the heterocyclic group contains 1 N atom, and optionally, further contains 1, 2 or 3 heteroatoms, the heteroatoms being independently selected from O, N or S; X1 is selected from N and CR X1 ; X2 is selected from N and CR X2 ; X3 selected from N and CR X3 ; The condition is that X1, X2 and X3 are not N at the same time; R X1 , R X2 , R X3 Each is independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkyl and C 1-3 Haloalkoxy; L is a bond, -O-, -S-, or an optionally substituted group: -C 0-4 Alkylene-N(R1)-, -C 0-4 Alkylene-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-N(R1)-, -C 0-4 Alkylene-N(R1)-S(O)2-, -C 0-4 Alkylene-C(O)-N(R1)-S(O)2-, -C 0-4 Alkylene-C(O)-N(R1)-, -C 0-4 Alkylene-S(O)2-N(R1)-, -C 1-4 Alkylene-, -C 3-6 Cycloalkyl-C 0-4 Alkylene-C(O)-N(R1)-, 3-10 membered heterocyclic-C 0-4 wherein the optional substitution refers to being unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; R1 is selected from hydrogen, deuterium, or an optionally substituted group: 1-3 Alkyl and C 3-6 wherein the optional substitution refers to being unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; R is selected from -N(R2)R3, -S(O)2R4, or is optionally replaced by one or more R w1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 5-12 membered heteroaryl, C 6-12 Aryl; wherein R w1 is selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, -C(O)-N(R2)R3, or optionally replaced by one or more R w2 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl; wherein R w2 is selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3, -S(O)2R4, -C(O)N(R7)R8, -C(O)OR9, or optionally substituted by one or more R w3 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 6-10 Aryl, 5-12 membered heteroaryl; wherein R w3 is selected from deuterium, halogen, oxo, -CN, -OH, -N(R2)R3, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl, C 1-4 Haloalkyl and C 1-4 Haloalkoxy; R2 and R3 are each independently selected from hydrogen, deuterium, or the following groups which are optionally substituted: 1-6 Alkyl, C 3-6 wherein the optional substitution refers to being unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; R4 is selected from hydrogen, deuterium, or an optionally substituted group: 1-3 Alkyl and C 3-6 wherein the optional substitution refers to being unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; R5 is selected from hydrogen, deuterium, or an optionally substituted group: 1-3 Alkyl and C 3-6 wherein the optional substitution refers to being unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; R6 is selected from hydrogen, deuterium, or an optionally substituted group: 1-3 Alkyl, C 3-6 Cycloalkyl and C 4-6 wherein the optional substitution refers to being unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C1-4 alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; R7 and R8 are each independently selected from hydrogen, deuterium, or the following groups which are optionally substituted: 1-3 Alkyl, C 3-6 Cycloalkyl and C 4-6 wherein the optional substitution refers to being unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; R9 is selected from hydrogen, deuterium, or an optionally substituted group: 1-6 Alkyl and C 3-6 wherein the optional substitution refers to being unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; a is selected from 0, 1, 2, 3 and 4; b is selected from 0, 1, 2, 3 and 4; Unless otherwise specified, the heteroatoms in the above heterocyclic or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4; The prerequisite is that the definitions of the above variables are combined to form a stable chemical structure.

2. The compound according to claim 1, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, wherein: When the bicyclic system formed by ring A and ring B is When b is not 0, Representation and Linking site; and / or, ring A and ring B are not both 6-membered aromatic ring systems, that is, when ring A is phenyl or pyridyl, ring B is not phenyl or pyridyl; And / or, the compound represented by formula (I) is not:

3. The compound according to any one of claims 1 to 2, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, wherein: The bicyclic ring system composed of ring A and ring B is selected from: in, Representation and ring connection site.

4. The compound according to any one of claims 1 to 3, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, wherein: Selected from:

5. The compound according to any one of claims 1 to 4, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, wherein: Ring C is an optionally substituted 5-8 membered heterocyclyl; preferably, Ring C is selected from optionally substituted: Preferably, Ring C is selected from optionally substituted: Preferably, Ring C is selected from optionally substituted: in, Representative and ring The connection site, represents the attachment site to L; Wherein, the optional substitution refers to being unsubstituted or being substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -NH2, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 The alkylene group is substituted with a haloalkoxy substituent.

6. The compound according to any one of claims 1 to 5, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, wherein: Structure fragment for Preferably, for in, represents the attachment site to ring B, Represents the attachment site to ring C.

7. The compound according to any one of claims 1 to 6, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, wherein: L is a bond, -O-, or an optionally substituted group: -C 0-4 Alkylene-N(R1)-, -C 0-4 Alkylene-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-, -C 0-4 Alkylene-N(R1)-C(O)-N(R1)-, -C 0-4 Alkylene-C(O)-N(R1)-S(O)2-, -C 0-4 Alkylene-C(O)-N(R1)-, -C 1-4 Alkylene-, -C 3-6 Cycloalkyl-C 0-4 wherein the optional substitution refers to being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; Alternatively, L is a bond, -O-, Methylene, ethylene, propylene, -C(O)- or -S(O)2-; preferably, in these groups, the left side is connected to ring C.

8. The compound according to any one of claims 1 to 7, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, wherein: R is -N(R2)R3, -S(O)2R4, or is optionally replaced by one or more R w1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 6-12 membered aryl; wherein R w1 is selected from deuterium, halogen, oxo, -CN, -OH, -NR2R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, or optionally replaced by one or more R w2 Substituted with the following groups: C1-4 alkyl, C 1-4 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl; wherein R w2 is selected from deuterium, halogen, oxo, -CN, -OH, -NR2R3, -S(O)2R4, -C(O)NR7R8, -C(O)OR9, or optionally substituted by one or more R w3 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 6-10 substituted by a substituent of an aryl group or a 5-12-membered heteroaryl group; R w3 Selected from deuterium, halogen, oxo, -CN, -OH, -NR2R3, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Haloalkyl and C 1-4 Haloalkoxy; Or, R is 9. The compound according to any one of claims 1 to 8, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, wherein: The compound is a compound represented by formula (II-1) or formula (II-2): Among them, ring A, ring B, R A , R B , X1, X2, X3, L, R, a, b are as defined in rights 1-8; Y is N, CR Y ; R Y Selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Halogenated alkoxy.

10. The compound according to any one of claims 1 to 9, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, wherein: The compound is a compound represented by formula (III-1), formula (III-2), formula (III-3) or formula (III-4): Among them, R A , R B , X1, X2, X3, L, R, a, b, and Y are as defined in rights 1-9.

11. The compound according to any one of claims 1 to 10, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, wherein: The compound is a compound represented by formula (V): Wherein, X3 and R are as defined in rights 1-10; R a , R b are independently selected from hydrogen, deuterium and C 1-4 alkyl.

12. The compound according to claim 1, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, wherein: Selected from: Ring C is for L is R is 13. A compound, or a stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein: The compound is selected from:

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or its tautomer, stereoisomer, isotopic derivative or a pharmaceutically acceptable salt thereof.

15. Use of the compound according to any one of claims 1 to 13, or its tautomer, stereoisomer, isotopic derivative or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 14 as a drug or in the preparation of a drug; preferably, the drug is a drug used as a CYP11B2 inhibitor; the drug is a drug for preventing and / or treating CYP11B2-mediated diseases; further preferably, the drug is a drug for treating and / or preventing diseases or conditions caused by increased aldosterone; further preferably, the drug is a drug for treating and / or preventing cardiovascular and cerebrovascular diseases or kidney disease; further preferably, the drug is a drug for treating and / or preventing hypertension, hyperaldosteronism, Cushing's disease, heart failure or chronic kidney disease; further preferably, the drug is a drug for treating and / or preventing refractory hypertension, primary aldosteronism hypertension, primary aldosteronism, Cushing's disease, heart failure or chronic kidney disease.