CN114075168A

CN114075168A - Pyrazole derivative and application thereof in medicine

Info

Publication number: CN114075168A
Application number: CN202110894690.XA
Authority: CN
Inventors: 张晨; 何平; 宣兆利; 宁文涛; 魏琦; 叶飞; 万松林; 李瑶; 倪佳; 严庞科
Original assignee: Haisco Pharmaceutical Group Co Ltd
Current assignee: Haisco Pharmaceutical Group Co Ltd
Priority date: 2020-08-14
Filing date: 2021-08-09
Publication date: 2022-02-22

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuteron, a solvate, a prodrug, a metabolite and pharmacy thereofAcceptable salts or eutectic crystals, and intermediates and preparation methods thereof, and application of the acceptable salts or eutectic crystals in preparation of medicines for treating diseases related to BTK activity or expression.

Description

Pyrazole derivative and application thereof in medicine

Technical Field

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparation of drugs for treating diseases related to BTK activity or expression quantity.

Background

Bruton's Tyrosine Kinase (BTK) is a member of the non-receptor protein tyrosine kinase Tec family, is a key regulator in the B cell antigen receptor (BCR) signaling pathway, and is distributed in the lymphatic, hematopoietic, and blood systems. BTK mutations cause activation of signal pathways such as proliferation, differentiation and angiogenesis of downstream tumor cells, leading to X-linked agammaglobulinemia, non-hodgkin's lymphoma (NHL) and many B-cell malignancies, including Chronic Lymphocytic Leukemia (CLL), mantle cell lymphoma and diffuse large B-cell lymphoma. Because the BTK is mainly expressed in B cells and marrow cells, the BTK is a target with better targeting and safety.

The small molecule targeted drug developed based on the BTK target provides a brand new way for treating B cell tumors including Chronic Lymphocytic Leukemia (CLL), mantle cell lymphoma, diffuse large B cell lymphoma and the like. The drugs approved to be marketed aiming at the target at present comprise ibrutinib, acarabutinib, zebutinib and the like which are all irreversible inhibitors, and the BTK binding site of the drugs often generates C481S mutation, so that the activity of the drugs is reduced, and the drug resistance is generated. Therefore, more BTK inhibitors are developed, the problem of drug resistance generated by C481S mutation is solved, the BTK inhibitors have good inhibition effect on mutant BTK and wild BTK, and simultaneously the BTK selectivity is improved, and other toxic and side effects are avoided.

Disclosure of Invention

The invention aims to provide a compound capable of inhibiting BTK or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparing a medicament for treating diseases related to BTK activity or expression.

The invention provides a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein

In some embodiments, ring C is selected from C_3-12Carbocyclyl, 3-to 12-membered heterocyclyl, C_6-12Aryl or 5-to 12-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, cyano, -O, -NR^1aR^1b、-OR^1a、-C(＝O)R^1a、-NR^1aC(＝O)R^1b、-C(＝O)NR^1aR^1b、NR^1aS(＝O)₂R^1b、-S(＝O)₂NR^1aR^1b、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Carbocyclyl, 4 to 12 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, ring C is selected from C_3-7Monocyclic carbocyclic group, C_4-12And a cyclic carbocyclic group, C_5-12Spirocyclic carbocyclic group, C_5-12Cyclocarbocyclic group of bridged ring, 3-7 membered monocyclic heterocyclic group, 4-12 membered fused heterocyclic group, 5-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group, C_6-12Aryl or 5-to 12-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, cyano, -O, -NR^1aR^1b、-OR^1a、-C(＝O)R^1a、-NR^1aC(＝O)R^1b、-C(＝O)NR^1aR^1b、C_1-4Alkyl radical, C_2-4Alkynyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Carbocyclyl or 4-to 6-membered heterocyclyl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, ring C is selected from C_3-6Monocyclic carbocyclic group, C_4-10And a cyclic carbocyclic group, C_5-11Spirocyclic carbocyclic group, C_5-12Cyclocarbocyclic group of bridged ring, 3-to 6-membered monocyclic heterocyclic group, 4-to 10-membered fused heterocyclic group, 5-to 11-membered spiro heterocyclic group, 5-to 12-membered bridged heterocyclic group, C_6-10Aryl or 5-to 10-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, cyano, -O, -NR^1aR^1b、-OR^1a、-C(＝O)R^1a、-NR^1aC(＝O)R^1b、-C(＝O)NR^1aR^1b、C_1-4Alkyl radical, C_2-4Alkynyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Carbocyclyl or 4-to 6-membered heterocyclyl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, ring C is selected from one of the following substituted or unsubstituted substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, furyl, pyrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, oxolanyl, oxocyclohexyl, 3-azabicyclo [3.2.1]Octyl, 3-oxabicyclo [3.2.1 ]]Octyl, 8-azabicyclo [3.2.1 ]]Octyl, 8-oxabicyclo [3.2.1 ]]Octyl, 2-azabicyclo [2.2.1 ]]Heptylalkyl, 2-oxabicyclo [2.2.1]Heptylalkyl, 3-azabicyclo [3.3.1]Nonyl, 3-oxabicyclo [3.3.1]Nonanyl, 6-azabicyclo [3.1.1]Heptylalkyl, 6-oxabicyclo [3.1.1]A heptylalkyl group,

To the left of which is directly attached Y, and when substituted, is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, ═ O, CF₃、NH₂、N(CH₃)₂、NHCH₃、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂Hydroxymethyl, methyl, ethyl, isopropyl, tert-butyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxocyclohexyl or morpholinyl;

in some embodiments, R¹Is selected from-C (═ O) R^1AOr- (CH)₂)_n-C_3-12Carbocyclyl, said carbocyclyl being optionally substituted with 0 to 4 substituentsFrom H, halogen, OH, cyano, NH₂、N(C_1-6Alkyl radical)₂、NHC_1-6Alkyl radical, C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by alkoxy, said-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-6Alkyl radical)₂、NHC_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkoxy, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl is substituted by a substituent;

in some embodiments, R¹Is selected from- (CH)₂)_n-C_3-10Carbocyclyl or-C (═ O) R^1ASaid carbocyclyl is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by alkoxy, said-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl radical, C_1-4Alkoxy, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl substituent is taken;

in some embodiments, R¹Is selected from- (CH)₂)_n-C_3-6Monocyclic carbocyclic group, - (CH)₂)_n-C_4-10And a cyclic carbocyclic group, - (CH)₂)_n-C_5-10Spiro carbocyclic group, - (CH)₂)_n-C_5-10Cyclic ring of carbon-containing ring or-C (═ O) R^1ASaid carbocyclyl is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6CycloalkanesRadical or C_1-4Substituted by alkoxy, said-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl radical, C_1-4Alkoxy, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl substituent is taken;

in some embodiments, R¹Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

-CH₂-cyclopropyl, -CH₂-cyclobutyl, -CH₂-cyclopentyl, -CH₂-cyclohexyl, -CH₂- - -azetidinyl, - -CH₂-azacyclopentyl, -CH₂-azacyclohexyl, -CH₂-piperidinyl, -CH₂-morpholinyl, -CH₂-piperazinyl, -CH₂-oxetanyl, -CH₂-oxocyclopentyl, -CH₂-oxacyclohexyl, -C (O) -cyclopropyl, -C (O) -cyclobutyl, -C (O) -cyclopentyl, -C (O) -cyclohexyl, -C (O) -azetidinyl, -C (O) -azacyclohexyl, -C (O) -piperidinyl, -C (O) -morpholinyl, -C (O) -piperazinyl, -C (O) -oxetanyl, -C (O) -oxocyclopentyl, -C (O) -oxocyclohexyl, -C (O) -CH₂NH₂、-C(O)CH₂NHCH₃、-C(O)CH₂N(CH₃)₂、-C(O)-CH₂-azetidinyl or-C (O) -CH₂-an azacyclopentyl group, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Oxetanyl, oxolanyl, oxocyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, piperidinyl, piperazinyl, morpholinyl or-CH₂-optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, OH, cyano, CF₃、CH₂OH、CH₂F、NH₂、NHCH₃、N(CH₃)₂Methyl, ethyl, methoxy;

in some embodiments, R^1AIs selected from C_3-12Saturated carbocyclyl, 4-to 12-membered heterocyclyl or- (CH)₂)_m-NR^1aR^1bSaid carbocyclyl, heterocyclyl or-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-6Alkyl radical)₂、NHC_1-6Alkyl radical, C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R^1AIs selected from C_3-10Saturated carbocyclic group, 4-to 10-membered heterocyclic group or- (CH)₂)_m-NR^1aR^1bSaid carbocyclyl, heterocyclyl or-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R^1ASelected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclo-hexyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, oxolanyl, oxocyclohexyl or- (CH)₂)_m-NR^1aR^1bThe cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclohexyl, piperidinyl, morpholinyl, piperazinyl or-CH₂-optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, OH, cyano, CF₃、NH₂、NHCH₃、N(CH₃)₂、CH₂OH、CH₂F. Methyl, ethyl, cyclopropyl, cyclobutyl or methoxy;

in some embodiments, R^1a、R^1bEach independently selected from H, C_1-6Alkyl radical, C_3-12Carbocyclyl, 4-to 12-membered heterocyclyl, C_6-12Aryl or 5 to 12 membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Alkoxy, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R^1a、R^1bEach independently selected from H, C_1-4Alkyl radical, C_3-6Monocyclic carbocyclic group, C_4-10And a cyclic carbocyclic group, C_5-10Spirocyclic carbocyclic group, C_5-10Bridged carbocyclyl, 4-to 6-membered monocyclic heterocyclyl, 4-to 10-membered fused heterocyclyl, 5-to 10-membered spiro heterocyclyl, 5-to 10-membered bridged heterocyclyl, C_6-10Aryl or 5-to 10-membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R^1a、R^1bEach independently selected from H, C_1-4Alkyl radical, C_3-6A monocyclic carbocyclyl or a 3-to 6-membered monocyclic heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R^1a、R^1bEach independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxocyclopentyl, oxocyclohexyl or morpholinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxobutyl, oxocyclopentyl, oxocyclohexyl or morpholinyl being optionally substituted by 0 to 4 substituents selected from H, F, Cl, Br, OH, cyano, NH₂、CH₂F、CF₃Methyl, ethyl, cyclopropyl or methoxy;

in some embodiments, R^1a、R^1bForm a 4-to 12-membered heterocyclic group with the atom to which it is directly attached, said heterocyclic group being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_1-6Alkoxy or 3 to 10 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R^1a、R^1bThe atoms directly attached thereto form a 4 to 6 membered monocyclic heterocyclyl, a 5 to 11 membered spiroheterocyclyl, a 4 to 10 membered fused heterocyclyl or a 5 to 10 membered bridged heterocyclyl, said heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_1-6Alkoxy or 3 to 10 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R^1a、R^1bThe atom to which it is directly attached forms one of the following substituted or unsubstituted substituents: azetidinyl, azacyclopentyl, azacyclohexyl,

When substituted, is optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, OH, cyano, NH₂、CH₂F、CF₃Methyl, ethyl, cyclopropyl or methoxy;

in some embodiments, R²Selected from H, OH, halogen, C_1-6Alkyl or-NR^1aR^1bSaid alkyl group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, -NR^1aR^1b、C_1-6Alkoxy radical, C_1-6Alkoxyalkyl or C_3-12Carbocyclyl or a 4-to 12-membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R²Selected from H, OH, halogen, C_1-4Alkyl or-NR^1aR^1bSaid alkyl group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, -NR^1aR^1b、C_1-4Alkoxy radical, C_1-4Alkoxyalkyl or C_3-6Carbocyclyl or 4-to 6-membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R²Is selected from-NR^1aR^1b；

In some embodiments, R²Is selected from NH₂；

In some embodiments, ring a is selected from C_6-12Aryl or 5-to 12-membered heteroaryl, said aryl or heteroaryl optionally further substituted with 0 to 4R^a(ii) substituted, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, ring a is selected from phenyl or 5-to 6-membered heteroaryl, optionally further substituted with 0 to 4R^a(ii) substituted, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, ring a is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, optionally further substituted with 0 to 4R^aSubstitution;

in some embodiments, ring a is selected from one of the following substituted or unsubstituted substituents:

when substituted, is optionally further substituted with 0 to 4R^aSubstitution;

in some embodiments, R^aEach independently selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy or C_3-6Cycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, ═ O, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy or C_1-6Substituted with a substituent of alkoxyalkyl;

in some embodiments, R^aEach independently selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl radical, C_2-4Alkynyl, C_1-4Alkoxy or C_3-6Cycloalkyl, said alkyl, alkynyl, alkoxy or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, R^aEach independently selected from H, F, Cl, Br, I, OH, cyano, NH₂Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally further substituted by 0 to 4 substituents selected from H, F, OH, cyano, NH₂Methyl, ethyl, CF₃Cyclopropyl groupCyclobutyl, cyclopentyl, cyclohexyl or methoxy;

in some embodiments, R^aEach independently selected from H, F, Cl, Br, I, OH, cyano, NH₂、CF₃Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

in some embodiments, R^aEach independently selected from H, F, Cl, Br, I, OH, cyano, NH₂Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

in some embodiments, M is selected from C_1-4Alkylene optionally further substituted with 0 to 4R^m1Substitution;

in some embodiments, M is selected from methylene, ethylene or propylene, optionally further substituted with 0 to 4R^m1Substitution;

in some embodiments, M is selected from methylene, ethylene, or propylene;

in some embodiments, M is selected from methylene;

in some embodiments, R^m1Each independently selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6An alkoxy group;

in some embodiments, R^m1Each independently selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4An alkoxy group;

in some embodiments, R^m1Each independently selected from H, F, OH, cyano, NH₂Methyl, ethyl or CF₃；

In some embodiments, Q is selected from-C (═ O) NR^q-or-NR^qC (═ O) -, left side directly attached to ring B;

in some embodiments, Q is selected from-C (═ O) NH-, attached directly to ring B on the left;

in some embodiments, R^qSelected from H, C_1-6Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by a substituent of alkoxy;

in some embodiments, R^qSelected from H, C_1-4Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, R^qSelected from H, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

In some embodiments, ring B is selected from C_6-12Aryl or 5 to 12 membered heteroaryl, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, ring B is selected from phenyl or 5 to 6 membered heteroaryl, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, Y is selected from a bond or C_1-6Alkylene optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by a substituent of alkoxy;

in some embodiments, Y is selected from a bond or C_1-4Alkylene optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, Y is selected from the group consisting of a bond, methylene, ethylene, or propylene, said methylene, ethylene, or propylene optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, OH, cyano, NH₂、CF₃、CH₂OH、CH₂F. Methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy or isopropoxy;

in some embodiments, ring B is selected from phenyl, pyrazolyl, pyrrolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, 1,2, 4-oxadiazolyl, pyridyl, pyridazinyl, pyrazinyl, or pyrimidinyl;

in some embodiments, R³Each independently selected from H, halogen, OH, ═ O, cyano, COOH, NH₂、NHC_1-6Alkyl, N (C)_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Deuterated alkoxy, -X-C_3-12Carbocyclyl or-X-4-12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, ═ O, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl, 4-7 membered heterocycloalkyl or C_1-6(ii) alkoxyalkyl, said heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R³Each independently selected from H, halogen, OH, ═ O, cyano, COOH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Deuterated alkoxy, -X-C_3-10Carbocyclyl or-X-4 to 10 membered heterocyclyl, said alkyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, ═ O, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, 4-7 membered heterocycloalkyl or C_1-4(ii) alkoxyalkyl, said heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

in some embodiments, R³Each independently selected from H, F, Cl, Br, I, OH, ═ O, cyano, NH₂、NHCH₃、N(CH₃)₂Methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, ethynyl, -OCD₃Methoxy, ethoxy or isopropoxy, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, methoxy, ethoxy or isopropoxy being optionally further substituted by 0 to 4 substituents selected from H, F, OH, ═ O, cyano, NH₂、CF₃、CH₂OH、CH₂F. Methyl, methoxy, ethoxy or isopropoxy;

in some embodiments, X is selected from the group consisting of a bond, -NR^x-, -O-or-S-;

in some embodiments, X is selected from a bond or-O-;

in some embodiments, R^xIs selected from H or C_1-6Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by a substituent of alkoxy;

in some casesIn the embodiment, R^xIs selected from H or C_1-4Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy;

in some embodiments, n, p are each independently selected from 0, 1,2, 3 or 4;

in some embodiments, m is selected from 1,2, 3, or 4;

in some embodiments, n is selected from 0, 1, 2.

As a first embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

ring C is selected from C_3-12Carbocyclyl, 3-to 12-membered heterocyclyl, C_6-12Aryl or 5-to 12-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, cyano, -O, -NR^1aR^1b、-OR^1a、-C(＝O)R^1a、-NR^1aC(＝O)R^1b、-C(＝O)NR^1aR^1b、NR^1aS(＝O)₂R^1b、-S(＝O)₂NR^1aR^1b、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Carbocyclyl, 4 to 12 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R¹is selected from-C (═ O) R^1AOr- (CH)₂)_n-C_3-12Carbocyclyl optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-6Alkyl radical)₂、NHC_1-6Alkyl radical, C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Of alkoxy groupsSubstituted by a substituent group, said-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-6Alkyl radical)₂、NHC_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkoxy, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl is substituted by a substituent;

R^1Ais selected from C_3-12Saturated carbocyclyl, 4-to 12-membered heterocyclyl or- (CH)₂)_m-NR^1aR^1bSaid carbocyclyl, heterocyclyl or-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-6Alkyl radical)₂、NHC_1-6Alkyl radical, C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R^1a、R^1beach independently selected from H, C_1-6Alkyl radical, C_3-12Carbocyclyl, 4-to 12-membered heterocyclyl, C_6-12Aryl or 5 to 12 membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Alkoxy, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

or R^1a、R^1bForm a 4-to 12-membered heterocyclic group with the atom to which it is directly attached, said heterocyclic group being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_1-6Alkoxy or 3 to 10 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R²selected from H, OH, halogen, C_1-6Alkyl or-NR^1aR^1bWhat is, what isSaid alkyl group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, -NR^1aR^1b、C_1-6Alkoxy radical, C_1-6Alkoxyalkyl or C_3-12Carbocyclyl or a 4-to 12-membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

ring A is selected from C_6-12Aryl or 5-to 12-membered heteroaryl, said aryl or heteroaryl optionally further substituted with 0 to 4R^a(ii) substituted, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

R^aeach independently selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy or C_3-6Cycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, ═ O, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy or C_1-6Substituted with a substituent of alkoxyalkyl;

q is selected from-C (═ O) NR^q-or-NR^qC (═ O) -, left side directly attached to ring B;

R^qselected from H, C_1-6Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by a substituent of alkoxy;

m is selected from C_1-4Alkylene optionally further substituted with 0 to 4R^m1Substitution;

R^m1each independently selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6An alkoxy group;

y is selected from a bond or C_1-6Alkylene optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by a substituent of alkoxy;

ring B is selected from C_6-12Aryl or 5 to 12 membered heteroaryl, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

R³each independently selected from H, halogen, OH, ═ O, cyano, COOH, NH₂、NHC_1-6Alkyl, N (C)_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Deuterated alkoxy, -X-C_3-12Carbocyclyl or-X-4-12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, ═ O, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl, 4-7 membered heterocycloalkyl or C_1-6(ii) alkoxyalkyl, said heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N; x is selected from the group consisting of a bond, -NR^x-, -O-or-S-;

R^xis selected from H or C_1-6Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by a substituent of alkoxy;

n and p are each independently selected from 0, 1,2, 3 or 4;

m is selected from 1,2, 3 or 4.

As a second embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

ring C is selected from C_3-7Monocyclic carbocyclic group, C_4-12And a cyclic carbocyclic group, C_5-12Spirocyclic carbocyclic group, C_5-12Cyclocarbocyclic group of bridged ring, 3-7 membered monocyclic heterocyclic group, 4-12 membered fused heterocyclic group, 5-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group, C_6-12Aryl or 5-to 12-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, cyano, -O, -NR^1aR^1b、-OR^1a、-C(＝O)R^1a、-NR^1aC(＝O)R^1b、-C(＝O)NR^1aR^1b、C_1-4Alkyl radical, C_2-4Alkynyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Carbocyclyl or 4-to 6-membered heterocyclyl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

ring A is selected from phenyl or 5-6 membered heteroaryl, said phenyl or heteroaryl optionally further substituted with 0 to 4R^a(ii) substituted, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

R^aeach independently selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl radical, C_2-4Alkynyl, C_1-4Alkoxy or C_3-6Cycloalkyl, said alkyl, alkynyl, alkoxy or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy;

ring B is selected from phenyl or 5 to 6 membered heteroaryl, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

R^xis selected from H or C_1-4Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy;

the definitions of the remaining substituents are consistent with the first embodiment of the present invention.

As a third embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

R¹is selected from- (CH)₂)_n-C_3-10Carbocyclyl or-C (═ O) R^1ASaid carbocyclyl is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by alkoxy, said-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl radical, C_1-4Alkoxy, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl is substituted by a substituent;

R^1Ais selected from C_3-10Saturated carbocyclic group, 4-to 10-membered heterocyclic group or- (CH)₂)_m-NR^1aR^1bSaid carbocyclyl, heterocyclyl or-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R^1a、R^1beach independently selected from H, C_1-4Alkyl radical, C_3-6Monocyclic carbocyclic group, C_4-10And a cyclic carbocyclic group, C_5-10Spirocyclic carbocyclic group, C_5-10Bridged carbocyclyl, 4-to 6-membered monocyclic heterocyclyl, 4-to 10-memberedAnd a heterocyclic ring group, a 5-to 10-membered spiro heterocyclic group, a 5-to 10-membered bridged heterocyclic group, C_6-10Aryl or 5-to 10-membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

or R^1a、R^1bThe atoms directly attached thereto form a 4 to 6 membered monocyclic heterocyclyl, a 5 to 11 membered spiroheterocyclyl, a 4 to 10 membered fused heterocyclyl or a 5 to 10 membered bridged heterocyclyl, said heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_1-6Alkoxy or 3 to 10 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R²selected from H, OH, halogen, C_1-4Alkyl or-NR^1aR^1bSaid alkyl group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, -NR^1aR^1b、C_1-4Alkoxy radical, C_1-4Alkoxyalkyl or C_3-6Carbocyclyl or 4-to 6-membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R^m1each independently selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4An alkoxy group;

y is selected from a bond or C_1-4Alkylene optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy;

R^qselected from H, C_1-4Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy;

R³each independently selected from H, halogen, OH, ═ O, cyano, COOH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Deuterated alkoxy, -X-C_3-10Carbocyclyl or-X-4 to 10 membered heterocyclyl, said alkyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, ═ O, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, 4-7 membered heterocycloalkyl or C_1-4(ii) alkoxyalkyl, said heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

x is selected from a bond or-O-;

the remaining substituents are defined in accordance with either one or both of the schemes of the present invention.

As a fourth embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, said phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally further substituted with 0 to 4R^aSubstitution;

ring C is selected from C_3-6Monocyclic carbocyclic group, C_4-10And a cyclic carbocyclic group, C_5-11Ring of spiro ringCyclic group, C_5-12Cyclocarbocyclic group of bridged ring, 3-to 6-membered monocyclic heterocyclic group, 4-to 10-membered fused heterocyclic group, 5-to 11-membered spiro heterocyclic group, 5-to 12-membered bridged heterocyclic group, C_6-10Aryl or 5-to 10-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, cyano, -O, -NR^1aR^1b、-OR^1a、-C(＝O)R^1a、-NR^1aC(＝O)R^1b、-C(＝O)NR^1aR^1b、C_1-4Alkyl radical, C_2-4Alkynyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Carbocyclyl or 4-to 6-membered heterocyclyl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N; r¹Is selected from C_3-6Monocyclic carbocyclic group, C_4-10And a cyclic carbocyclic group, C_5-10Spirocyclic carbocyclic group, C_5-10Cyclic ring of carbon-containing ring or-C (═ O) R^1ASaid carbocyclyl is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy;

R^1Aselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclo-hexyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, oxolanyl, oxocyclohexyl or- (CH)₂)_m-NR^1aR^1bThe cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclohexyl, piperidinyl, morpholinyl, piperazinyl or-CH₂-optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, OH, cyano, CF₃、NH₂、NHCH₃、N(CH₃)₂、CH₂OH、CH₂F. Methyl, ethyl, cyclopropyl, cyclobutyl or methoxy;

R²is selected from-NR^1aR^1b；

R^1a、R^1bEach independently selected from H, C_1-4Alkyl radical, C_3-6A monocyclic carbocyclyl or a 3-to 6-membered monocyclic heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N; m is selected from methylene, ethylene or propylene, said methylene, ethylene or propylene being optionally further substituted with 0 to 4R^m1Substitution;

R^m1each independently selected from H, F, OH, cyano, NH₂Methyl, ethyl or CF₃；

n is selected from 0, 1 or 2;

the remaining substituents are defined in accordance with any one of the first, second or third aspects of the present invention.

As a fifth embodiment of the present invention, there is provided a compound represented by the general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

ring B is selected from phenyl, pyrazolyl, pyrrolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, 1,2, 4-oxadiazolyl, pyridyl, pyridazinyl, pyrazinyl or pyrimidinyl;

R³each independently selected from H, F, Cl, Br, I, OH, ═ O, cyano, NH₂、NHCH₃、N(CH₃)₂Methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, ethynyl, -OCD₃Methoxy, ethoxy or isopropoxy, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, methoxy, ethoxy or isopropoxy being optionally further substituted by 0 to 4 substituents selected from H, F, OH, ═ O, cyano, NH₂、CF₃、CH₂OH、CH₂F. Methyl, methoxy, ethoxy or isopropoxy;

ring C is selected from one of the following substituted or unsubstituted substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, furyl, pyrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, oxolanyl, oxocyclohexyl, 3-azabicyclo [3.2.1]Octyl, 3-oxabicyclo [3.2.1 ]]Octyl, 8-azabicyclo [3.2.1 ]]Octyl, 8-oxabicyclo [3.2.1 ]]Octyl, 2-azabicyclo [2.2.1 ]]Heptylalkyl, 2-oxabicyclo [2.2.1]Heptylalkyl, 3-azabicyclo [3.3.1]Nonyl, 3-oxabicyclo [3.3.1]Nonanyl, 6-azabicyclo [3.1.1]Heptylalkyl, 6-oxabicyclo [3.1.1]A heptylalkyl group,

To the left of which is directly attached Y, and when substituted, is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, ═ O, CF₃、NH₂、N(CH₃)₂、NHCH₃、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂Hydroxymethyl, methyl, ethyl, isopropyl, tert-butyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxocyclohexyl or morpholinyl; y is selected from the group consisting of a bond, methylene, ethylene or propylene, said methylene, ethylene or propylene being optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, OH, cyano, NH₂、CF₃、CH₂OH、CH₂F. Methyl, ethyl, isopropyl, cyclicPropyl, methoxy, ethoxy or isopropoxy;

R^1a、R^1beach independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxocyclopentyl, oxocyclohexyl or morpholinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxobutyl, oxocyclopentyl, oxocyclohexyl or morpholinyl being optionally substituted by 0 to 4 substituents selected from H, F, Cl, Br, OH, cyano, NH₂、CH₂F、CF₃Methyl, ethyl, cyclopropyl or methoxy;

or R^1a、R^1bThe atom to which it is directly attached forms one of the following substituted or unsubstituted substituents: azetidinyl, azacyclopentyl, azacyclohexyl,

R²is selected from NH₂；

M is selected from methylene, ethylene or propylene;

R^aeach independently selected from H, F, Cl, Br, I, OH, cyano, NH₂Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally further substituted by 0 to 4 substituents selected from H, F, OH, cyano, NH₂Methyl, ethyl, CF₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or methoxy;

R^qselected from H, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

The remaining substituents are defined in accordance with any one of the first, second, third or fourth aspects of the present invention.

As a sixth embodiment of the present invention, there is provided a compound represented by the general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

m is selected from methylene;

q is selected from-C (═ O) NH-, and is directly attached to ring B on the left;

ring a is selected from one of the following substituted or unsubstituted substituents:

when substituted, is optionally further substituted with 0 to 4R^aSubstitution;

R^aeach independently selected from H, F, Cl, Br, I, OH, cyano, NH₂、CF₃、CH₂OH、CH₂F. Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

R¹selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

the remaining substituents are defined in accordance with any one of the first, second, third, fourth or fifth aspects of this invention.

The invention relates to a compound or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein the compound is selected from one of the following structures:

in some embodiments of the general formula (I), ring C is selected from C_3-12Carbocyclyl, 3-to 12-membered heterocyclyl, C_6-12Aryl or 5-to 12-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, cyano, -O, -NR^1aR^1b、-OR^1a、-C(＝O)R^1a、-NR^1aC(＝O)R^1b、-C(＝O)NR^1aR^1b、NR^1aS(＝O)₂R^1b、-S(＝O)₂NR^1aR^1b、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Carbocyclyl, 4 to 12 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), ring C is selected from C_3-7Monocyclic carbocyclic group, C_4-12And a cyclic carbocyclic group, C_5-12Spirocyclic carbocyclic group, C_5-12Cyclocarbocyclic group of bridged ring, 3-7 membered monocyclic heterocyclic group, 4-12 membered fused heterocyclic group, 5-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group, C_6-12Aryl or 5-to 12-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, cyano, -O, -NR^1aR^1b、-OR^1a、-C(＝O)R^1a、-NR^1aC(＝O)R^1b、-C(＝O)NR^1aR^1b、C_1-4Alkyl radical, C_2-4Alkynyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Carbocyclyl or 4-to 6-membered heterocyclyl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), ring C is selected from C_3-6Monocyclic carbocyclic group, C_4-10And a cyclic carbocyclic group, C_5-11Spirocyclic carbocyclic group, C_5-12Cyclocarbocyclic group of bridged ring, 3-to 6-membered monocyclic heterocyclic group, 4-to 10-membered fused heterocyclic group, 5-to 11-membered spiro heterocyclic group, 5-to 12-membered bridged heterocyclic group, C_6-10Aryl or 5-to 10-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, cyano, -O, -NR^1aR^1b、-OR^1a、-C(＝O)R^1a、-NR^1aC(＝O)R^1b、-C(＝O)NR^1aR^1b、C_1-4Alkyl radical, C_2-4Alkynyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Carbocyclyl or 4-to 6-membered heterocyclyl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of formula (I), ring C is selected from one of the following substituted or unsubstituted substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, furyl, pyrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, oxolanyl, oxocyclohexyl, 3-azabicyclo [3.2.1]Octyl, 3-oxabicyclo [3.2.1 ]]Octyl, 8-azabicyclo [3.2.1 ]]Octyl, 8-oxabicyclo [3.2.1 ]]Octyl, 2-azabicyclo [2.2.1 ]]Heptylalkyl, 2-oxabicyclo [2.2.1]Heptylalkyl, 3-azabicyclo [3.3.1]Nonyl, 3-oxabicyclo [3.3.1]Nonanyl, 6-azabicyclo [3.1.1]Heptylalkyl, 6-oxabicyclo [3.1.1]A heptylalkyl group,

To the left of which is directly attached Y, and when substituted, is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, ═ O, CF₃、NH₂、N(CH₃)₂、NHCH₃、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂Hydroxymethyl, methyl, ethyl, isopropyl, tert-butyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxocyclohexyl or morpholinyl.

In some embodiments of the general formula (I), R¹Is selected from-C (═ O) R^1AOr- (CH)₂)_n-C_3-12Carbocyclyl optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-6Alkyl radical)₂、NHC_1-6Alkyl radical, C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by alkoxy, said-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-6Alkyl radical)₂、NHC_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkoxy, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl substituents.

In some embodiments of the general formula (I), R¹Is selected from- (CH)₂)_n-C_3-10Carbocyclyl or-C (═ O) R^1ASaid carbocyclyl is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl, halogen substituted C_1-4Alkyl radicalHydroxy-substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by alkoxy, said-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl radical, C_1-4Alkoxy, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4The substituent of the alkyl is taken.

In some embodiments of the general formula (I), R¹Is selected from- (CH)₂)_n-C_3-6Monocyclic carbocyclic group, - (CH)₂)_n-C_4-10And a cyclic carbocyclic group, - (CH)₂)_n-C_5-10Spiro carbocyclic group, - (CH)₂)_n-C_5-10Cyclic ring of carbon-containing ring or-C (═ O) R^1ASaid carbocyclyl is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by alkoxy, said-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl radical, C_1-4Alkoxy, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4The substituent of the alkyl is taken.

In some embodiments of the general formula (I), R¹Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Oxetanyl, oxolanyl, oxocyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, piperidinyl, piperazinyl, morpholinyl or-CH₂-optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, OH, cyano, CF₃、CH₂OH、CH₂F、NH₂、NHCH₃、N(CH₃)₂Methyl, ethyl, methoxy.

In some embodiments of the general formula (I), R^1AIs selected from C_3-12Saturated carbocyclyl, 4-to 12-membered heterocyclyl or- (CH)₂)_m-NR^1aR^1bSaid carbocyclyl, heterocyclyl or-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-6Alkyl radical)₂、NHC_1-6Alkyl radical, C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Alkoxy, said heterocyclyl containing from 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), R^1AIs selected from C_3-10Saturated carbocyclic group, 4-to 10-membered heterocyclic group or- (CH)₂)_m-NR^1aR^1bSaid carbocyclyl, heterocyclyl or-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocyclyl containing from 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), R^1ASelected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclo-hexyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, oxolanyl, oxocyclohexyl or- (CH)₂)_m-NR^1aR^1bThe cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclohexyl, piperidinyl, morpholinyl, piperazinyl or-CH₂-optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, OH, cyano, CF₃、NH₂、NHCH₃、N(CH₃)₂、CH₂OH、CH₂F. Methyl, ethyl, cyclopropyl, cyclobutyl or methoxy.

In some embodiments of the general formula (I), R^1a、R^1bEach independently selected from H, C_1-6Alkyl radical, C_3-12Carbocyclyl, 4-to 12-membered heterocyclyl, C_6-12Aryl or 5 to 12 membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Alkoxy, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), R^1a、R^1bEach independently selected fromH、C_1-4Alkyl radical, C_3-6Monocyclic carbocyclic group, C_4-10And a cyclic carbocyclic group, C_5-10Spirocyclic carbocyclic group, C_5-10Bridged carbocyclyl, 4-to 6-membered monocyclic heterocyclyl, 4-to 10-membered fused heterocyclyl, 5-to 10-membered spiro heterocyclyl, 5-to 10-membered bridged heterocyclyl, C_6-10Aryl or 5-to 10-membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), R^1a、R^1bEach independently selected from H, C_1-4Alkyl radical, C_3-6A monocyclic carbocyclyl or a 3-to 6-membered monocyclic heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocyclyl containing from 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), R^1a、R^1bEach independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxocyclopentyl, oxocyclohexyl or morpholinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxobutyl, oxocyclopentyl, oxocyclohexyl or morpholinyl being optionally substituted by 0 to 4 substituents selected from H, F, Cl, Br, OH, cyano, NH₂、CH₂F、CF₃Methyl, ethyl, cyclopropyl or methoxy.

In some embodiments of the general formula (I), R^1a、R^1bForm a 4-to 12-membered heterocyclic group with the atom to which it is directly attached, said heterocyclic group being optionally further substituted by 0 to 4 substituents selected from H, halogen,OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_1-6Alkoxy or 3 to 10 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), R^1a、R^1bThe atoms directly attached thereto form a 4 to 6 membered monocyclic heterocyclyl, a 5 to 11 membered spiroheterocyclyl, a 4 to 10 membered fused heterocyclyl or a 5 to 10 membered bridged heterocyclyl, said heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_1-6Alkoxy or 3 to 10 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), R^1a、R^1bThe atom to which it is directly attached forms one of the following substituted or unsubstituted substituents: azetidinyl, azacyclopentyl, azacyclohexyl,

When substituted, is optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, OH, cyano, NH₂、CH₂F、CF₃Methyl, ethyl, cyclopropyl or methoxy.

In some embodiments of the general formula (I), R²Selected from H, OH, halogen, C_1-6Alkyl or-NR^1aR^1bSaid alkyl group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, -NR^1aR^1b、C_1-6Alkoxy radical, C_1-6Alkoxyalkyl or C_3-12Carbocyclyl or a 4-to 12-membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), R²Selected from H, OH, halogen, C_1-4Alkyl or-NR^1aR^1bSaid alkyl group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, -NR^1aR^1b、C_1-4Alkoxy radical, C_1-4Alkoxyalkyl or C_3-6Carbocyclyl or a 4-to 6-membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), R²Is selected from-NR^1aR^1b。

In some embodiments of the general formula (I), R²Is selected from NH₂。

In some embodiments of formula (I), ring A is selected from C_6-12Aryl or 5-to 12-membered heteroaryl, said aryl or heteroaryl optionally further substituted with 0 to 4R^aAnd substituted, said heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of formula (I), ring A is selected from phenyl or 5-to 6-membered heteroaryl, optionally further substituted with 0 to 4R^aAnd substituted, said heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N.

In certain embodiments of formula (I), ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, optionally further substituted with 0 to 4R^aAnd (4) substitution.

In some embodiments of formula (I), ring A is selected from one of the following substituted or unsubstituted substituents:

when substituted, is optionally further substituted with 0 to 4R^aAnd (4) substitution.

In some embodiments of the general formula (I), R^aEach independently selected from H, halogen, OH, cyano、NH₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy or C_3-6Cycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, ═ O, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy or C_1-6Substituted by a substituent of alkoxyalkyl.

In some embodiments of the general formula (I), R^aEach independently selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl radical, C_2-4Alkynyl, C_1-4Alkoxy or C_3-6Cycloalkyl, said alkyl, alkynyl, alkoxy or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy.

In some embodiments of the general formula (I), R^aEach independently selected from H, F, Cl, Br, I, OH, cyano, NH₂Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally further substituted by 0 to 4 substituents selected from H, F, OH, cyano, NH₂Methyl, ethyl, CF₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or methoxy.

In some embodiments of the general formula (I), R^aEach independently selected from H, F, Cl, Br, I, OH, cyano, NH₂、CF₃Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments of the general formula (I), R^aEach independently selected from H, F, Cl, Br, I, OH, cyanogenRadical, NH₂Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments of the general formula (I), M is selected from C_1-4Alkylene optionally further substituted with 0 to 4R^m1And (4) substitution.

In some embodiments of formula (I), M is selected from methylene, ethylene, or propylene, optionally further substituted with 0 to 4R^m1And (4) substitution.

In some embodiments of formula (I), M is selected from methylene, ethylene, or propylene.

In some embodiments of formula (I), M is selected from methylene.

In some embodiments of the general formula (I), R^m1Each independently selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6An alkoxy group.

In some embodiments of the general formula (I), R^m1Each independently selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4An alkoxy group.

In some embodiments of the general formula (I), R^m1Each independently selected from H, F, OH, cyano, NH₂Methyl, ethyl or CF₃。

The present invention relates to certain embodiments of formula (I) wherein Q is selected from-C (═ O) NR^q-or-NR^qC (═ O) -, left side is directly attached to ring B.

In some embodiments of formula (I), Q is selected from-C (═ O) NH-, and is attached directly to ring B on the left.

In some embodiments of the general formula (I), R^qSelected from H, C_1-6Alkyl or C_3-6Cycloalkyl radicalsSaid alkyl or cycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by a substituent of alkoxy.

In some embodiments of the general formula (I), R^qSelected from H, C_1-4Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy.

In some embodiments of the general formula (I), R^qSelected from H, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

In some embodiments of formula (I), Y is selected from a bond or C_1-6Alkylene optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by a substituent of alkoxy.

In some embodiments of formula (I), Y is selected from a bond or C_1-4Alkylene optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy.

In some embodiments of formula (I), Y is selected from the group consisting of a bond, methylene, ethylene, or propylene, said methylene, ethylene, or propylene optionally further substituted by 0Up to 4 groups selected from H, F, Cl, Br, OH, cyano, NH₂、CF₃、CH₂OH、CH₂F. Methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy or isopropoxy.

In some embodiments of formula (I), ring B is selected from C_6-12Aryl or 5 to 12 membered heteroaryl, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N.

The present invention relates to certain embodiments of formula (I) wherein ring B is selected from phenyl or a 5 to 6 membered heteroaryl group, said heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of formula (I), ring B is selected from phenyl, pyrazolyl, pyrrolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, 1,2, 4-oxadiazolyl, pyridyl, pyridazinyl, pyrazinyl, or pyrimidinyl.

In some embodiments of the general formula (I), R³Each independently selected from H, halogen, OH, ═ O, cyano, COOH, NH₂、NHC_1-6Alkyl, N (C)_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Deuterated alkoxy, -X-C_3-12Carbocyclyl or-X-4-12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, ═ O, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl, 4-7 membered heterocycloalkyl or C_1-6Alkoxyalkyl, said heterocyclyl or heterocycloalkyl containing from 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), R³Each independently selected from H, halogen, OH, ═ O, cyano, COOH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Deuterated alkoxy, -X-C_3-10Carbocyclyl or-X-4 to 10 membered heterocyclyl, said alkyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, ═ O, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, 4-7 membered heterocycloalkyl or C_1-4Alkoxyalkyl, said heterocyclyl or heterocycloalkyl containing from 1 to 4 heteroatoms selected from O, S, N.

In some embodiments of the general formula (I), R³Each independently selected from H, F, Cl, Br, I, OH, ═ O, cyano, NH₂、NHCH₃、N(CH₃)₂Methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, ethynyl, -OCD₃Methoxy, ethoxy or isopropoxy, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, methoxy, ethoxy or isopropoxy being optionally further substituted by 0 to 4 substituents selected from H, F, OH, ═ O, cyano, NH₂、CF₃、CH₂OH、CH₂F. Methyl, methoxy, ethoxy or isopropoxy.

In some embodiments of formula (I), X is selected from the group consisting of a bond, -NR^x-, -O-or-S-.

In some embodiments of formula (I), X is selected from a bond or-O-.

In some embodiments of the general formula (I), R^xIs selected from H or C_1-6Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl radicalsOr C_1-6Substituted by a substituent of alkoxy.

In some embodiments of the general formula (I), R^xIs selected from H or C_1-4Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy.

In some embodiments of formula (I), n, p are each independently selected from 0, 1,2, 3, or 4.

In some embodiments of formula (I), m is selected from 1,2, 3, or 4.

In some embodiments of formula (I), n is selected from 0, 1 or 2.

The invention relates to a pharmaceutical composition, which comprises the compound or stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, and a pharmaceutically acceptable carrier.

The invention relates to an application of a compound or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof in preparing a medicament for treating diseases related to BTK activity or expression, preferably an application in preparing a tumor medicament.

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

Where carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I are involved in the radicals and compounds of the invention, including their isotopes, and where carbon, hydrogen, oxygen, sulfur or nitrogen are involved in the radicals and compounds of the invention, optionally further substituted with one or more of their corresponding isotopes, where isotopes of carbon include¹²C、¹³C and¹⁴c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including¹⁶O、¹⁷O and¹⁸isotopes of O, sulfur including³²S、³³S、³⁴S and³⁶isotopes of S, nitrogen include¹⁴N and¹⁵isotopes of N, F include¹⁷F and¹⁹isotopes of F, chlorine including³⁵Cl and³⁷cl, isotopes of bromine including⁷⁹Br and⁸¹Br。

"halogen" means F, Cl, Br or I.

"halo-substituted" refers to F, Cl, Br, or I substitution, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "halogen-substituted" is simply referred to as "halo".

"alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including, but not limited to, alkyl of 1 to 20 carbon atoms, alkyl of 1 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; alkyl groups, as used herein, are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent or tetravalent.

"heteroalkyl" means that 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms in a substituted or unsubstituted alkyl group are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH)₂)v-X(CH₂)v-X(CH₂) v-H (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, a heteroatom including but not limited to N, O or S, and at least 1X is selected from a heteroatom, and either N or S in a heteroatom can be oxidized to various oxidation states). The heteroalkyl group may be monovalent, divalent, trivalent, or tetravalent.

"alkylene" refers to a substituted or unsubstituted, straight and branched chain, divalent saturated hydrocarbon radical, including- (CH)₂)_v- (v is an integer of 1 to 10), examples of alkylene include, but are not limited to, methylene, ethylene, propyleneAnd butylene, and the like.

"Heteroalkylidene" means a substituted or unsubstituted alkylene group in which 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH)₂)v-X(CH₂)v-X(CH₂) v-, v is an integer from 1 to 5, each X is independently selected from the group consisting of a bond, N, O or S, and at least 1X is selected from the group consisting of N, O or S.

"cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having from 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like. Cycloalkyl as found herein, is as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

"heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl groups may be attached to a heteroatom or carbon atom, heterocycloalkyl groups may be attached to an aromatic ring or to a non-aromatic ring, heterocycloalkyl groups may be attached to a bridged or spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidyl, piperazinyl. The heterocycloalkyl radical may be monovalent, divalent, trivalent or tetravalent

"alkenyl" means a substituted or unsubstituted straight and branched chain unsaturated hydrocarbon group having at least 1, and typically 1,2 or 3 carbon double bonds, the backbone including, but not limited to, 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; alkenyl groups are present herein, the definition of which is consistent with the present definition. The alkenyl group may be monovalent, divalent, trivalent or tetravalent.

"alkynyl" refers to substituted or unsubstituted, straight and branched chain, monovalent unsaturated hydrocarbon radicals having at least 1, and typically 1,2 or 3 carbon-carbon triple bonds, including, but not limited to, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone, and examples of alkynyl include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; alkynyl groups can be monovalent, divalent, trivalent or tetravalent.

"alkoxy" means a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

"carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system, the carbocyclyl may be attached to the aromatic or non-aromatic ring, which is optionally monocyclic, bridged or spiro. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentylA-2-alkenyl group, a 1-cyclopentyl-3-alkenyl group, a cyclohexyl group, a 1-cyclohexyl-2-alkenyl group, a 1-cyclohexyl-3-alkenyl group, a cyclohexenyl group, a benzene ring, a naphthalene ring, a substituted phenyl group, a,

"carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system and contain 1 or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O or S, optionally substituted N, S of the heterocyclyl ring being oxidizable to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples of which include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithiayl, dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, dihydropyranyl, spirocyclo-pyridyl, spiro-pyridyl, spirocyclo-pyridyl, oxacycloheptyl, azanyl, pyridyl, oxathianyl, thianyl, thienyl, pyridyl, etc, Benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [3.2.1]Octyl, azabicyclo [5.2.0 ] groups]Nonoalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]A heptylalkyl group,

"Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"spiro" or "spirocyclic" refers to a polycyclic group that shares a single atom (referred to as a spiro atom) between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spiro system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings may contain 0 or more (including but not limited to 1,2, 3 or 4) double bonds, and optionally may contain 0 to 5 rings selected from N, O or S (═ O)_nA heteroatom of (a).

The "spiro" or "spirocyclic group" may be monovalent, divalent, trivalent, or tetravalent.

"fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1,2, 3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the fused ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (═ O)_nOr O, n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

the "fused ring" or "fused ring group" may be monovalent, divalent, trivalent or tetravalent.

"bridged ring" or "bridged ring group" refers to a substituted or unsubstituted ring containing any two atoms not directly connectedPolycyclic groups, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom containing groups (including but not limited to N, S (═ O) n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include

Cubane and adamantane. The "bridge ring" or "bridge ring group" may be monovalent, divalent, trivalent or tetravalent.

"carbocyclyl", "spirocarbocyclyl" or "carbospirocyclic" refers to a "spiro" ring whose ring system consists of only carbon atoms. The "carbospiro", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospiro" group, as referred to herein, is defined in accordance with the definition of spiro.

"carbocyclic", "fused carbocyclic", or "carbocyclic" refers to "fused rings" in which the ring system consists of only carbon atoms. "carbocyclic ring", "fused carbocyclic ring group", "fused carbocyclic group", or "fused carbocyclic group" as used herein, is defined in accordance with fused rings.

"Carbobridged ring", "bridged carbocyclyl" or "carbocyclyl" refers to a "bridged ring" in which the ring system consists of only carbon atoms. "Carbobridged ring", "bridged carbocyclyl", or "carbobridyclyl" as used herein, is defined in accordance with the definition of bridged ring.

"Heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to "heterocyclyl" or "heterocycle" of a monocyclic ring system, and heterocyclyl, "monocyclic heterocyclyl" or "heteromonocyclic" as found herein, is defined consistent with the definition of heterocycle.

"Heterocyclo", "heterocyclocyclyl" or "heterocyclocyclyl" means a "fused ring" containing heteroatoms. The term "fused ring" as used herein refers to a "fused ring," fused ring group, "fused heterocyclic group," or "fused ring group," which is defined as being fused.

"Heterospirocyclic", "heterospirocyclic", "spiroheterocyclic" or "heterospirocyclic" refers to "spirocyclic" containing heteroatoms. The definition of heterospiro, "heterospiro ring", "spiro heterocyclic" or "heterospiro ring" as used herein is consistent with spiro rings.

"heterobridged ring," "heterobridged ring group," "bridged heterocyclic group," or "heterobridged ring group" refers to a "bridged ring" containing a heteroatom. The term "heterobridged ring", "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group", as used herein, is defined in accordance with the bridged ring.

"aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single or fused ring, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include a benzene ring, a naphthalene ring, a substituted naphthalene group, a substituted or substituted naphthalene group, a substituted benzene or substituted benzene ring, a substituted benzene or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene,

The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the attachment site is located on the aryl ring.

"heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains from 1 to 5 selected heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (═ O) n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include

Heteroaryl, as used herein, is defined in accordance with the present definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the attachment site is on the heteroaryl ring.

The "5-membered and 5-membered heteroaromatic ring" means a 5-and 5-membered fused heteroaromatic ring in which at least 1 ring of 2 fused rings contains 1 or more heteroatoms (including but not limited to O, S or N), and the whole group has aromaticity, and non-limiting examples include pyrrolopyrrole rings, pyrazolopyrrole rings, pyrazolopyrazole rings, pyrrolofuran rings, pyrazolofuran rings, pyrrolothiophene rings, pyrazolothiophene rings.

"5 and 6 membered heteroaromatic ring" means a 5 and 6 membered fused heteroaromatic ring wherein at least 1 ring of the 2 fused rings contains more than 1 heteroatom (including but not limited to O, S or N) and the entire group is aromatic, non-limiting examples include benzo 5 membered heteroaryl, 6 membered heteroaromatic ring and 5 membered heteroaromatic ring.

"substituted" or "substituted" means substituted with 1 or more (including but not limited to 2, 3, 4, or 5) substituents including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH)₂)_m-C(＝O)-R^a、-O-(CH₂)_m-C(＝O)-R^a、-(CH₂)_m-C(＝O)-NR^bR^c、-(CH₂)_mS(＝O)_nR^a、-(CH₂)_m-alkenyl-R^a、OR^dOr- (CH)₂)_m-alkynyl-R^a(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cEtc. wherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and mixtures thereofSelection of R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed.

"contains 1 to 5 heteroatoms selected from O, S, N" means containing 1,2, 3, 4 or 5 heteroatoms selected from O, S, N.

"0 to X substituents selected from …" means substituted with 0, 1,2, 3 … X substituents selected from …, X being selected from any integer between 1 and 10. If "substituted with 0 to 4 substituents selected from …" is intended to mean substituted with 0, 1,2, 3, or 4 substituents selected from …. If "substituted with 0 to 5 substituents selected from …" is meant substituted with 0, 1,2, 3, 4, or 5 substituents selected from …. By "heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the heterobridged ring is optionally further substituted with 0, 1,2, 3 or 4 substituents selected from H or F.

X-Y membered rings (X is selected from integers less than Y greater than 3 and Y is selected from any integer between 4 and 12) include X +1, X +2, X +3, X +4 … Y membered rings. Rings include heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterospirocyclic, or heterobridged rings. For example, "4-7 membered heteromonocyclic" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterobicyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterobicyclic ring.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, and the free base obtained by reaction with a non-toxic inorganic or organic acid.

"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuteroides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.

By "carrier" is meant a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.

By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying an amino or carboxyl group in a compound of the invention, which modification may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate.

"animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.

"tautomer" refers to functional group isomers resulting from rapid movement of an atom in two positions in a molecule, such as keto-enol isomers and amide-imino-enol isomers, and the like.

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

“IC₅₀"is the concentration of drug or inhibitor required to inhibit half of a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.).

Detailed Description

To accomplish the objects of the present invention, the compounds "commercially available chemicals" used in the reactions described herein are prepared from standard commercial sources including Shanghai Aladdin Biotechnology GmbH, Shanghai Merlin Biotechnology GmbH, Sigma-Aldrich, Afahesa (China) Chemicals GmbH, echiei (Shanghai) chemical developments GmbH, Annagi chemistry, Shanghai Tantaceae technology GmbH, Corlon Chemicals, Bailinguo science GmbH, and the like, starting from commercially available chemicals and/or compounds described in the chemical literature according to organic synthesis techniques known to those skilled in the art.

References and monographs in this field detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide articles describing the preparation for reference. These references and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; sandler et al, "Organic Functional Group precursors," 2nd ed, Academic Press, New York, 1983; h.o.house, "Modern Synthetic Reactions", 2nd ed., w.a.benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: Reactions, mechanics and Structure", 4th Ed., Wiley Interscience, New York, 1992; fuhrhop, J.and Penzlin G. "Organic Synthesis: hubs, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527-29074-5; hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-; march, J. "Advanced Organic Chemistry: Reactions, mechanics, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-; otera, J. (editor) "Modern carbon Chemistry" (2000) Wiley-VCH, ISBN: 3-527-; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-; solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-; stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73volumes.

Specific and similar reactants can be selectively identified by an index of known chemicals prepared by the chemical abstracts society of america, which is available in most public and university libraries and online. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which standard chemical supply plants (e.g., those listed above) provide custom synthesis services. References to the preparation and selection of pharmaceutically acceptable Salts of the compounds described herein are P.H.Stahl & C.G.Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich,2002.

The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shifts (. delta.) are given in units of 10-6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS);

MS measurement (Agilent 6120B (ESI)) and Agilent 6120B (APCI));

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6mm, 3.5. mu.M);

the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5 mm;

the column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier;

the known starting materials of the present invention can be synthesized by methods known in the art or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical industry, Shaoshanghi chemical technology, and Bailingwei technology;

tf: a trifluoromethanesulfonyl group;

boc: a tert-butoxycarbonyl group;

ts: a p-toluenesulfonyl group;

cbz: a benzyloxycarbonyl group;

TMS: trimethylsilyl group.

The first synthesis method comprises the following steps:

the general formula (II-a) and the general formula (II-b) are subjected to condensation reaction to obtain a corresponding general formula (II-c);

the compound (1F) is subjected to nucleophilic substitution, free radical reaction and the like to obtain a corresponding general formula (II-d);

the general formula (II-d) and the general formula (II-e) are subjected to nucleophilic substitution reaction to obtain a corresponding general formula (II-f);

the general formula (II-f) and the general formula (II-c) are subjected to coupling reaction to obtain a corresponding general formula (II-g);

the general formula (II-g) and the general formula (II-h) are subjected to condensation reaction, nucleophilic substitution or reductive amination reaction to obtain the corresponding general formula (II-j);

hydrolyzing a cyano group by the compound of the general formula (II-j) under the reaction conditions of acid, alkali and the like to obtain a corresponding general formula (II); or the compound of the general formula (II-g) is obtained by hydrolyzing cyano to obtain a compound of the general formula (II-k) and then carrying out condensation reaction with the compound of the general formula (II-h) to obtain the corresponding general formula (II).

R¹⁰Selected from Cl, Br, I, OTf, etc.;

R¹¹selected from Cl, Br, I, OTf, OMs, OTs, OSO₂CF₂CF₂CF₂CF₃CHO, ═ O, OH, or the like;

R¹²selected from Cl, Br, I, OTf, OMs, OTs, OSO₂CF₂CF₂CF₂CF₃Etc.;

R¹³selected from B (OH)₂Borate, alkyl-substituted tin, etc.;

the remaining groups are as defined above for any one of the embodiments of formula (I).

Example 1

5-amino 1- (1- (3, 3-difluorocyclobutanecarbonyl) piperidin-4-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide; (Compound 1)

5-amino-1-(1-(3,3-difluorocyclobutanecarbonyl)piperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide；

The first step is as follows: 4- (Methanesulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester (1B)

tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate

Tert-butyl 4-hydroxypiperidine-1-carboxylate 1A (5.00g, 24.84mmol) and triethylamine (3.77g, 37.26mmol) were dissolved in 30mL of dichloromethane, and methanesulfonyl chloride (3.41g, 29.81mmol) was added dropwise in an ice-water bath, and after completion of the addition, the mixture was naturally returned to room temperature and stirred for 1 hour. After the reaction was completed, 50mL of water was added for extraction. The organic phase was dried over anhydrous sodium sulfate and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1:10) and concentrated to give the title compound as a yellow oil (1B) (6.5g, 93.66% yield).

The second step is that: (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) boronic acid (1E)

(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)boronic acid

The compound 5-fluoro-2-methoxybenzoic acid 1C (0.71g,4.10mmol) and 4-aminomethylphenylboronic acid hydrochloride (1D) (0.92g,4.92mmol), N-methylimidazole (0.84g,10.25mmol) were added to 15mL of dry DMF, O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (2.87g,10.25mmol) was added portionwise in an ice-water bath, allowed to naturally rise to room temperature and stirred for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20mL × 3), the organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE: EA ═ 1:1) to give the objective compound 1E (0.94g, yield: 74.89%).

LCMS m/z＝304.1[M+H]⁺

The third step: 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (1G)

5-amino-3-bromo-1H-pyrazole-4-carbonitrile

The compound 5-amino-1H-pyrazole-4-carbonitrile (1F) (1.0g,9.25mmol) was dissolved in 15mL of dry DMF, NBS (2.47g,13.88mmol) was added portionwise at room temperature, and after the addition was completed, the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (50mL), extracted with EA (20mL × 3), the organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE: EA ═ 2:1) to give the objective compound (1G) (1.30G, yield: 75.15%).

LCMS m/z＝187.0[M+H]⁺

The fourth step: 4- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (1H)

tert-butyl 4-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate

The compound 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (1G) (1.0G,5.35mmol), tert-butyl 4- (methanesulfonyloxy) piperidine-1-carboxylate (1B) (1.79G,6.42mmol), cesium carbonate (2.61G,8.02mmol) was dissolved in 15mL of dry DMF and stirred at room temperature overnight. The reaction solution was quenched with water (50mL), extracted with EA (20mL × 3), the organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE: EA ═ 2:1) to give the objective compound 1H (0.90g, yield: 45.46%).

LCMS m/z＝370.1[M+H]⁺

The fifth step: 4- (5-amino-4-cyano-3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (1I)

tert-butyl 4-(5-amino-4-cyano-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

The compound tert-butyl 4- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) piperidine-1-carboxylate (1H) (0.50g,1.35mmol), (4- (5-fluoro-2-methoxybenzamide) methyl) phenyl) boronic acid (1E) (0.53g,1.76mmol), cesium carbonate (0.92g,2.82mmol), Pd (dppf) Cl₂(103.4mg,0.14mmol) was added to a mixed solvent of 10mL dioxane and water (v/v. sub.5: 1), and the mixture was replaced with nitrogen 3 times, heated to 110 ℃ and reacted for 3 hours. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to give the target compound (1I) (0.42g, yield: 56.69%).

LCMS m/z＝549.2[M+H]⁺

And a sixth step: 5-amino-3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxamide (1J)

5-amino-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide

The compound 4- (5-amino-4-cyano-3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (1I) (100mg,0.18mmol) was dissolved in 5mL sulfuric acid (90%), heated to 100 ℃ for reaction for 1 hour, the reaction solution was cooled to room temperature, the pH was adjusted to 10 in an ice-water bath, EA extraction (20mL × 3) was performed, the organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to column chromatography (DCM: CH: DCM)₃OH ═ 10:1) gave the target compound (1J) (0.06g, yield: 70.5%).

LCMS m/z＝467.2[M+H]⁺

The seventh step: 5-amino 1- (1- (3, 3-difluorocyclobutanecarbonyl) piperidin-4-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide; (Compound 1)

Compound 1J (46.6mg,0.10mmol) and 3, 3-difluorocyclobutane-1-carboxylic acid (13.6mg,0.1mmol) were dissolved in 5mL dry DMF and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was isolated as a liquid phase to give the title compound 1(0.012g, yield: 20.54%). The preparation conditions are as follows: instrument and preparative column: the liquid phase was prepared using WATERS 2767, column format Xbridge C18,5 μm, 19mm x 250mm in internal diameter x length.

The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution.

Mobile phase system: acetonitrile/(containing 0.05% ammonia) water. Gradient elution: the acetonitrile content is 30-75%, and the elution time is 15 min.

LCMS m/z＝585.3[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.54–7.46(s,4H),7.28–7.21(m,1H),7.16(dd,1H),4.69–4.60(m,3H),4.42–4.31(m,1H),4.04–3.97(m,1H),3.95(s,3H),3.30–3.20(m,2H),2.92–2.72(m,5H),2.10–1.91(m,4H).

Example 2

5-amino-1- (1- (2- (dimethylamino) acetyl) piperidin-4-yl) -3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 2)

5-amino-1-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

(1J) (46.6mg,0.10mmol) and N, N-dimethylglycine (10.3mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to obtain the objective compound 2(0.01g, yield: 18.14%).

LCMS m/z＝552.3[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.60(dd,1H),7.54–7.46(m,4H),7.28–7.21(m,1H),7.16(dd,1H),4.71–4.61(m,3H),4.46–4.35(m,1H),4.35–4.20(m,2H),3.95(s,3H),3.87–3.77(m,1H),3.30–3.22(m,1H),2.99–2.85(m,7H),2.20–1.94(m,4H).

Example 3

5-amino-1- (1-cyclopropanecarbonylpiperidin-4-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 3)

5-amino-1-(1-cyclopropanecarbonylpiperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

Compound (1J) (46.6mg,0.10mmol) and cyclopropylcarboxylic acid (8.5mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was freed of the solvent under reduced pressure, and the residue was removedThe residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to obtain target compound 3(0.015g, yield: 28.03%).

LCMS m/z＝535.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.54–7.45(m,4H),7.27–7.21(m,1H),7.16(dd,1H),4.70–4.59(m,3H),4.54–4.44(m,1H),4.44–4.32(m,1H),3.95(s,3H),2.89–2.74(m,1H),2.22–1.89(m,6H),0.94–0.76(m,4H).

Example 4

5-amino-1- (1- (3, 3-dimethylcyclobutanecarbonyl) piperidin-4-yl) -3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 4)

5-amino-1-(1-(3,3-dimethylcyclobutanecarbonyl)piperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

Compound (1J) (46.6mg,0.10mmol) and 3, 3-dimethylbutylcyclobutyric acid (12.8mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature, and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to obtain target compound 4(0.015g, yield: 25.98%).

LCMS m/z＝577.3[M+H]⁺

Example 5

5-amino-3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- (1- [ (2R) -1-methylpyrrolidine-2-carbonyl ] piperidin-4-yl) -1H-pyrazole-4-carboxamide (Compound 5)

5-amino-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1-(1-[(2R)-1-methylpyrrolidine-2-carbonyl]piperidin-4-yl)-1H-pyrazole-4-carboxamide

Compound (1J) (46.6mg,0.10mmol) and (2R) -1-methylpyrrolidine-2-carboxylic acid (12.9mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature, and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave title compound 5(0.018g, yield: 31.14%).

LCMS m/z＝578.3[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.54–7.43(m,4H),7.29–7.21(m,1H),7.16(dd,1H),4.73–4.62(m,3H),4.47–4.33(m,1H),4.11–3.91(m,5H),3.51–3.39(m,1H),3.30–3.22(m,1H),2.94–2.75(m,2H),2.70–2.60(m,3H),2.53–2.38(m,1H),2.13–1.95(m,7H).

Example 6

5-amino-3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- (1- [ (2S) -1-methylpyrrolidine-2-carbonyl ] piperidin-4-yl) -1H-pyrazole-4-carboxamide (Compound 6)

5-amino-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1-(1-[(2S)-1-methylpyrrolidine-2-carbonyl]piperidin-4-yl)-1H-pyrazole-4-carboxamide

Compound (1J) (46.6mg,0.10mmol) and (2S) -1-methylpyrrolidine-2-carboxylic acid (12.9mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42 m) was added at room temperatureg,0.15mmol), and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to give the title compound 6(0.017g, yield: 29.41%).

LCMS m/z＝578.3[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.54–7.43(m,4H),7.29–7.21(m,1H),7.16(dd,1H),4.73–4.62(m,3H),4.47–4.33(m,1H),4.11–3.83(m,5H),3.45–3.36(m,1H),3.30–3.20(m,1H),2.94–2.69(m,2H),2.67–2.57(m,3H),2.49–2.37(m,1H),2.13–1.95(m,7H).

Example 7

5-amino-1- (1-cyclobutane-3-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 7)

5-amino-1-(1-cyclobutanecarbonylazetidin-3-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

The first step is as follows: 3- [ (perfluorobutanesulfonyl) oxy ] azetidine-1-carboxylic acid tert-butyl ester (7B)

tert-butyl 3-[(nonafluorobutanesulfonyl)oxy]azetidine-1-carboxylate

Intermediate N-Boc-3-hydroxyazetidine (7A) (5.00g, 28.87mmol) and triethylamine (3.77g, 37.26mmol) were dissolved in 30mL of dichloromethane, and perfluorobutanesulfonyl fluoride (9.59g, 31.75mmol) was added dropwise under an ice-water bath, followed by stirring naturally at room temperature for 3 hours. After the reaction was completed, 50mL of water was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a yellow oil (7B) (12.0g, 91.31% yield) which was used directly in the next step.

The second step is that: 3- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) azetidine-1-carboxylic acid tert-butyl ester (7D)

tert-butyl 3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)azetidine-1-carboxylate

The compound 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (1G) (1.0G,5.35mmol), tert-butyl 3- [ (perfluorobutanesulfonyl) oxy ] azetidine-1-carboxylate (7B) (2.19G,6.42mmol), cesium carbonate (2.61G,8.02mmol) were dissolved in 15mL dry DMF and stirred at room temperature overnight. The reaction solution was quenched with water (50mL), extracted with EA (20mL × 3), the organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE: EA ═ 2:1) to give the objective compound (7D) (0.56g, yield: 30.60%).

LCMS m/z＝342.1[M+H]+

¹H NMR(400MHz,DMSO-d₆)δ7.06(s,2H),5.13–5.02(m,1H),4.25–4.13(m,2H),4.10–3.96(m,2H),1.40(s,9H).

The third step: 3- (5-amino-4-cyano-3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazol-1-yl) azelaic acid-1-carboxylic acid tert-butyl ester (7E)

tert-butyl 3-(5-amino-4-cyano-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

The compound tert-butyl 3- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) azetidine-1-carboxylate (7D) (0.50g,1.46mmol), (4- (5-fluoro-2-methoxybenzamide) methyl) phenyl) boronic acid (1E) (0.50g,1.75mmol), cesium carbonate (0.92g,2.82mmol), Pd (dppf) Cl₂(103.4mg,0.14mmol) was addedTo a mixed solvent of 10mL dioxane and water (v/v ═ 5:1), the mixture was replaced with nitrogen 3 times, and the mixture was heated to 110 ℃ to react for 3 hours. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave the title compound (7E) (0.55g, yield: 72.31%).

LCMS m/z＝421.1[M-100]+

The fourth step: 5-amino-1- (azetidin-3-yl) -3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazole-4-carboxamide (7F)

5-amino-1-(azetidin-3-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

Compound 7E (400mg,0.76mmoL) was dissolved in 10mL sulfuric acid (90%), heated to 100 ℃ and reacted for 1 hour, the reaction solution was cooled to room temperature, PH was adjusted to 10 in an ice-water bath, EA extraction (20mL × 3) was performed, organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave the title compound 7F (0.29g, yield: 86.08%).

LCMS m/z＝439.1[M+H]+

The fifth step: 5-amino-1- (1-cyclobutane-3-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 7)

Compound 7F (44.0mg,0.10mmol) and cyclobutanecarboxylic acid (10.05mg,0.1mmol) were dissolved in 5mL dryN-methylimidazole (12.3mg,0.15mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) were added to dry DMF at room temperature, and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave target compound 7(0.020g, yield: 38.29%).

LCMS m/z＝521.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.57–7.47(m,4H),7.28–7.21(m,1H),7.16(dd,1H),5.23–5.13(m,1H),4.67(s,2H),4.59–4.49(m,2H),4.42–4.31(m,2H),3.95(s,3H),3.26–3.14(m,1H),2.33–2.21(m,2H),2.19–2.07(m,2H),2.05–1.92(m,1H),1.90–1.80(m,1H).

Example 8

5-amino-3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- (1- (1-fluorocyclopropanecarbonyl) azetidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 8)

5-amino-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1-(1-(1-fluorocyclopropanecarbonyl)azetidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 7F (44.0mg,0.10mmol) and 1-fluorocyclopropane-1-carboxylic acid (10.40mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (42mg,0.15mmol) was added at room temperature, and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to give target compound 8(0.013g, yield: 24.79%).

LCMS m/z＝525.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.59–7.48(m,4H),7.28–7.21(m,1H),7.16(dd,1H),5.32–5.22(m,1H),4.93–4.84(m,2H),4.68(s,2H),4.53–4.43(m,2H),3.96(s,3H),1.37–1.23(m,4H).

Example 9

5-amino-3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- (1- [ (1R,2R) -2-fluorocyclopropanecarbonyl ] azetidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 9)

5-amino-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1-(1-[(1R,2R)-2-fluorocyclopropanecarbonyl]azetidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 7F (44.0mg,0.10mmol) and (1R,2R) -2-fluorocyclopropane-1-carboxylic acid (10.40mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature to continue the reaction for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to obtain the objective compound 9(0.010g, yield: 19.07%).

LCMS m/z＝525.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.58–7.47(m,4H),7.28–7.21(m,1H),7.16(dd,1H),5.29–5.19(m,1H),4.93–4.85(m,1H),4.76–4.70(m,2H),4.67(s,2H),4.49–4.36(m,2H),3.95(s,3H),1.88–1.78(m,1H),1.72–1.60(m,1H),1.15–1.04(m,1H).

Example 10

5-amino-1- (1- (cyclopropylmethyl) azetidin-3-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 10)

5-amino-1-(1-(cyclopropylmethyl)azetidin-3-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

Compound 7F (44.0mg,0.10mmol) and cyclopropanecarboxaldehyde (14.10mg,0.2mmol) were dissolved in 5mL dry DMA, stirred at room temperature for an additional 1 hour and then sodium triacetoxyborohydride (63.5mg,0.3mmol) was added. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to obtain target compound 10(0.010g, yield: 20.32%).

LCMS m/z＝493.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.59–7.49(m,4H),7.29–7.21(m,1H),7.17(dd,1H),5.25–5.35(m,1H),4.68(s,2H),4.57–4.42(m,4H),3.97(s,3H),3.13(d,2H),1.06–0.97(m,1H),0.70–0.62(m,2H),0.41–0.33(m,2H).

Example 11

5-amino-3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- (1- [ (1S, 2S) -2-fluorocyclopropanecarbonyl ] azetidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 11)

5-amino-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1-(1-[(1S,2S)-2-fluorocyclopropanecarbonyl]azetidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 7F (44.0mg,0.10mmol) and (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid (10.40mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature to continue the reaction for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to obtain target compound 11(0.015g, yield: 28.57%).

LCMS m/z＝525.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.58–7.47(m,4H),7.28–7.21(m,1H),7.16(dd,1H),5.29–5.19(m,1H),4.93–4.85(m,1H),4.76–4.70(m,2H),4.68(s,2H),4.49–4.36(m,2H),3.95(s,3H),1.88–1.78(m,1H),1.72–1.60(m,1H),1.16–1.03(m,1H).

Example 12

5-amino-3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- (1- [ (1R, 2S) -2-fluorocyclopropanecarbonyl ] azetidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 12)

5-amino-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1-(1-[(1R,2S)-2-fluorocyclopropanecarbonyl]azetidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 7F (44.0mg,0.10mmol) and (1R, 2S) -2-fluorocyclopropane-1-carboxylic acid (10.40mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature to continue the reaction for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to give the title compound 12(0.017g, yield: 32.36%).

LCMS m/z＝525.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.60–7.48(m,4H),7.28–7.22(m,1H),7.16(dd,1H),5.29–5.20(m,1H),4.87–4.73(m,3H),4.68(s,2H),4.46–4.32(m,2H),3.96(s,3H),2.17–2.00(m,1H),1.50–1.36(m,1H),1.30–1.17(m,1H).

Example 13

5-amino-3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- (1- [ (1S,2R) -2-fluorocyclopropanecarbonyl ] azetidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 13)

5-amino-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1-(1-[(1S,2R)-2-fluorocyclopropanecarbonyl]azetidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 7F (44.0mg,0.10mmol) and (1S,2R) -2-fluorocyclopropane-1-carboxylic acid (10.40mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature to continue the reaction for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave title compound 13(0.017g, yield: 32.36%).

LCMS m/z＝525.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.60–7.48(m,4H),7.28–7.22(m,1H),7.16(dd,1H),5.29–5.20(m,1H),4.86–4.72(m,3H),4.68(s,2H),4.44–4.32(m,2H),3.96(s,3H),2.17–2.03(m,1H),1.50–1.37(m,1H),1.30–1.19(m,1H).

Example 14

5-amino-1- (1- (2, 2-difluorocyclopropanecarbonyl) azetidin-3-yl) -3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 14)

5-amino-1-(1-(2,2-difluorocyclopropanecarbonyl)azetidin-3-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

Compound 7F (44.0mg,0.10mmol) and 2, 2-difluorocyclopropane-1-carboxylic acid (12.2mg,0.1mmol) were dissolved in 5mL dry DMF and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave target compound 14(0.018g, yield: 33.18%).

LCMS m/z＝543.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.59–7.47(m,4H),7.28–7.20(m,1H),7.16(dd,1H),5.29–5.20(m,1H),4.77–4.65(m,4H),4.49–4.37(m,2H),3.96(s,3H),2.66–2.55(m,1H),2.06–1.94(m,1H),1.84–1.73(m,1H).

Example 15

5-amino-1- [1- (1-fluorocyclopropanecarbonyl) -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (compound 15)

5-amino-1-[1-(1-fluorocyclopropanecarbonyl)-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Compound 1J (46.6mg,0.10mmol) and 1-fluorocyclopropanecarboxylic acid (10.4mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature, and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases combined and saturatedWashing with brine (20 mL. times.3), drying over anhydrous sodium sulfate, filtering, removing the solvent from the filtrate under reduced pressure, and separating the residue by column chromatography (DCM: CH)₃OH ═ 10:1) to give the title compound 15(0.01g, yield: 18.14%).

LCMS m/z＝553.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.81(t,1H),7.56–7.37(m,5H),7.36–7.29(m,1H),7.21–7.15(m,1H),6.39(s,2H),4.60–4.27(m,5H),3.89(s,3H),3.22–2.88(m,2H),2.02–1.76(m,4H),1.34–1.11(m,4H).

Example 16

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [1- (tetrahydrofuran-3-carbonyl) -4-piperidinyl ] pyrazole-4-carboxamide (compound 16)

5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[1-(tetrahydrofuran-3-

carbonyl)-4-piperidyl]pyrazole-4-carboxamide

Compound 1J (46.6mg,0.10mmol) and 3-tetrahydrofurecarboxylic acid (11.6mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to give target compound 16(0.015g, yield: 28.03%).

LCMS m/z＝565.3[M+H]⁺

Example 17

5-amino-1- [1- (1-aminocyclopropanecarbonyl) -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (compound 17)

5-amino-1-[1-(1-aminocyclopropanecarbonyl)-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Compound 1J (46.6mg,0.10mmol) and Boc-1-aminocyclopropylcarboxylic acid (20.1mg,0.1mmol) were dissolved in 5mL dry DMF and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20mL quench), the organic phases combined, washed with brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent removed from the filtrate under reduced pressure, the residue was redissolved in 3mL of 4N dioxane HCl solution, stirred for 1 hour, adjusted to pH 8 with MeOH, concentrated under reduced pressure, and the residue was isolated by column chromatography (DCM: CH)₃OH ═ 10:1) to obtain target compound 17(0.015g, yield: 25.98%).

LCMS m/z＝550.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.80(t,1H),7.50(dd,1H),7.47–7.37(m,4H),7.36–7.29(m,1H),7.18(dd,1H),6.38(s,2H),4.59–4.31(m,5H),3.89(s,3H),3.04–2.80(m,2H),2.34–

2.18(m,2H),1.95–1.77(m,4H),0.87–0.78(m,2H),0.69–0.59(m,2H).

Example 18

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [1- (oxoalkane-3-carbonyl) -4-piperidinyl ] pyrazole-4-carboxamide (compound 18)

5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[1-(oxetane-3-carbonyl)-4-piperidyl]pyrazole-4-carboxamide

Compound 1J (46.6mg,0.10mmol) and alkylene-3-carboxylic acid (10.2mg,0.1mmol) were dissolved in 5mL dry DMFTo the reaction mixture was added N-methylimidazole (12.3mg,0.15mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) at room temperature, and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), EA extracted ((20 mL. times.3), the combined organic phases were washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave target compound 18(0.018g, yield: 31.14%).

LCMS m/z＝551.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.53–7.43(m,4H),7.29–7.21(m,1H),7.16(dd,1H),4.90–4.83(m,4H),4.72–4.60(d,3H),4.41–4.30(m，1H),4.27–4.18(m,1H),3.95(s,3H),3.66–3.58(d,1H),3.23–3.11(m,1H),2.89–2.77(m,1H),2.06–1.89(m,4H).

Example 19

5-amino-1- [1- [ (1S,2R) -2-fluorocyclopropanecarbonyl ] -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 19)

5-amino-1-[1-[(1S,2R)-2-fluorocyclopropanecarbonyl]-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Compound 1J (46.6mg,0.10mmol) and (1S,2R) -2-fluorocyclopropane-1-carboxylic acid (10.4mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature to continue the reaction for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave title compound 19(0.017g, yield: 29.41%).

LCMS m/z＝553.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.81(t,1H),7.51(dd,1H),7.48–7.37(m,4H),7.36–7.29(m,1H),7.18(dd,1H),6.38(s,2H),4.93–4.63(m,1H),4.54(m,2H),4.53–4.31(m,3H),3.89(s,3H),3.30–3.14(m,1H),2.77–2.57(m,2H),2.01–1.64(m,4H),1.44–1.30(m,1H),1.21–1.06(m,1H).

Example 20

5-amino-1- [1- [ (1R,2R) -2-fluorocyclopropanecarbonyl ] -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 20)

5-amino-1-[1-[(1R,2R)-2-fluorocyclopropanecarbonyl]-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Compound 1J (46.6mg,0.10mmol) and (1R,2R) -2-fluorocyclopropane-1-carboxylic acid (10.4mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature to continue the reaction for 1 hour. The reaction mixture was quenched with water (50mL), EA extracted ((20 mL. times.3), the combined organic phases were washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to give the title compound 20(0.017g, yield: 29.41%).

LCMS m/z＝553.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.80(t,1H),7.51(dd,1H),7.49–7.36(m,4H),7.36–7.29(m,1H),7.18(dd,1H),6.38(s,2H),5.03–4.79(m,1H),4.54(d,2H),4.51–4.30(m,3H),3.89(s,3H),3.26–3.12(m,1H),2.81–2.68(m,1H),2.26–2.08(m,1H),2.06–1.61(m,4H),1.57–1.44(m,1H),1.05–0.94(m,1H).

Synthesis of intermediate 21 e:

synthesis of (R) -5-amino-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide 21e

(R)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

The first step is as follows:

tert-butyl(S)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

(S) -3- ((methanesulfonyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester:

compound 21a (20g, 10.69mmol) was dissolved in 150mL of dichloromethane, triethylamine (44mL, 32.01mmol) was added, methanesulfonyl chloride (9.9mL, 12.83mmol) was slowly added under ice bath, and the reaction was allowed to proceed overnight. After the reaction of the starting materials was completed, 150mL of a saturated sodium bicarbonate solution was added to dilute the reaction, ten minutes later, the organic layer was separated, the aqueous phase was extracted 2 times with 40mL of dichloromethane, the organic phases were combined and then washed 3 times with a potassium dihydrogen phosphate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the target compound 21b as a yellow oily liquid (27.83g, yield: 98%).

LCMS m/z＝210.1[M+H]⁺

The second step is that:

tert-butyl(R)-3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

(R) -3- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

Compound 21b (22.84g, 86.6mmol) and 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (8.05g, 43.3mmol) were dissolved in 100mL of N, N-dimethylformamide, cesium carbonate (28.05g, 86.6mmol) was added, and the reaction was stirred at 70 ℃ overnight. After the reaction was completed, 150mL of water was added to dilute the reaction, 70mL of ethyl acetate was extracted 3 times, then the organic phases were combined, washed with water 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography gave the title compound 21b as a brown solid (6.01g, yield: 39%).

LCMS m/z＝357.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ7.04(s,2H),4.84–4.72(m,1H),3.64–3.34(m,4H),2.25-2.06(m,2H),1.41(s,9H)

The third step:

tert-butyl(R)-3-(5-amino-4-cyano-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

(R) -3- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

Compound 21c (2g, 5.63mmol) and (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) boronic acid (1.88g, 6.19mmol) were added to a sealed tube, dissolved with 15mL of 1, 4-dioxane, followed by addition of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.41g,0.56mmol) and cesium carbonate (3.67g, 12.38mmol), and the reaction stirred at 110 ℃ for 4 hours. After the reaction, 100mL of water was added to dilute the reaction, the reaction was extracted with ethyl acetate 3 times, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography gave the title compound 21d as a black solid (1.5g, yield: 45%).

LCMS m/z＝435.2[M-100]⁺

The fourth step:

(R) -5-amino-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide

Compound 21d (1g, 1.88mmol) was dissolved in 5mL of 90% concentrated sulfuric acid, then warmed to 90 ℃ and stirred for 1.5 hours. After the reaction is finished, cooling to room temperature, slowly dropwise adding the reaction solution into an ammonia water solution, adjusting the pH to 8-9, extracting with ethyl acetate for 3 times, drying an organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure. Purification by column chromatography gave the title compound 21e as a grey solid (550mg, yield: 65%).

LCMS m/z＝453.2[M+H]⁺

Example 21

(R) -5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1- (1-fluorocyclopropane-1-carbonyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 21)

(R)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 21e (37mg, 0.082mmol) and compound 1-fluorocyclopropane-1-carboxylic acid (8mg, 0.074mmol) were dissolved in 3mL of N, N-dimethylformamide, diisopropylethylamine (0.04mL, 0.246mmol) was added, and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (47mg, 0.123mmol) was added at room temperature and reacted for 3 hours. After the raw materials completely react, 20mL of water is added to dilute the reaction, then 10mL of ethyl acetate is used for extracting for 3 times, organic phases are combined, the organic phases are washed by water for 3 times, then the organic phases are dried by anhydrous sodium sulfate, and after filtration, the organic phases are concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH ═ 20/1) gave compound 21 as a pale yellow solid (20mg, yield: 45%).

LCMS m/z＝539.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.80(t,1H),7.51(dd,1H),7.48–7.37(m,4H),7.35–7.30(m,1H),7.18(dd,1H),6.43(s,2H),5.02–4.87(m,1H),4.54(d,2H),4.12–3.92(m,2H),3.89(s,3H),3.81–3.60(m,2H),2.40–2.18(m,2H),1.30–1.16(m,4H).

Example 22

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- ((R) -1- ((1R, 2R) -2-fluorocyclopropane-1-carbonyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 22)

5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((R)-1-((1R,2R)-2-fluorocyclopropane-1-carbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 21e (45mg, 0.100mmol) and compound (1R,2R) -2-fluorocyclopropane-1-carboxylic acid (9mg, 0.090mmol) were dissolved in 3mL of N, N-dimethylformamide, diisopropylethylamine (0.05mL, 0.300mmol) was added, and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (57mg, 0.149mmol) was added at room temperature and reacted for 3 hours. After the raw materials completely react, 20mL of water is added to dilute the reaction, then 10mL of ethyl acetate is used for extracting for 3 times, organic phases are combined, the organic phases are washed by water for 3 times, then the organic phases are dried by anhydrous sodium sulfate, and after filtration, the organic phases are concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH ═ 20/1) gave compound 22 as a white solid (26mg, yield: 48%).

LCMS m/z＝539.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.81(t,1H),7.50(dd,1H),7.48–7.36(m,4H),7.36–7.29(m,1H),7.18(dd,1H),6.44(d,2H),5.04–4.77(m,2H),4.54(d,2H),4.03–3.83(m,4H),3.79–3.70(m,1H),3.67–3.55(m,1H),3.46–3.37(m,1H),2.42–2.22(m,2H),2.08–1.96(m,1H),1.59–1.48(m,1H),1.06–0.92(m,1H).

Example 23

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- ((R) -1- ((1S, 2R) -2-fluorocyclopropane-1-carbonyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 23)

5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((R)-1-((1S,2R)-2-fluorocyclopropane-1-carbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 21e (45mg, 0.100mmol) and compound (1S,2R) -2-fluorocyclopropane-1-carboxylic acid (9mg, 0.090mmol) were dissolved in 3mL of N, N-dimethylformamide, diisopropylethylamine (0.05mL, 0.300mmol) was added, and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (57mg, 0.149mmol) was added at room temperature and reacted for 3 hours. After the raw materials completely react, 20mL of water is added to dilute the reaction, then 10mL of ethyl acetate is used for extracting for 3 times, organic phases are combined, the organic phases are washed by water for 3 times, then the organic phases are dried by anhydrous sodium sulfate, and after filtration, the organic phases are concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH ═ 20/1) gave compound 23 as a white solid (28mg, yield: 52%).

LCMS m/z＝539.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.81(t,1H),7.50(dd,1H),7.49–7.37(m,4H),7.36–7.29(m,1H),7.18(dd,1H),6.43(d,2H),5.04–4.87(m,1H),4.87–4.64(m,1H),4.54(d,2H),4.13–3.85(m,4H),3.79–3.66(m,1H),3.62–3.53(m,1H),3.41–3.33(m,1H),2.42–2.29(m,2H),2.28–2.02(m,1H),1.49–1.33(m,1H),1.19–1.06(m,1H).

Example 24

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- ((R) -1- ((1R, 2S) -2-fluorocyclopropane-1-carbonyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 24)

5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((R)-1-((1R,2S)-2-fluorocyclopropane-1-carbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 21e (54mg, 0.119mmol) and compound (1R, 2S) -2-fluorocyclopropane-1-carboxylic acid (11mg, 0.107mmol) were dissolved in 4mL of N, N-dimethylformamide, 1-methylimidazole (0.02mL, 0.242mmol) was added, and N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (51mg, 0.180mmol) was added at room temperature and reacted for 3 hours. After the raw materials completely react, 20mL of water is added to dilute the reaction, then 10mL of ethyl acetate is used for extracting for 3 times, organic phases are combined, the organic phases are washed by water for 3 times, then the organic phases are dried by anhydrous sodium sulfate, and after filtration, the organic phases are concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH ═ 20/1) gave compound 24 as a white solid (39mg, yield: 60%).

LCMS m/z＝539.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.81(t,1H),7.53–7.48(m,1H),7.48–7.43(m,2H),7.43–7.38(m,2H),7.36–7.29(m,1H),7.18(dd,1H),6.43(d,2H),5.05–4.63(m,2H),4.54(d,2H),4.13–3.85(m,4H),3.81–3.65(m,1H),3.64–3.52(m,1H),3.44–3.34(m,1H),2.43–2.28(m,2H),2.28–2.20(m,1H),1.49–1.31(m,1H),1.19–1.06(m,1H).

Example 25

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- ((R) -1- ((1R, 2S) -2-fluorocyclopropane-1-carbonyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 25)

Compound 21e (53mg, 0.117mmol) and compound (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid (11mg, 0.107mmol) were dissolved in 4mL of N, N-dimethylformamide, 1-methylimidazole (0.02mL, 0.242mmol) was added, and N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (51mg, 0.180mmol) was added at room temperature and reacted for 3 hours. After the raw materials completely react, 20mL of water is added to dilute the reaction, then 10mL of ethyl acetate is used for extracting for 3 times, organic phases are combined, the organic phases are washed by water for 3 times, then the organic phases are dried by anhydrous sodium sulfate, and after filtration, the organic phases are concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH ═ 20/1) gave compound 25 as a white solid (38mg, yield: 60%).

LCMS m/z＝539.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.85–8.74(m,1H),7.51(dd,1H),7.49–7.37(m,4H),7.36–7.29(m,1H),7.18(dd,1H),6.43(d,2H),5.06–4.75(m,2H),4.54(d,2H),4.15–3.84(m,4H),3.83–3.73(m,1H),3.71–3.62(m,1H),3.61–3.34(m,1H),2.43–2.21(m,2H),2.09–1.97(m,1H),1.59–1.46(m,1H),1.05–0.94(m,1H).

Synthesis of intermediate 26 e:

synthesis of (S) -5-amino-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide 26e

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

The first step is as follows:

tert-butyl(R)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate(26b)

(R) -3- ((methanesulfonyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester:

compound 26a (20g, 10.69mmol) was dissolved in 150mL of dichloromethane, triethylamine (44mL, 32.01mmol) was added, methanesulfonyl chloride (9.9mL, 12.83mmol) was slowly added under ice bath, and the reaction was allowed to proceed overnight. After the reaction of the starting materials was completed, 150mL of saturated sodium bicarbonate solution was added to dilute the reaction, ten minutes later, the organic layer was separated, the aqueous phase was extracted 2 times with 40mL of dichloromethane, the organic phases were combined, then washed 3 times with potassium dihydrogen phosphate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target compound 26b as a yellow oily liquid (26g, yield: 92%).

The second step is that:

tert-butyl(S)-3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(26c)

(S) -3- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

Compound 26b (20.7g, 78.0mmol) and 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (7.29g, 39mmol) were dissolved in 100mL of N, N-dimethylformamide, cesium carbonate (50.8g, 156mmol) was added, and the reaction was stirred at 70 ℃ overnight. After the reaction was completed, 150mL of water was added to dilute the reaction, 70mL of ethyl acetate was extracted 3 times, then the organic phases were combined, washed with water 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography gave the title compound 26c as a brown solid (3.6g, yield: 36.8%).

LCMS m/z＝357.1[M+H]⁺

The third step:

tert-butyl(S)-3-(5-amino-4-cyano-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(26d)

(S) -3- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

Compound 26c (3.3g, 9.3mmol) and (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) boronic acid (3.37g, 11.11mmol) were added to a sealed tube, dissolved with 150mL of 1, 4-dioxane, followed by addition of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.68g,0.93mmol) and cesium carbonate (6.1g, 18.6mmol), and the reaction stirred at 110 ℃ for 4 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and then 100mL of water was added to dilute the reaction mixture, followed by extraction with ethyl acetate for 3 times, drying the organic phase with anhydrous sodium sulfate, filtration, and concentration under reduced pressure. Purification by column chromatography gave the title compound 26d as a black solid (2.3g, yield: 42%).

LCMS m/z＝435.2[M-100]⁺

The fourth step:

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide(26e)

(S) -5-amino-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide

Compound 26d (4.75g, 8.89mmol) was dissolved in 15mL of 90% concentrated sulfuric acid, and then the reaction was stirred at 90 ℃ for 1.5 hours. After the reaction is finished, cooling to room temperature, slowly dropwise adding the reaction solution into an ammonia water solution, adjusting the pH to 8-9, extracting with ethyl acetate for 3 times, drying an organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure. Purification by column chromatography gave the title compound 26e as a grey solid (2.5g, yield: 62%).

LCMS m/z＝453.2[M+H]⁺

Example 26

(S) -5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1- (1-fluorocyclopropane-1-carbonyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 26)

(S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 26e (100mg, 0.22mmol) and compound 1-fluorocyclopropane-1-carboxylic acid (23mg, 0.22mmol) were dissolved in 3mL of N, N-dimethylformamide, and N-methylimidazole (0.07mL, 0.884mmol) was added to N, N, N ', N' -tetramethylformamidine hexafluorophosphate (124mg, 0.44mmol) at room temperature and reacted for 3 hours. After the raw materials completely react, 20mL of water is added to dilute the reaction, then 10mL of ethyl acetate is used for extracting for 3 times, organic phases are combined, the organic phases are washed by water for 3 times, then the organic phases are dried by anhydrous sodium sulfate, and after filtration, the organic phases are concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH 20/1) gave compound 26 as a white solid (35mg, yield: 29%).

LCMS m/z＝539.2[M+H]⁺

Example 27

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- ((S) -1- ((1S, 2S) -2-fluorocyclopropane-1-carbonyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 27)

5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((S)-1-((1S,2S)-2-fluorocyclopropane-1-carbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 26e (0.1mg, 0.22mmol) and compound (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid (23mg, 0.22mmol) were dissolved in 3mL of N, N-dimethylformamide, and N-methylimidazole (0.07mL, 0.884mmol) was added to N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (124mg, 0.44mmol) at room temperature and reacted for 3 hours. After the raw materials completely react, 20mL of water is added to dilute the reaction, then 10mL of ethyl acetate is used for extracting for 3 times, organic phases are combined, the organic phases are washed by water for 3 times, then the organic phases are dried by anhydrous sodium sulfate, and after filtration, the organic phases are concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH 20/1) gave compound 27 as a white solid (30mg, yield: 25%).

LCMS m/z＝539.2[M+H]⁺

Example 28

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- ((S) -1- ((1R, 2S) -2-fluorocyclopropane-1-carbonyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 28)

5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((S)-1-((1R,2S)-2-fluorocyclopropane-1-carbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 26e (0.1mg, 0.22mmol) and compound (1R, 2S) -2-fluorocyclopropane-1-carboxylic acid (23mg, 0.22mmol) were dissolved in 3mL of N, N-dimethylformamide, and N-methylimidazole (0.07mL, 0.884mmol) was added to N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (124mg, 0.44mmol) at room temperature and reacted for 3 hours. After the raw materials completely react, 20mL of water is added to dilute the reaction, then 10mL of ethyl acetate is used for extracting for 3 times, organic phases are combined, the organic phases are washed by water for 3 times, then the organic phases are dried by anhydrous sodium sulfate, and after filtration, the organic phases are concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH 20/1) gave compound 28 as a white solid (37mg, yield: 30%).

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.56–7.42(m,4H),7.28–7.20(m,1H),7.16(dd,1H),5.04–4.87(m,1H),4.86–4.62(m,3H),4.17–3.78(m,6H),3.76–3.46(m,1H),2.58–2.20(m,3H),1.52–1.34(m,1H),1.33–1.17(m,1H).

LCMS m/z＝539.2[M+H]⁺

Example 29

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- ((S) -1- ((1R, 2R) -2-fluorocyclopropane-1-carbonyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 29)

5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((S)-1-((1R,2R)-2-fluorocyclopropane-1-carbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 26e (0.1mg, 0.22mmol) and compound (1R, 2S) -2-fluorocyclopropane-1-carboxylic acid (23mg, 0.22mmol) were dissolved in 3mL of N, N-dimethylformamide, and N-methylimidazole (0.07mL, 0.884mmol) was added to N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (124mg, 0.44mmol) at room temperature and reacted for 3 hours. After the raw materials completely react, 20mL of water is added to dilute the reaction, then 10mL of ethyl acetate is used for extracting for 3 times, organic phases are combined, the organic phases are washed by water for 3 times, then the organic phases are dried by anhydrous sodium sulfate, and after filtration, the organic phases are concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH 20/1) gave compound 29 as a white solid (41mg, yield: 33%).

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.55–7.41(m,4H),7.28–7.20(m,1H),7.16(dd,1H),5.03–4.70(m,2H),4.69–4.61(m,2H),4.17–3.52(m,7H),2.57–2.27(m,2H),2.06–1.94(m,1H),1.74–1.61(m,1H),1.11–1.00(m,1H).

LCMS m/z＝539.2[M+H]⁺

Example 30

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- ((S) -1- ((1S, 2R) -2-fluorocyclopropane-1-carbonyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (Compound 30)

5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((S)-1-((1S,2R)-2-fluorocyclopropane-1-carbonyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

Compound 26e (0.1mg, 0.22mmol) and compound (1R, 2S) -2-fluorocyclopropane-1-carboxylic acid (23mg, 0.22mmol) were dissolved in 3mL of N, N-dimethylformamide, and N-methylimidazole (0.07mL, 0.884mmol) was added to N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (124mg, 0.44mmol) at room temperature and reacted for 3 hours. After the raw materials completely react, 20mL of water is added to dilute the reaction, then 10mL of ethyl acetate is used for extracting for 3 times, organic phases are combined, the organic phases are washed by water for 3 times, then the organic phases are dried by anhydrous sodium sulfate, and after filtration, the organic phases are concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH 20/1) gave compound 30 as a white solid (23mg, yield: 19%).

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.56–7.43(m,4H),7.30–7.20(m,1H),7.16(dd,1H),5.04–4.86(m,1H),4.86–4.62(m,3H),4.17–3.77(m,6H),3.76–3.49(m,1H),2.57–2.22(m,3H),1.50–1.35(m,1H),1.31–1.18(m,1H).

LCMS m/z＝539.2[M+H]⁺

Example 31

5-amino-1- [ (3S) -1- (2, 2-difluorocyclopropanecarbonyl) pyrrolidin-3-yl ] -3- (4- { [ ((5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 31)

5-amino-1-[(3S)-1-(2,2-difluorocyclopropanecarbonyl)pyrrolidin-3-yl]-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide.

Compound 26e (0.1mg, 0.22mmol) and compound 2, 2-difluorocyclopropane-1-carboxylic acid (23mg, 0.189mmol) were dissolved in 3mL of N, N-dimethylformamide, and N-methylimidazole (0.07mL, 0.884mmol) was added to N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (124mg, 0.44mmol) at room temperature and reacted for 3 hours. After the raw materials completely react, 20mL of water is added to dilute the reaction, then 10mL of ethyl acetate is used for extracting for 3 times, organic phases are combined, the organic phases are washed by water for 3 times, then the organic phases are dried by anhydrous sodium sulfate, and after filtration, the organic phases are concentrated under reduced pressure. Purification by column chromatography (DCM/MeOH 20/1) gave compound 31 as a white solid (32mg, yield: 25%).

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.54–7.44(m,4H),7.28–7.20(m,1H),7.16(dd,1H),5.07–4.87(m,1H),4.66(s,2H),4.15–3.78(m,6H),3.78–3.51(m,1H),2.88–2.72(m,1H),2.59–2.30(m,2H),2.07–1.96(m,1H),1.82–1.68(m,1H).

LCMS m/z＝557.2[M+H]⁺

Example 32

5-amino-1- (1-cyclobutylpiperidin-4-yl) -3- (4- { [ ((5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 32)

5-amino-1-(1-cyclobutylpiperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide.

The first step is as follows:

n- (4- (5-amino-4-cyano-1- (piperidin-4-yl) -1H-pyrazol-3-yl) benzyl) -5-fluoro-2-methoxybenzamide hydrochloride (32a)

N-(4-(5-amino-4-cyano-1-(piperidin-4-yl)-1H-pyrazol-3-yl)benzyl)-5-fluoro-2-methoxybenzamide hydrochloride.

Compound 1I (1.0g,1.82mmol) was dissolved in 10mL of 1, 4-dioxane hydrochloride solution at room temperature and reacted for 3 h. After the reaction of the starting materials was complete, it was directly spin dried under reduced pressure to give off-white solid 32a (1.1g crude) which was used directly in the next reaction.

LCMS m/z＝449.2[M+H]+

The second step is that:

n- [ (4- (5-amino-4-cyano-1- (1-cyclobutylpiperidin-4-yl) -1H-pyrazol-3-yl) phenyl) methyl ] -5-fluoro-2-methoxybenzamide (32b)

N-[(4-(5-amino-4-cyano-1-(1-cyclobutylpiperidin-4-yl)-1H-pyrazol-3-yl)phenyl)methyl]-5-fluoro-2-methoxybenzamide.

Starting material 32a (0.1g,0.21mmol) and cyclobutanone (0.1mL,1.34mmol) were dissolved in 5mL of N, N-dimethylformamide, followed by addition of anhydrous magnesium sulfate (200mg) and dropwise addition of glacial acetic acid (0.01mL,0.17 mmol). The nitrogen was replaced with gas three times, and the system was heated to 70 ℃ for 1 hour. Sodium acetoxyborohydride (0.14g,0.66mmol) was added and the reaction was continued for 2 hours maintaining the temperature. And after the reaction of the raw materials is finished, cooling the system to room temperature. The reaction mixture was diluted with 50mL of ethyl acetate, quenched with 5mL of water and then adjusted to alkaline by the addition of saturated sodium bicarbonate. The organic phase was washed 3 times with 15 mL. The organic phase was dried, dried and column chromatographed (DCM: MeOH ═ 20:1) to give product 32b (68mg, yield: 61%) as a viscous liquid.

LCMS m/z＝503.3[M+H]+

The third step:

5-amino-1-(1-cyclobutylpiperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)

formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide.

Starting material 32b (68mg,0.14mmol) was placed in a 25mL round bottom flask, 5mL of 90% sulfuric acid solution was added, and the system was heated to 90 ℃ for 2 hours. LCMS and dot plate are sent for monitoring, and after the raw material reaction is finished, the system solution is added into 40mL of ice-water mixture. After the system is cooled to room temperature, saturated sodium carbonate is dripped to adjust the pH value to 8-9. The aqueous phase was then extracted three times with ethyl acetate 30mL, the organic phase dried and column chromatographed (DCM: MeOH ═ 20:1) to give product 32 as a viscous liquid (20mg, yield: 28%).

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.53–7.46(m,4H),7.29–7.20(m,1H),7.16(dd,1H),4.67(s,2H),4.27–4.17(m,1H),3.96(s,3H),3.28–3.11(m,3H),2.44–2.32(m,2H),2.31–2.11(m,4H),2.12–1.97(m,4H),1.85–1.68(m,2H).

LCMS m/z＝521.2[M+H]⁺

Example 33

5-amino-1- (1- (cyclopropylmethyl) piperidin-4-yl) -3- (4- { [ ((5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 33)

5-amino-1-(1-(cyclopropylmethyl)piperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxy phenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide.

The first step is as follows:

n- [ (4- (5-amino-4-cyano-1- (1- (cyclopropylmethyl) piperidin-4-yl) -1H-pyrazol-3-yl) phenyl) methyl ] -5-fluoro-2-methoxybenzamide (33a)

N-[(4-(5-amino-4-cyano-1-(1-(cyclopropylmethyl)piperidin-4-yl)-1H-pyrazol-3-yl)phenyl)methyl]-5-fluoro-2-methoxybenzamide.

Two starting materials 32a (0.1g,0.21mmol) and cyclobutanone (0.1mL,1.34mmol) were dissolved in 5mL of N, N-dimethylformamide, followed by addition of anhydrous magnesium sulfate (200mg) and dropwise addition of glacial acetic acid (0.01mL,0.17 mmol). The nitrogen was replaced with gas three times, and the system was heated to 70 ℃ for 1 hour. Sodium acetoxyborohydride (0.14g,0.66mmol) was added and the reaction was continued for 2 hours maintaining the temperature. And after the reaction of the raw materials is finished, cooling the system to room temperature. The reaction was diluted with 50mL of ethyl acetate and quenched dropwise with 5mL of water, followed by addition of saturated sodium bicarbonate to adjust the pH to basic. The organic phase was washed 3 times with 15 mL. The organic phase was dried, dried and column chromatographed (DCM: MeOH ═ 20:1) to give product 33a (68mg, yield: 61%) as a viscous liquid.

LCMS m/z＝503.3[M+H]⁺

The second step is that:

Raw material 33a (68mg,0.14mmol) was dissolved in 5mL of dimethyl sulfoxide, placed in an ice bath for 3min, 1mL of hydrogen peroxide was added, and a solution of NaOH (11mg, 0.28mmol) dissolved in 1mL of water was slowly added dropwise to the mixed system in the ice bath. After the dropwise addition is finished, the temperature is raised to room temperature for reaction for 2 hours after the system does not release heat obviously. After the reaction was completed, 10mL of water was added for dilution, the aqueous phase was extracted three times with 30mL of ethyl acetate, the organic phase was dried by spin-drying, and column chromatography (DCM: MeOH ═ 20:1) gave product 33(18mg, yield: 25%) as a viscous liquid.

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.53–7.46(m,4H),7.29–7.21(m,1H),7.16(dd,1H),4.67(s,2H),4.32–4.22(m,1H),3.96(s,3H),3.57–3.48(m,2H),2.79–2.67(t,4H),2.38–2.24(m,2H),2.13–2.04(m,2H),1.08–0.96(m,1H),0.71–0.63(m,2H),0.34–0.27(m,2H).

LCMS m/z＝521.2[M+H]⁺

Example 34

5-amino-1- [ [ (3R) -1- (3, 3-dimethylcyclobutanecarbonyl) pyrrolidin-3-yl ] methyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (compound 34)

5-amino-1-[[(3R)-1-(3,3-dimethylcyclobutanecarbonyl)pyrrolidin-3-yl]methyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

The first step is as follows: tert-butyl (3R) -3- (methylsulfonoxymethyl) pyrrolidine-1-carboxylic acid ester (34b)

tert-butyl(3R)-3-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate

Intermediate t-butyl (3R) -3- (hydroxymethyl) pyrrolidine-1-carboxylate 34a (5.00g, 24.84mmol) and triethylamine (3.77g, 37.26mmol) were dissolved in 30mL of dichloromethane, methanesulfonyl chloride (3.41g, 29.81mmol) was added dropwise under an ice-water bath, and after completion of addition, the mixture was allowed to return to room temperature and stirred for 1 h. After the reaction was completed, 50mL of water was added for extraction. The organic phase was dried over anhydrous sodium sulfate and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1:10) and concentrated to give the title compound as a yellow oil (34b) (6.5g, 93.66% yield).

The second step is that: tert-butyl (3R) -3- [ (5-amino-3-bromo-4-cyano-pyrazol-1-yl) methyl ] pyrrolidine-1-carboxylic acid salt (34c)

tert-butyl(3R)-3-[(5-amino-3-bromo-4-cyano-pyrazol-1-yl)methyl]pyrrolidine-1-carboxylate

Compound 1G (1.0G,5.35mmol), and 34a (1.79G,6.42mmol), cesium carbonate (2.61G,8.02mmol) were dissolved in 15mL dry DMF and stirred at 100 ℃ for 1 hour. The reaction solution was quenched with water (50mL), extracted with EA (20mL × 3), the organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE: EA ═ 2:1) to give the objective compound 34c (0.90g, yield: 45.46%).

LCMS m/z＝371.1[M+H]⁺

The third step: tert-butyl (3R) -3- [ [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] methyl ] pyrrolidine-1-carboxylate (34d)

tert-butyl(3R)-3-[[5-amino-4-cyano-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazol-1-yl]methyl]pyrrolidine-1-carboxylate

Compound 34c (0.50g,1.35mmol) and 1E (0.53g,1.76mmol), cesium carbonate (0.92g,2.82mmol), Pd (dppf) Cl₂(103.4mg,0.14mmol) was added to a mixed solvent of 10mL dioxane and water (v/v. sub.5: 1), and the mixture was replaced with nitrogen 3 times, heated to 110 ℃ and reacted for 3 hours. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to obtain target compound 34d (0.42g, yield: 56.69%).

LCMS m/z＝493.2[M-56]⁺

The fourth step: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [ [ (3R) -pyrrolidin-3-yl ] methyl ] pyrazole-4-carboxamide (34e)

5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[[(3R)-pyrrolidin-3-yl]methyl]pyrazole-4-carboxamide

Compound 34d (100mg,0.18mmoL) was dissolved in 5mL sulfuric acid (90%), heated to 90 ℃ and reacted for 1 hour, the reaction solution was cooled to room temperature, pH was adjusted to 10 in an ice-water bath, EA extraction (20mL × 3) was performed, organic phases were combined, saturated brine washing (20mL × 3) was performed, dried over anhydrous sodium sulfate, filtration was performed, the solvent was removed from the filtrate under reduced pressure, and the residue was subjected to column chromatography (DCM: CH: solvent)₃OH ═ 10:1) to obtain target compound 34e (0.06g, yield: 70.5%).

LCMS m/z＝467.2[M+H]⁺

The fifth step: 5-amino-1- [ [ (3R) -1- (3, 3-dimethylcyclobutanecarbonyl) pyrrolidin-3-yl ] methyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (compound 34)

Compound 34e (46.6mg,0.10mmol) and 3, 3-dimethylcyclobutane-1-carboxylic acid (13.6mg,0.1mmol) were dissolved in 5mL dry DMF and N-methylimidazole (12.8mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature and the reaction was continued for 1 hour. The reaction mixture was quenched with water (50mL), extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1), to give target compound 34 as a white solid (0.012g, yield: 20.54%).

LCMS m/z＝577.3[M+H]⁺

Example 35

5-amino-1- [ [ (3R) -1- (2, 2-difluorocyclopropanecarbonyl) pyrrolidin-3-yl ] methyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 35)

5-amino-1-[[(3R)-1-(2,2-difluorocyclopropanecarbonyl)pyrrolidin-3-yl]methyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Compound 34e (46.6mg,0.10mmol) and 2, 2-difluorocyclopropane-1-carboxylic acid (10.4mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature and the reaction was continued for 1 hour. The reaction solution was quenched with 50mL of water and extracted with EA(20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave title compound 35 as a white solid (0.01g, yield: 18.14%).

LCMS m/z＝571.2[M+H]⁺

Example 36

5-amino-1- [ [ (3R) -1- (cyclopropylmethyl) pyrrolidin-3-yl ] methyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 36)

5-amino-1-[[(3R)-1-(cyclopropylmethyl)pyrrolidin-3-yl]methyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Compound 34e (46.6mg,0.10mmol) and cyclopropanecarboxaldehyde (21.12mg,0.3mmol) were dissolved in 5mL dry DMA, three drops of acetic acid were added at room temperature, and after 1 hour of further reaction, sodium triacetoxyborohydride (63.3mg, 0.3mmol) was added. The reaction mixture was quenched with 50mL of water, extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave target compound 36 as a white solid (0.01g, yield: 18.14%).

LCMS m/z＝521.2[M+H]⁺

¹H NMR(400MHz,CD₃OD)δ7.61(dd,1H),7.54–7.47(m,4H),7.28–7.21(m,1H),7.16(dd,1H),4.67(s,2H),4.02–3.91(m,5H),2.95–2.78(m,4H),2.70–2.60(m,1H),2.49(d,2H),2.11–1.99(m,1H),1.77–1.64(m,1H),1.00–0.87(m,1H),0.60–0.51(m,2H),0.23–0.16(m,2H).

Example 37

5-amino-1- [ [ (3R) -1- [ (1S, 2S) -2-fluorocyclopropanecarbonyl ] pyrrolidin-3-yl ] methyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 37)

5-amino-1-[[(3R)-1-[(1S,2S)-2-fluorocyclopropanecarbonyl]pyrrolidin-3-yl]methyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Compound 34e (46.6mg,0.10mmol) and (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid (10.04mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (42mg,0.15mmol) was added at room temperature to continue the reaction for 1 hour. The reaction mixture was quenched with 50mL of water, extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) to obtain target compound 37(0.01g, yield: 18.14%).

LCMS m/z＝553.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.86–8.75(m,1H),7.54–7.37(m,5H),7.37–7.29(m,1H),7.22–7.15(m,1H),6.44–6.35(m,2H),4.99–4.75(m,1H),4.54(d,2H),4.02–3.93(m,2H),3.89(s,3H),3.81–3.71(m,1H),3.56–3.34(m,2H),3.28–3.12(m,1H),2.86–2.59(m,1H),2.07–1.87(m,2H),1.84–1.59(m,1H),1.58–1.45(m,1H),1.03–0.90(m,1H).

Example 38

5-amino-1- [ [ (3R) -1- (1-fluorocyclopropanyl) pyrrolidin-3-yl ] methyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 38)

5-amino-1-[[(3R)-1-(1-fluorocyclopropanecarbonyl)pyrrolidin-3-yl]methyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Compound 34e (46.6mg,0.10mmol) and 1-fluorocyclopropane-1-carboxylic acid (10.04mg,0.1mmol) were dissolved in 5mL of dry DMF, and N-methylimidazole (12.3mg,0.15mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (42mg,0.15mmol) was added at room temperature, and the reaction was continued for 1 hour. The reaction mixture was quenched with 50mL of water, extracted with EA (20 mL. times.3), the organic phases were combined, washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave title compound 38 as a white solid (0.01g, yield: 18.14%).

LCMS m/z＝553.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.81(t,1H),7.51(dd,1H),7.48–7.37(m,4H),7.37–7.29(m,1H),7.18(dd,1H),6.40(s,2H),4.54(d,2H),3.99(d,2H),3.89(s,3H),3.85–3.69(m,1H),3.60–3.44(m,2H),3.43–3.14(m,1H),2.78–2.57(m,1H),2.07–1.85(m,1H),1.82–1.60(m,1H),1.30–1.11(m,4H)。

Biological test example

1. Cell proliferation inhibitory Activity

OCI-LY10 cell culture medium is RPMI1640+ 10% FBS, and is cultured at 37 deg.C and 5% CO₂An incubator. Cells were plated in 96-well plates. OCI-LY10 cells 10000/well, 90. mu.L/well, at 37 ℃ with 5% CO₂Incubated under conditions overnight. The following day 10. mu.L of each well of test compound was added at different concentrations. Each concentration was set to 3 more wells, the last column was DMSO vehicle control, at 37 ℃, 5% CO₂The culture was continued under the conditions for 72 hours. After 72 hours, 50. mu.L of detection reagent (Cell visual Assay, Promega, G7573) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and measured for fluorescence signal using an Envision2104 plate reader (Perkinelmer). The inhibition was calculated using formula (1) where RLU compound is the reading of the drug treated group, RLU control is the average of the solvent control group, and RLU blank is the average of the cell-free wells. IC was calculated using GraphPad Prism software₅₀The value is obtained.

IR (%) - (1- (RLU compound-RLU blank)/(RLU control-RLU blank)) × 100% (formula 1)

And (4) conclusion: the compounds of the examples of the invention have good inhibitory activity on proliferation of OCI-LY10 cells, wherein the inhibitory activity of compounds 21 and 23 on proliferation of OCI-LY10 cells is less than 100 nM.

2. In vitro BTK C481S kinase assay

Kinase BTK C481S (Carna, Cat.No. 08-547) was prepared into 2.5 Xkinase solution, substrates FAM-P2(GL Biochem, Cat.No.112394) and ATP ((Sigma, Cat.No. A7699-1G) were prepared into 2.5 Xsubstrate solution, 5. mu.L of compounds with different concentrations were added to a 384-well plate, 10. mu.L of 2.5 Xkinase solution was added, incubation was carried out at room temperature for 10 minutes, 10. mu.L of 2.5 Xsubstrate solution was added, incubation was carried out at 28 ℃ for an appropriate time, 30. mu.L of stop solution was added to terminate the reaction, detection was carried out using Caliper EZ readXLader 2 instrument, IC calculation was carried out using Fit excel add-in version 5.4.0.8 software₅₀The value is obtained.

And (4) conclusion: the compound of the embodiment of the invention has good inhibitory activity on BTK C481S kinase, wherein the inhibitory activity of the compounds 1,2,4, 7-26, 28-33, 35 and 37 on BTK C481S kinase is less than 100nM, for example, the inhibitory activity of the compounds 22, 23 and 25 on BTK C481S kinase is 7.8nM, 8.7nM and 5.5nM respectively.

Claims

1. A compound or its stereoisomer, deuteron, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is selected from the compounds shown in the general formula (I), wherein

R¹is selected from-C (═ O) R^1AOr- (CH)₂)_n-C_3-12Carbocyclyl optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-6Alkyl radical)₂、NHC_1-6Alkyl radical, C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by alkoxy, said-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-6Alkyl radical)₂、NHC_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkoxy, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl is substituted by a substituent;

R²selected from H, OH, halogen, C_1-6Alkyl or-NR^1aR^1bSaid alkyl group is optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, -NR^1aR^1b、C_1-6Alkoxy radical, C_1-6Alkoxyalkyl or C_3-12Carbocyclyl or a 4-to 12-membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R^qselected from H, C_1-6Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl being optionally further substitutedFrom 0 to 4 of the groups selected from H, halogen, OH, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl or C_1-6Substituted by a substituent of alkoxy;

R³each independently selected from H, halogen, OH, ═ O, cyano, COOH, NH₂、NHC_1-6Alkyl, N (C)_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Deuterated alkoxy, -X-C_3-12Carbocyclyl or-X-4-12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, ═ O, cyano, NH₂、C_1-6Alkyl, halogen substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl, 4-7 membered heterocycloalkyl or C_1-6(ii) alkoxyalkyl, said heterocyclyl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, N;

x is selected from the group consisting of a bond, -NR^x-, -O-or-S-;

n and p are each independently selected from 0, 1,2, 3 or 4;

m is selected from 1,2, 3 or 4.

2. The compound of claim 1, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,

R^aeach independently selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl radical, C_2-4Alkynyl, C_1-4Alkoxy radicalOr C_3-6Cycloalkyl, said alkyl, alkynyl, alkoxy or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy;

R^xis selected from H or C_1-4Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy.

3. The compound of claim 2, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,

R^1Ais selected from C_3-10Saturated carbocyclic group, 4-to 10-membered heterocyclic group or- (CH)₂)_m-NR^1aR^1bSaid carbocyclyl, heterocyclyl or-CH₂-optionally substituted by 0 to 4 substituents selected from H, halogen,OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R^1a、R^1beach independently selected from H, C_1-4Alkyl radical, C_3-6Monocyclic carbocyclic group, C_4-10And a cyclic carbocyclic group, C_5-10Spirocyclic carbocyclic group, C_5-10Bridged carbocyclyl, 4-to 6-membered monocyclic heterocyclyl, 4-to 10-membered fused heterocyclyl, 5-to 10-membered spiro heterocyclyl, 5-to 10-membered bridged heterocyclyl, C_6-10Aryl or 5-to 10-membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Alkoxy, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;

x is selected from a bond or-O-.

4. The compound of claim 3, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,

ring C is selected from C_3-6Monocyclic carbocyclic group, C_4-10And a cyclic carbocyclic group, C_5-11Spirocyclic carbocyclic group, C_5-12Cyclocarbocyclic group of bridged ring, 3-to 6-membered monocyclic heterocyclic group, 4-to 10-membered fused heterocyclic group, 5-to 11-membered spiro heterocyclic group, 5-to 12-membered bridged heterocyclic group, C_6-10Aryl or 5-to 10-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, halogen, cyano, -O, -NR^1aR^1b、-OR^1a、-C(＝O)R^1a、-NR^1aC(＝O)R^1b、-C(＝O)NR^1aR^1b、C_1-4Alkyl radical, C_2-4Alkynyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Carbocyclyl or 4-to 6-membered heterocyclyl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N; r¹Is selected from C_3-6Monocyclic carbocyclic group, C_4-10And a cyclic carbocyclic group, C_5-10Spirocyclic carbocyclic group, C_5-10Cyclic ring of carbon-containing ring or-C (═ O) R^1ASaid carbocyclyl is optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, NH₂、N(C_1-4Alkyl radical)₂、NHC_1-4Alkyl radical, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_3-6Cycloalkyl or C_1-4Substituted by a substituent of alkoxy;

R²is selected from-NR^1aR^1b；

R^m1each independently selected from H, F, OH, cyano, NH₂Methyl, ethyl or CF_3；

n is selected from 0, 1 or 2.

5. The compound of claim 4, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,

R³each independently selected from H, F, Cl, Br, I, OH, ═ O, cyano, NH₂、NHCH₃、N(CH₃)₂Methyl, ethyl, isopropyl, tert-butyl, cyclopropylCyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, ethynyl, -OCD₃Methoxy, ethoxy or isopropoxy, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, methoxy, ethoxy or isopropoxy being optionally further substituted by 0 to 4 substituents selected from H, F, OH, ═ O, cyano, NH₂、CF₃、CH₂OH、CH₂F. Methyl, methoxy, ethoxy or isopropoxy;

To the left of which is directly attached Y, and when substituted, is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, ═ O, CF₃、NH₂、N(CH₃)₂、NHCH₃、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂Hydroxymethyl, methyl, ethyl, isopropyl, tert-butyl, ethynyl, methoxy, cyclopropyl, cycloButyl, cyclopentyl, cyclohexyl, oxetanyl, oxocyclopentyl, oxocyclohexyl, or morpholinyl; y is selected from the group consisting of a bond, methylene, ethylene or propylene, said methylene, ethylene or propylene being optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, OH, cyano, NH₂、CF₃、CH₂OH、CH₂F. Methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy or isopropoxy;

R²is selected from NH₂；

M is selected from methylene, ethylene or propylene;

R^aeach independently selected from H, F, Cl, Br, I, OH, cyano, NH₂Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropylCyclobutyl, cyclopentyl or cyclohexyl, said methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally further substituted by 0 to 4 substituents selected from H, F, OH, cyano, NH₂Methyl, ethyl, CF₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or methoxy;

6. The compound of claim 5, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,

m is selected from methylene;

when substituted, is optionally further substituted with 0 to 4R^aSubstitution;

R¹selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

7. The compound of claim 1, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the following structures:

8. a pharmaceutical composition comprising a compound of any one of claims 1-7, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.

9. Use of a compound according to any one of claims 1-7, or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with BTK activity or expression.

10. The use according to claim 9, wherein the disease is selected from the group consisting of tumors.