TW202317537A - Malt 1 inhibitors, preparation method and use thereof - Google Patents

Abstract

The present disclosure discloses a compound represented by formula III, a preparation method thereof, a pharmaceutical composition containing the same, and its use as a MALT1 inhibitor for preventing and/or treating autoimmune diseases, inflammatory disease, cancer, tumor.

Description

A kind of MALT 1 inhibitor and its preparation method and application

The disclosure belongs to the field of medicine, and relates to a MALT1 inhibitor, its preparation method, a pharmaceutical composition containing it, and its use for preventing and/or treating autoimmune diseases, inflammatory diseases, cancer, and tumors.

Mucosa-associated-lymphoid-tissuelymphoma-translocation1 (MALT1) is an important protein molecule in the upstream of NF-κB signaling pathway, which is similar to B-cell chronic lymphocytic leukemia/lymphoma protein (B-cell Chronic lymphocyticleukemia/lymphoma10, BCL10) and membrane-associated guanylate kinase 1 (caspase-recruitment domain (CARD) containing membrane-associated guanylatekinase protein 1, CARMA1) with caspase recruitment structure form a complex CBM, which transmits the proximal antigen receptor protein signal Give IκB kinase (IKK), and then activate NF-κB signaling pathway. Excessive activation of MALT1-NF-κB signaling pathway is closely related to inflammation and tumorigenesis.

In the first aspect, the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof

in,

Ring A is selected from 9-15 membered heteroaryls containing 1-4 heteroatoms;

、 Preferred ring A is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thio-1,2-dihydroisoquinolin-5-yl, quinoline-5-yl , Isoquinolin-5-yl, Thieno[2,3-c]pyridin-4-yl, Naphthyl,

,

R ₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered Heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy Substituent group, ethoxy group, cyclopropoxy group, nitro group, cyano group, amino group, hydroxyl group;

R ₂ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl, -COR _2a , -SO ₂ R _2b , -NHCOR _2c , hydroxyl; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy Base, C _3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl , isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl, side oxygen substituents;

R _2a , R _2b , and R _2c are each independently selected from amino, C _1-6 alkyl, phenyl, p-methylphenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, and hydroxyl;

R ₃ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl, -COR _3a , -SO ₂ R _3b , -NHCOR _3c ; where the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy , C _3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, Substituents of isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;

R _3a , R _3b , and R _3c are each independently selected from amino, C _1-6 alkyl, phenyl, p-methylphenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, and hydroxyl;

R ₄ and R ₅ are each independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, hydroxyl group, methylsulfonyl group; wherein the C _1-6 alkyl group, C _3-6 cycloalkyl group, C _1-6 alkoxy group, C _{3 -6} cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl , n-butyl, isobutyl, nitro, cyano, amino, hydroxyl substituents;

The proviso is that the compound shown in formula I does not include the following compounds:

In the second aspect, the present disclosure also provides compounds represented by formulas I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or pharmaceutically acceptable salts thereof,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ are as defined in formula I.

In some embodiments, in the compound represented by formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik or a pharmaceutically acceptable salt thereof, _R is selected from _hydrogen , C _-6 alkyl, _{C 1-6} alkoxy, C 3-6 cycloalkoxy, C _3-6 cycloalkyl, -COR _2a , -SO ₂ R _2b , -NHCOR _2c , nitro, cyano, Halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, hydroxyl; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkane Oxygen, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl , isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl, side oxygen substituents;

R _2a , R _2b , and R _2c are each independently selected from amino, C _1-6 alkyl, phenyl, p-methylphenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic, and hydroxyl.

In some embodiments, in the compound represented by formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik or a pharmaceutically acceptable salt thereof, _R is selected from _hydrogen , C _-6 alkyl, C _1-6 alkoxy, _C 3-6 cycloalkoxy, C _3-6 cycloalkyl, -COR _2a , -SO ₂ R _2b , -NHCOR _2c , cyano, halogen, 3 -6-membered heterocyclic group; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclic group is optionally 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl, side oxygen;

R _2a , R _2b , and R _2c are each independently selected from amino, C _1-6 alkyl, phenyl, p-methylphenyl, C _3-6 cycloalkyl, and 3-6 membered heterocyclic group.

In some embodiments, in the compound represented by formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik or a pharmaceutically acceptable salt thereof, _R is selected from _hydrogen , C _-6 alkyl, cyano, halogen, 3-6 membered heterocyclic group, -COR _2a , -NHCOR _2c ; the C _1-6 alkyl, 3-6 membered heterocyclic group is optionally selected from 1-3 Halogen substitution; R _2a and R _2c are each independently selected from amino, C _1-6 alkyl; preferred R ₂ is selected from hydrogen, trifluoromethyl, cyano, halogen, 3-6 membered heterocyclic group, - CONH ₂ , -NHCOCH ₃ .

In some embodiments, in the compound represented by formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik or a pharmaceutically acceptable salt thereof, _R is selected from hydrogen, _{C -6} alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen; wherein the C _1-6 alkyl, C _{3- 6} Cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, Substituents of n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;

Preferably R _is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 selected from halogen, methyl, ethyl, cyclopropyl Substituents of radical, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl.

More preferably R ₁ is selected from hydrogen, cyclopropyl, trifluoromethyl.

In some embodiments, in the compound represented by formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik or a pharmaceutically acceptable salt thereof, _R is selected from _hydrogen , C _-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered Heteroaryl, -COR _3a , -SO ₂ R _3b , -NHCOR _3c ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy Base, 3-6-membered heterocyclic group, 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, Substituents of isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;

R _3a , R _3b , and R _3c are each independently selected from amino, C _1-6 alkyl, phenyl, p-methylphenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic, and hydroxyl.

In some embodiments, in the compound represented by formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik or a pharmaceutically acceptable salt thereof, _R is selected from _hydrogen , C _-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryl are optionally 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;

Preferably R ₃ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy; the C _1-6 alkyl, C _1-6 alkoxy is optionally substituted by 1-3 selected from halogen;

More preferably R ₃ is selected from halogen substituted C _1-6 alkyl;

Most preferably _R3 is trifluoromethyl.

In some embodiments, in the compound represented by formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik or a pharmaceutically acceptable salt thereof, R _{and R} are independently selected from From C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, amino, halogen, 3-6 membered heterocycle Base, 3-6 membered heteroaryl, hydroxyl, methylsulfonyl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy , 3-6-membered heterocyclic group, 3-6-membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, iso Substituted by butyl, nitro, cyano, amino, hydroxyl substituents;

Preferably R _{and R} are independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, amine group, halogen, hydroxyl, methylsulfonyl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 Substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxyl;

More preferably R ₄ and R ₅ are independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, nitro, cyano, amino, halogen, hydroxyl, methylsulfonyl; wherein the C _1-6 Alkyl and C _3-6 cycloalkyl are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, Substituents of cyano, amino, hydroxyl;

_Optimum R and _R are independently selected from methyl, ethyl, methoxy, cyclopropyl, nitro, cyano, amino, halogen, hydroxyl, methylsulfonyl; wherein the methyl, ethyl , methoxy, and cyclopropyl are optionally substituted by 1-3 substituents selected from halogen, nitro, cyano, amino, and hydroxyl.

In certain embodiments, R ₄ is independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy.

In a third aspect, the present disclosure also provides the following compound or a pharmaceutically acceptable salt thereof,

In a fourth aspect, the present disclosure also provides a compound represented by formula II or a pharmaceutically acceptable salt thereof,

in,

Ring B is selected from 9-15 membered heteroaryls containing 1-4 heteroatoms;

Preferred ring B is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thiol-1,2-dihydroisoquinolin-5-yl, quinoline-5-yl, Isoquinolin-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl, naphthyl,

R ₆ and R ₁₀ are each independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, hydroxyl group, methylsulfonyl group; wherein the C _1-6 alkyl group, C _3-6 cycloalkyl group, C _1-6 alkoxy group, C _{3 -6} cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl , n-butyl, isobutyl, nitro, cyano, amino, hydroxyl substituents;

R ₇ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, hydroxyl, 3- 6-membered heterocyclic group, 3-6 membered heteroaryl group; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3- The 6-membered heterocyclic group and the 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, Substituents of methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;

R ₈ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl, hydroxyl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3- The 6-membered heterocyclic group and the 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, Replaced by substituents of nitro, cyano and amino groups;

、

、-NH-CO-CH₃；其中該C_1-6烷基、C_3-6環烷基、C_1-6烷氧基、C_3-6 環烷氧基、3-6員雜環基、-O-3-6員雜環基、3-6員雜芳基、-NH-CO-CH₃視需要被1-3個選自鹵素、甲基、乙基、環丙基、正丙基、異丙基、正丁基、異丁基、硝基、氰基、胺基、側氧的取代基所取代； R ₉ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heteroaryl, 3- 6-membered heterocyclic group, -O-3-6-membered heterocyclic group, -COR _9a , -SO ₂ R _9b ,

,

, -NH-CO-CH ₃ ; where the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl , -O-3-6-membered heterocyclic group, 3-6-membered heteroaryl group, -NH-CO-CH ₃ optionally selected from halogen, methyl, ethyl, cyclopropyl, n-propyl Substituents of base, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, side oxygen;

R _9a , R _9b and R _9c are each independently selected from amino, C _1-6 alkyl, phenyl, p-methylphenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, hydroxyl;

The proviso is that the compound shown in formula II does not include the following compounds:

In certain embodiments, the compound represented by formula II or a pharmaceutically acceptable salt thereof:

in,

Ring B is selected from 9-15 membered heteroaryls containing 1-4 heteroatoms;

Preferred ring B is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thiol-1,2-dihydroisoquinolin-5-yl, quinoline-5-yl, Isoquinolin-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl, naphthyl,

R ₆ and R ₁₀ are each independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, hydroxyl group, methylsulfonyl group; wherein the C _1-6 alkyl group, C _3-6 cycloalkyl group, C _1-6 alkoxy group, C _{3 -6} cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl , n-butyl, isobutyl, nitro, cyano, amino, hydroxyl substituents;

R ₇ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, hydroxyl, 3- 6-membered heterocyclic group, 3-6 membered heteroaryl group; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3- The 6-membered heterocyclic group and the 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, Substituents of methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;

R ₈ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl, hydroxyl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3- The 6-membered heterocyclic group and the 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, Replaced by substituents of nitro, cyano and amino groups;

；其中該C_1-6烷 基、C_3-6環烷基、C_1-6烷氧基、C_3-6環烷氧基、3-6員雜環基、3-6員雜芳基視需要被1-3個選自鹵素、甲基、乙基、環丙基、正丙基、異丙基、正丁基、異丁基、硝基、氰基、胺基的取代基所取代； R ₉ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heteroaryl, 3- 6-membered heterocyclyl, -COR _9a , -SO ₂ R _9b ,

; Wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 member heterocyclyl, 3-6 member heteroaryl Optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino ;

R _9a , R _9b and R _9c are each independently selected from amino, C _1-6 alkyl, phenyl, p-methylphenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, hydroxyl;

The proviso is that the compound shown in formula II does not include the following compounds:

In the fifth aspect, the present disclosure also provides compounds represented by formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or pharmaceutically acceptable Salt,

Preferred formula II-a;

R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ are as defined in formula II.

；其中該C_1-6烷基、C_3-6環烷基、C_1-6烷氧基、C_3-6環烷氧基、3-6 員雜環基視需要被1-3個選自鹵素、甲基、乙基、環丙基、正丙基、異丙基、正丁基、異丁基、硝基、氰基、胺基、側氧的取代基所取代； In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, R ₉ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl , -COR _9a , -SO ₂ R _9b ,

; Wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl are optionally selected from 1-3 Substituents from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, side oxygen;

R _9a , R _9b and R _9c are each independently selected from amino, C _1-6 alkyl, phenyl, p-methylphenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, hydroxyl;

Preferably, R ₉ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy; the C _1-6 alkyl, C _1-6 alkoxy is optionally substituted by 1-3 halogens.

；其中該3-6員雜環基視需要被1-3個選自鹵素、甲基、 乙基、環丙基、正丙基、異丙基、正丁基、異丁基、硝基、氰基、胺基的取代基所取代； In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, R ₉ is selected from 3-6 membered heterocyclyl, -COR _9a , -SO ₂ R _9b ,

; Wherein the 3-6 membered heterocyclic group is optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, Substituted by cyano and amino substituents;

R _9a , R _9b and R _9c are each independently selected from amino, C _1-6 alkyl, phenyl, p-methylphenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, and hydroxyl.

In some embodiments, the compound represented by formula II-d or formula II-g or a pharmaceutically acceptable salt thereof, wherein

；其中該C_1-6烷 基、C_3-6環烷基、C_1-6烷氧基、C_3-6環烷氧基、3-6員雜環基、3-6員雜芳基視需要被1-3個選自鹵素、甲基、乙基、環丙基、正丙基、異丙基、正丁基、異丁基、硝基、氰基、胺基的取代基所取代； R ₉ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heteroaryl, 3- 6-membered heterocyclyl, -COR _9a , -SO ₂ R _9b ,

; Wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 member heterocyclyl, 3-6 member heteroaryl Optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino ;

R _9a , R _9b and R _9c are each independently selected from amino, C _1-6 alkyl, phenyl, p-methylphenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, hydroxyl;

Preferably _R9 is selected from trifluoromethyl and triazole.

、

、

、 In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, _R9 is selected from

,

,

,

、

、

、

、

、-NH-CO-CH₃、

、 二氟甲氧基。 In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, R ₉ is selected from C _1-6 alkoxy, triazole, difluoromethyl,

,

,

,

,

, -NH-CO-CH ₃ ,

, Difluoromethoxy.

、

、二氟甲氧基、三氟甲氧基、

。 In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, R ₉ is selected from -NH-CO-CH ₃ , -OCHF ₂ ,

,

, difluoromethoxy, trifluoromethoxy,

.

、二氟甲氧基、三氟甲氧基、

。 In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, R ₉ is selected from -NH-CO-CH ₃ , -OCHF ₂ ,

, difluoromethoxy, trifluoromethoxy,

.

In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, _R9 is selected from trifluoromethyl.

In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, _R9 is selected from difluoromethyl.

In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, R _is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, hydroxyl; Wherein the C _1-6 alkyl group, C _3-6 cycloalkyl group, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, ring Propyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino substituents;

Preferably _R is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl, hydroxyl; wherein The C _1-6 alkyl group, C _3-6 cycloalkyl group, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl Substituents of group, nitro group, cyano group and amino group;

More preferably R ₈ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, nitro, cyano, halogen, hydroxyl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl Need to be substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, nitro, cyano, amino;

More preferably _R is selected from hydrogen, 1-3 halogen substituted alkyl, halogen;

Most preferably _R8 is selected from chlorine.

In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, R ₆ and R ₁₀ are each independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano , amino, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, hydroxyl group, methylsulfonyl group; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 Alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, normal Propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxyl substituents;

Preferred R ₆ and R ₁₀ are each independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, Amino, halogen, hydroxyl, methylsulfonyl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1- 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxyl;

More preferably R ₆ and R ₁₀ are each independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, nitro, cyano, amino, halogen, hydroxyl, methylsulfonyl; wherein the C _{1- 6} Alkyl, C _3-6 Cycloalkyl optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro , cyano, amino, hydroxyl substituents substituted;

Optimum R _{and R} are each independently selected from methyl, ethyl, methoxy, cyclopropyl, nitro, cyano, amino, halogen, hydroxyl, methylsulfonyl; wherein the methyl, ethyl The base, methoxy, and cyclopropyl are optionally substituted by 1-3 substituents selected from halogen, nitro, cyano, amino, and hydroxyl.

In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, R ₇ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen; wherein The C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, ring Substituents of propyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;

Preferably R _is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 selected from halogen, methyl, ethyl, cyclopropyl Substituents of radical, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl.

More preferably _R7 is selected from hydrogen, cyclopropyl, trifluoromethyl.

In some embodiments, the compound shown in formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or its pharmaceutically acceptable In the salt, R ₇ is trifluoromethyl.

In a sixth aspect, the present disclosure provides a compound represented by formula III or a pharmaceutically acceptable salt thereof,

in,

Y ₁ is CR ₁₄ or N;

Y ₂ is CR ₁₅ or N;

1) When Y ₁ is CR ₁₄ and Y ₂ is N,

Ring C is selected from optionally substituted by 1-3 R ₁₃

2) When Y ₁ is N and Y ₂ is CR ₁₅ ,

Ring C is selected from 6-10 membered aryl and 5-10 membered heteroaryl optionally substituted by 1-3 R ₁₃ ;

3) When both Y ₁ and Y ₂ are N,

Ring C is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups optionally substituted by 1-3 R ₁₃ ;

Each R ₁₃ is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3- 6-membered heterocyclic group, 3-6-membered heteroaryl group, -NHCOR _13a , -COR _13b , -SO ₂ R _13c , -SOR _13c ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryl are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl Substituents of base, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered Heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro , cyano, amino substituents are substituted;

R ₁₂ is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, the naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms optionally replaced by 1-3 R Substituted by _12a , the R _12a is selected from side oxygen, thio, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, Cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 ring Alkoxy, 3-6-membered heterocyclic group, 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl Substituents of group, isobutyl group, nitro group, cyano group and amino group;

R _13a , R _13b and R _13c are each independently selected from amino, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, p-methylphenyl;

R ₁₄ and R ₁₅ are each independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;

The proviso is that the compound shown in formula III does not include the following compounds:

In certain embodiments, the compound represented by formula III or a pharmaceutically acceptable salt thereof,

in,

Y ₁ is CR ₁₄ or N;

Y ₂ is CR ₁₅ or N;

1) When Y ₁ is CR ₁₄ and Y ₂ is N,

Ring C is selected from optionally substituted by 1-3 R ₁₃

2) When Y ₁ is N and Y ₂ is CR ₁₅ ,

Ring C is selected from 6-10 membered aryl and 5-10 membered heteroaryl optionally substituted by 1-3 R ₁₃ ;

3) When both Y ₁ and Y ₂ are N,

Ring C is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups optionally substituted by 1-3 R ₁₃ ;

Each R ₁₃ is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3- 6-membered heterocyclic group, 3-6-membered heteroaryl group, -NHCOR _13a , -COR _13b , -SO ₂ R _13c ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkane Oxygen, C _3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group may be optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl Substituents of base, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered Heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro , cyano, amino substituents are substituted;

R ₁₂ is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, the naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms optionally replaced by 1-3 R Substituted by _12a , the R _12a is selected from side oxygen, thio, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, Cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 ring Alkoxy, 3-6-membered heterocyclic group, 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl Substituents of group, isobutyl group, nitro group, cyano group and amino group;

R _13a , R _13b and R _13c are each independently selected from amino, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, p-methylphenyl;

R ₁₄ and R ₁₅ are each independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;

The proviso is that the compound shown in formula III does not include the following compounds:

In certain embodiments, the compound represented by formula III or a pharmaceutically acceptable salt thereof,

in,

Y ₁ is CR ₁₄ ;

_Y2 is N;

Ring C is selected from optionally substituted by 1-3 R ₁₃

R ₁₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered Heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro , cyano, amino substituents are substituted;

R ₁₂ is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, the naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms optionally replaced by 1-3 R Substituted by _12a , the R _12a is selected from side oxygen, thio, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, Cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 ring Alkoxy, 3-6-membered heterocyclic group, 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl Substituents of group, isobutyl group, nitro group, cyano group and amino group;

R ₁₃ is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl, -NHCOR _13a , -COR _13b , -SO ₂ R _13c , -SOCH ₃ ; where the C _1-6 alkyl, C _3-6 cycloalkyl, C _{1- 6} alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, Substituents of n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;

The proviso is that the compound shown in formula III does not include the following compounds:

In certain embodiments, the compound represented by formula III or a pharmaceutically acceptable salt thereof,

in,

Y ₁ is CR ₁₄ ;

_Y2 is N;

Ring C is selected from optionally substituted by 1-3 R ₁₃

R ₁₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 member heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 5-6 member Heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro , cyano, amino substituents are substituted;

R ₁₂ is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, the naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms optionally replaced by 1-3 R Substituted by _12a , the R _12a is selected from side oxygen, thio, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, Cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 ring Alkoxy, 3-6-membered heterocyclic group, 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl Substituents of group, isobutyl group, nitro group, cyano group and amino group;

R ₁₃ is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl, -NHCOR _13a , -COR _13b , -SO ₂ R _13c ; where the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy , C _3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, Substituents of isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;

The proviso is that the compound shown in formula III does not include the following compounds:

In the seventh aspect, the present disclosure also provides formula III-a, formula III-b, formula III-c, formula III-d, formula III-e, formula III-h or formula III-j, or formula III-k, formula The compound shown in III-m or its pharmaceutically acceptable salt,

； The compound shown in the preferred formula III-h

;

in,

n is an integer selected from 0-3,

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ are as defined in formula III.

In certain embodiments, the compound represented by formula III or a pharmaceutically acceptable salt thereof is a compound represented by formula III-i or a pharmaceutically acceptable salt thereof,

in,

n is an integer selected from 0-3,

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ are as defined in formula III.

In some embodiments, in the compounds represented by formula III, III-a, III-b, III-c, III-d, III-e, III-h, III-i or pharmaceutically acceptable salts thereof, R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl; preferred R ₁₄ is selected from hydrogen, methyl, cyclopropyl, halogen, nitro, Cyano, hydroxyl; more preferably R ₁₄ is selected from hydrogen.

In some embodiments, in the compound shown in formula III, III-a, III-b, III-c, III-d, III-e, III-h, III-i or a pharmaceutically acceptable salt thereof, wherein Each R ₁₃ is independently selected from trifluoromethyl, hydrogen, halogen; preferably R ₁₃ is independently selected from trifluoromethyl.

In some embodiments, in the compound shown in formula III, III-a, III-b, III-c, III-d, III-e, III-h, III-i or a pharmaceutically acceptable salt thereof, wherein Each R ₁₃ is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3- 6-membered heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 heterocyclic, 3- 6-membered heteroaryl is optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino replaced by substituents.

In some embodiments, in the compound shown in formula III, III-a, III-b, III-c, III-d, III-e, III-h, III-i or a pharmaceutically acceptable salt thereof, wherein Each R ₁₃ is independently selected from nitro, cyano, halogen, -NHCOR _13a , -COR _13b , -SO ₂ R _13c , -SOR _13c , wherein R _13a , R _13b and R _13c are independently selected from amine, C _1-6 alkyl, C _3-6 cycloalkyl.

In some embodiments, in the compound shown in formula III, III-a, III-b, III-c, III-d, III-e, III-h, III-i or a pharmaceutically acceptable salt thereof, wherein Each R ₁₃ is independently selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, -SOCH ₃ , halogen, cyano.

In the eighth aspect, the present disclosure also provides a compound represented by formula III-f or formula III-g or a pharmaceutically acceptable salt thereof,

Ring C, R ₁₁ , R ₁₂ , R ₁₅ are as defined in formula III.

In certain embodiments, in the compound represented by formula III, formula III-f or a pharmaceutically acceptable salt thereof, R _is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, halogen, nitric acid Base, cyano, hydroxyl; preferred R ₁₅ is selected from hydrogen, methyl, cyclopropyl, halogen, nitro, cyano, hydroxyl; more preferred R ₁₅ is selected from hydrogen.

In some embodiments, the compound shown in formula III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or its pharmaceutically acceptable In the salt, ring C is selected from 6-10 membered aryl and 5-10 membered heteroaryl optionally substituted by 1-3 R ₁₃ ;

Each R ₁₃ is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3- 6-membered heterocyclic group, 3-6-membered heteroaryl group, -NHCOR _13a , -COR _13b , -SO ₂ R _13c , SOR _13c ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _{1 -6} alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl , n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino substituents;

R _13a , R _13b and R _13c are each independently selected from amino, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, p-methylphenyl;

Preferably,

Ring C is selected from phenyl, naphthyl, 5-10 membered heteroaryl containing 1-3 heteroatoms optionally substituted by 1-3 R ₁₃ ;

Each R ₁₃ is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, containing 1 -3-6 membered heterocyclic group with 3 heteroatoms, 3-6 membered heteroaryl group with 1-3 heteroatoms, -NHCOR _13a , -COR _13b , -SO ₂ R _13c , SOR _13c ; where the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclic group containing 1-3 heteroatoms, containing 1- The 3-6 membered heteroaryl with 3 heteroatoms is optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro Substituents of group, cyano group and amino group;

The heteroatom is selected from N, O, S;

R _13a , R _13b and R _13c are each independently selected from amino, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, p-methylphenyl.

；較佳環C選自視 需要被1-3個R₁₃取代的

； In some embodiments, the compound shown in formula III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or its pharmaceutically acceptable In the salt, ring C is selected from _phenyl , pyridine, pyridazine, pyrazine, pyrimidine,

; Preferably ring C is selected from substituted by 1-3 R ₁₃ as required

;

、 三唑、-NHCOR_13a、-COR_13b、-SO₂R_13c、SOR_13c；其中該C_1-6烷基、C_3-6環烷基、C_1-6烷氧基、C_3-6環烷氧基、四氫呋喃、四氫呋喃酮、吡咯烷、吡 咯烷酮、三唑、

視需要被1-3個選自鹵素、甲基、乙基、環丙基、正丙 基、異丙基、正丁基、異丁基、硝基、氰基、胺基的取代基所取代； Each R ₁₃ is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, tetrahydrofuran, Tetrahydrofuranone, pyrrolidine, pyrrolidone,

, triazole, -NHCOR _13a , -COR _13b , -SO ₂ R _13c , SOR _13c ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 Cycloalkoxy, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone, triazole,

Optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino ;

R _13a , R _13b and R _13c are each independently selected from amino, methyl, cyclopropyl, phenyl, p-methylphenyl.

In some embodiments, the compound shown in formula III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i or In its pharmaceutically acceptable salt, R ₁₂ is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, the naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms. Need to be replaced by 1-3 R _12a , the R _12a is selected from side oxygen, thio, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl containing 1-3 heteroatoms, 3-6 membered heteroaryl containing 1-3 heteroatoms; the C _1-6 alkane Base, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl containing 1-3 heteroatoms, containing 1-3 heteroatoms The 3-6 membered heteroaryl is optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano , Amino substituents are substituted;

The heteroatom is selected from N, O, S.

、

、

； In some embodiments, the compound shown in formula III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i or Among its pharmaceutically acceptable salts, R ₁₂ is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thio-1,2-dihydroisoquinolin-5-yl, quino Lin-5-yl, isoquinolin-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl,

,

,

;

、

、

視需要被1-3個R_12a所取代，該R_12a選自C_1-6烷基、C_1-6烷氧基、 C_3-6環烷氧基、C_3-6環烷基、硝基、氰基、鹵素、包含1-3個雜原子的3-6員雜環基、包含1-3個雜原子的3-6員雜芳基；該C_1-6烷基、C_3-6環烷基、 C_1-6烷氧基、C_3-6環烷氧基、包含1-3個雜原子的3-6員雜環基、包含1-3個雜原子的3-6員雜芳基視需要被1-3個選自鹵素、甲基、乙基、環丙基、正丙基、異丙基、正丁基、異丁基、硝基、氰基、胺基的取代基所取代。 The 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thiol-1,2-dihydroisoquinolin-5-yl, quinoline-5 base, isoquinolin-5 -yl, naphthyl, thieno[2,3-c]pyridin-4-yl,

,

,

Optionally substituted by 1-3 R _12a , the R _12a is selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitr group, cyano group, halogen, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms; the C _1-6 alkyl, C _{3- 6} cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl containing 1-3 heteroatoms, 3-6 membered heterocyclyl containing 1-3 heteroatoms Heteroaryl is optionally substituted with 1-3 selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino base replaced.

； 該

視需要被1-3個R_12a所取代，該R_12a選自C_1-6烷基、C_1-6烷氧 基、C_3-6環烷氧基、C_3-6環烷基、硝基、氰基、鹵素、包含1-3個雜原子的3-6員雜環基、包含1-3個雜原子的3-6員雜芳基；該C_1-6烷基、C_3-6環烷基、C_1-6烷氧基、C_3-6環烷氧基、包含1-3個雜原子的3-6員雜環基、包含1-3個雜原子的3-6員雜芳基視需要被1-3個選自鹵素、甲基、乙基、環丙基、正丙基、異丙基、正丁基、異丁基、硝基、氰基、胺基的取代基所取代。 In certain embodiments, the compound shown in formula III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i or In its pharmaceutically acceptable salt, R ₁₂ is selected from

; Should

Optionally substituted by 1-3 R _12a , the R _12a is selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitr group, cyano group, halogen, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms; the C _1-6 alkyl, C _{3- 6} cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl containing 1-3 heteroatoms, 3-6 membered heterocyclyl containing 1-3 heteroatoms Heteroaryl is optionally substituted with 1-3 selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino base replaced.

In some embodiments, the compound shown in formula III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i or In its pharmaceutically acceptable salt, R ₁₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano , halogen; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 selected from halogen, methyl, Substituents of ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl replace;

Preferably R ₁₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 selected from halogen, methyl, ethyl, cyclopropyl Substituents of radical, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl.

More preferably R ₁₁ is selected from hydrogen, cyclopropyl, trifluoromethyl.

In the ninth aspect, the present disclosure also provides a compound represented by formula IV or a pharmaceutically acceptable salt thereof,

in,

X ₁ and X ₂ are independently selected from C, O, N, X ₃ is selected from C, N or a bond; preferably X ₁ is selected from N, X ₂ is selected from C, X ₃ is selected from N;

Ring D is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms;

R ₁₈ is selected from side oxygen, thio, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms; the C _1-6 alkyl, C _3-6 cycloalkyl, C _{1 -6} alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl containing 1-3 heteroatoms, 3-6 membered heteroaryl containing 1-3 heteroatoms are optionally replaced by 1 -3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

The heteroatom is selected from N, O, S;

m is an integer selected from 0-3;

R ₁₆ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered Heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro , cyano, amino substituents are substituted;

R ₁₇ is selected from 6-10 membered aryl, 5-10 membered heteroaryl optionally substituted by 1-3 R _17a ;

Each R _17a is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3- 6-membered heterocyclic group, 3-6-membered heteroaryl group, -NHCOR _17b , -COR _17c , -SO ₂ R _17d , -SOR _17d ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryl are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl Substituents of base, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R _17b , R _17c and R _17d are each independently selected from amino, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, p-methylphenyl.

、

、 In certain embodiments, in the compound represented by formula IV or a pharmaceutically acceptable salt thereof, ring D is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thio-1 ,2-Dihydroisoquinolin-5-yl, quinolin-5-yl, isoquinolin-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl,

,

,

R ₁₈ is selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, halogen, containing 1-3 hetero Atomic 3-6 membered heterocyclic group, 3-6 membered heteroaryl group containing 1-3 heteroatoms; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally replaced by 1-3 members selected from halogen , methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino substituents;

m is an integer selected from 0-3.

In certain embodiments, in the compound represented by formula IV or a pharmaceutically acceptable salt thereof, ring D is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl;

R ₁₈ is selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, halogen, containing 1-3 hetero Atomic 3-6 membered heterocyclic group, 3-6 membered heteroaryl group containing 1-3 heteroatoms; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally replaced by 1-3 members selected from halogen , methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino substituents;

m is an integer selected from 0-3.

In certain embodiments, in the compound represented by formula IV or a pharmaceutically acceptable salt thereof, R ₁₇ is selected from 6-10 membered aryl, 5-10 membered heteroaryl optionally substituted by 1-3 R _17a ;

Each R _17a is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3- 6-membered heterocyclic group, 3-6-membered heteroaryl group, -NHCOR _17b , -COR _17c , -SO ₂ R _17d , -SOR _17d ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryl are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl Substituted by base, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R _17b , R _17c and R _17d are each independently selected from amino, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, p-methylphenyl;

Preferably, R ₁₇ is selected from phenyl, naphthyl, 3-6 membered heteroaryl containing 1-3 heteroatoms optionally substituted by 1-3 R _17a ;

Each R _17a is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, containing 1 -3-6 membered heterocyclic group with 3 heteroatoms, 3-6 membered heteroaryl group with 1-3 heteroatoms, -NHCOR _17b , -COR _17c , -SO ₂ R _17d , -SOR _17d ; where the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclic group containing 1-3 heteroatoms, containing 1 - 3-6 membered heteroaryl with 3 heteroatoms optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, Replaced by substituents of nitro, cyano and amino groups;

The heteroatom is selected from N, O, S;

R _17b , R _17c and R _17d are each independently selected from amino, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, p-methylphenyl.

； In certain embodiments, in the compound represented by formula IV or a pharmaceutically acceptable salt thereof _, R ₁₇ is selected from phenyl, pyridine, pyridazine, pyrazine, pyrimidine,

;

、 三唑、-NHCOR_17b、-COR_17c、-SO₂R_17d、-SOR_17d；其中該C_1-6烷基、C_3-6環烷基、C_1-6烷氧基、C_3-6環烷氧基、四氫呋喃、四氫呋喃酮、吡咯烷、 吡咯烷酮、三唑、

視需要被1-3個選自鹵素、甲基、乙基、環丙基、正 丙基、異丙基、正丁基、異丁基、硝基、氰基、胺基的取代基所取代； Each R _17a is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, tetrahydrofuran, Tetrahydrofuranone, pyrrolidine, pyrrolidone,

, triazole, -NHCOR _17b , -COR _17c , -SO ₂ R _17d , -SOR _17d ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _{3- 6} cycloalkoxy, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone, triazole,

Optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino ;

R _17b , R _17c and R _17d are each independently selected from amino, methyl, cyclopropyl, phenyl, p-methylphenyl.

In certain embodiments, in the compound represented by formula IV or a pharmaceutically acceptable salt thereof, R ₁₇ is selected from pyridine optionally substituted by 1-3 R _17a ;

、 三唑、-NHCOR_17b、-COR_17c、-SO₂R_17d、-SOR_17d；其中該C_1-6烷基、C_3-6環烷基、C_1-6烷氧基、C_3-6環烷氧基、四氫呋喃、四氫呋喃酮、吡咯烷、 吡咯烷酮、三唑、

視需要被1-3個選自鹵素、甲基、乙基、環丙基、正 丙基、異丙基、正丁基、異丁基、硝基、氰基、胺基的取代基所取代； Each R _17a is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, tetrahydrofuran, Tetrahydrofuranone, pyrrolidine, pyrrolidone,

, triazole, -NHCOR _17b , -COR _17c , -SO ₂ R _17d , -SOR _17d ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _{3- 6} cycloalkoxy, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone, triazole,

Optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino ;

R _17b , R _17c and R _17d are each independently selected from amino, methyl, cyclopropyl, phenyl, p-methylphenyl;

Preferably,

； R ₁₇ is selected from the group optionally substituted by 1-3 R _17a

;

Each R _17a is independently selected from halogen, C _1-6 alkyl, C _3-6 cycloalkyl, nitro, cyano, 1-3 halogen substituted C _1-6 alkyl.

In certain embodiments, in the compound represented by formula IV or a pharmaceutically acceptable salt thereof, R ₁₆ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy 1-3 selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, Substituents of nitro, cyano, amino, hydroxyl;

Preferably R ₁₆ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 selected from halogen, methyl, ethyl, cyclopropyl Substituents of radical, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;

More preferably R ₁₆ is selected from hydrogen, cyclopropyl, trifluoromethyl.

In a tenth aspect, the present disclosure also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,

In the eleventh aspect, the present disclosure also provides an isotope substitution of the compound shown in the first aspect to the tenth aspect, preferably, the isotope substitution is deuterium atom substitution.

In the twelfth aspect, the present disclosure also provides a pharmaceutical composition, which comprises the compound described in the first aspect to the eleventh aspect or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% pharmaceutically acceptable excipients.

In the thirteenth aspect, the present disclosure also provides a method for preventing and/or treating disorders related to MALT1, which includes administering to a subject in need a therapeutically effective amount of the compound as described in the first aspect to the eleventh aspect or Its pharmaceutically acceptable salt or the pharmaceutical composition as described in the twelfth aspect.

The MALT1-related diseases include but not limited to autoimmune diseases, inflammatory diseases, cancers, tumors, etc., such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vascular inflammatory diseases, primary cancers of the hematopoietic system or solid tumors, including chronic myelogenous leukemia, myelogenous leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.

The present disclosure also provides a method for preventing and/or treating autoimmune diseases, inflammatory diseases, cancers, tumors, which comprises administering to a subject in need a therapeutically effective amount of the or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in the twelfth aspect.

The autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitic diseases, the cancers or tumors such as primary cancers or solid tumors of the hematopoietic system, including chronic myeloid Leukemia, myelogenous leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.

The present disclosure also provides the compound or pharmaceutically acceptable salt thereof described in the first aspect to the eleventh aspect or the pharmaceutical composition described in the twelfth aspect in the preparation of medicines for preventing and/or treating diseases related to MALT1 use.

The present disclosure also provides the compounds described in the first to eleventh aspects or pharmaceutically acceptable salts thereof or the pharmaceutical composition described in the twelfth aspect for the prevention and/or treatment of autoimmune diseases and inflammatory diseases , cancer, tumor medicine purposes.

The autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitic diseases, the cancer or tumor such as hematopoietic Cancer or solid tumors, including chronic myelogenous leukemia, myelogenous leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.

The present disclosure also provides the compound according to the first aspect to the eleventh aspect or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the twelfth aspect, which are used for preventing and/or treating diseases related to MALT1.

The present disclosure also provides the compounds described in the first to eleventh aspects or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the twelfth aspect, which are used for preventing and/or treating autoimmune diseases and inflammatory diseases , cancer, tumor purposes.

The autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitic diseases, the cancers or tumors such as primary cancers or solid tumors of the hematopoietic system, including chronic myeloid Leukemia, myelogenous leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.

The compounds described in this disclosure or their pharmaceutically acceptable salts or pharmaceutical compositions have a good inhibitory effect on MALT1, and the IC ₅₀ value of the inhibitory activity on MALT1 is between 0.01 and 1000nM, and the IC ₅₀ of certain compounds on the inhibitory activity on MALT1 The value is from 0.01 to 500nM, the IC50 value of the inhibitory activity of some compounds on MALT1 is from 0.01 to 300nM, the _IC50 value of the inhibitory activity of some compounds on MALT1 enzyme is from 0.01 to 200nM, the inhibitory activity of some compounds on MALT1 enzyme The IC ₅₀ value ranges from 0.01 to 100nM, the IC ₅₀ value of the inhibitory activity of some compounds on MALT1 enzyme is <100nM, and the IC ₅₀ value of the inhibitory activity of some compounds on MALT1 enzyme is <50nM.

Pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic mixtures Compounds and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all such mixtures are within the scope of the present disclosure. All such isomers and mixtures thereof are included within the scope of the present disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure resulting diastereomeric mixture. Enantiomers are required. Alternatively, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art Methods The diastereoisomers were resolved and the pure enantiomers were recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using a chiral stationary phase, optionally combined with chemical derivatization methods (e.g. amines to amines formate).

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。本揭露所述化合物的化學結構中，鍵“

”並未指定構型，即可以為Z構型或E構型，或者同時包含兩種構型。 In the chemical structure of the compound described in the present invention, the bond "

"indicates that no configuration is specified, i.e. if chiral isomers exist in the chemical structure, the bond"

"can be"

"or"

, or both "

"and"

"Two configurations. In the chemical structures of the compounds described in this disclosure, the bond"

" does not specify the configuration, it can be the Z configuration or the E configuration, or both configurations.

Although all of the above formulas are drawn as certain isomeric forms for simplicity, the present invention may include all isomers such as tautomers, rotamers, geometric isomers, diastereoisomers isomers, racemates and enantiomers.

Tautomers are structural isomers of organic compounds that are readily interconvertible by a chemical reaction called tautomerization. This reaction often results in the formal transfer of hydrogen atoms or protons shift, with the conversion of a single bond and an adjacent double bond. Some common tautomers are: keto-enol, lactam-lactimine. An example of a lactam-lactimine equilibrium is between A and B as shown below,

All tautomeric forms are within the scope of the invention. The naming of compounds does not exclude any tautomers.

Any isotopically labeled derivatives of the compounds described in the present disclosure, or pharmaceutically acceptable salts thereof, or isomers thereof are covered by the present disclosure. Atoms capable of being isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, and the like. They can be replaced by isotopes ² H(D), ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I, respectively. Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to mean deuterium having an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45 % deuterium incorporation).

The present disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

"Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C ₁ -C ₆ alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but not necessarily be present, and this specification includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not And the case of cyano substitution.

Explanation of terms:

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. agent. The purpose of the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.

"Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, agent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.

An "effective amount" or "therapeutically effective amount" as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to permit or facilitate diagnosis. Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dose of administration and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

"Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl and its various branched isomers, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, Side oxygen, nitro, cyano, C _1-6 alkyl _, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl Oxygen, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl Need to be substituted by one or more selected from halogen, deuterium, hydroxyl, side oxygen, nitro, cyano.

"Alkenyl" includes branched and straight chain alkenes or alkenes containing aliphatic hydrocarbon groups having 2 to 12 carbon atoms. For example "C _2-6 alkenyl" means alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3 - methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, Side oxygen, nitro, cyano, C _1-6 alkyl _, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl Oxygen, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl Need to be substituted by one or more selected from halogen, deuterium, hydroxyl, side oxygen, nitro, cyano.

"Alkynyl" includes branched and straight chain alkynyl groups or alkynes containing aliphatic hydrocarbon groups having 2 to 12 carbon atoms. For example ethynyl, propynyl (eg 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, Side oxygen, nitro, cyano, C _1-6 alkyl _, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl Oxygen, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl Need to be substituted by one or more selected from halogen, deuterium, hydroxyl, side oxygen, nitro, cyano.

The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; multicyclic cycloalkyls include spiro Cycloalkyl rings, fused rings and bridged rings. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl , side oxygen, nitro, cyano, C _1-6 alkyl _{, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy ,} C _3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 Alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl It is optionally substituted by one or more selected from halogen, deuterium, hydroxyl, side oxygen, nitro, cyano.

The cycloalkyl ring may be fused to an aryl or heteroaryl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl Alkyl etc. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano radical, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3 to ₆ membered heterocycloalkoxy group, C _3-8 cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 Alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, side oxygen, nitro, cyano.

The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. Cycloalkenyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano radical, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3 to ₆ membered heterocycloalkoxy group, C _3-8 cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 Alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, side oxygen, nitro, cyano. The term "heterocycloalkyl", "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more Atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contain 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperrolyl, Pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Multicyclic heterocycloalkyls include spiro, fused and bridged heterocycloalkyls. Non-limiting examples of "heterocycloalkyl" include:

和

，等等。

and

,etc.

The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring wherein the ring bonded to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

和

等。

and

wait.

Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, Cyano, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3 to ₆ membered heterocycloalkane Oxygen, C _3-8 cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _{2- 6} alkynyloxy, C _3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl are optionally replaced by one or more Substituted by halogen, deuterium, hydroxyl, side oxygen, nitro, cyano.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e. rings sharing adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6 to 12 members, e.g. phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:

Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy , C _3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl are optionally replaced by one or more selected from halogen, Deuterium, hydroxyl, side oxygen, nitro, cyano are substituted.

，

，

，等等。 The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl may be 5 to 12 membered or 5 to 10 membered, more preferably 5 or 6 membered. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,

,

,

,etc.

The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring where the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano radical, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3 to ₆ membered heterocycloalkoxy group, C _3-8 cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 Alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, side oxygen, nitro, cyano.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano radical, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3 to ₆ membered heterocycloalkoxy group, C _3-8 cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 Alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, side oxygen, nitro, cyano.

The term "alkenyloxy" refers to -O-(alkenyl), wherein alkenyl is as defined above.

The term "alkynyloxy" refers to -O-(alkynyl), wherein alkynyl is as defined above.

The term "cycloalkoxy" refers to -O-(cycloalkyl), wherein cycloalkyl is as defined above.

The term "heterocycloalkoxy" refers to -O-(heterocyclyl), wherein heterocyclyl is as defined above.

The term "cycloalkenyloxy" refers to -O-(cycloalkenyl), wherein cycloalkenyl is as defined above.

The term "hydroxyl" refers to a -OH group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "side oxygen" refers to a =O substituent.

The term "thio" refers to the =S substituent.

The present invention is further described below in conjunction with examples, but these examples do not limit the scope of the present invention.

Example

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR was carried out with a Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvents were deuterated dimethyl sulfide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

MS was measured with Shimadzu 2010 Mass Spectrometer or Agilent 6110A MSD mass spectrometer.

High performance liquid chromatography (HPLC) was determined using Shimadzu LC-20A systems, Shimadzu LC-2010HT series, Shimadzu DGU-20A5R, Shimadzu LC-30AD, Shimadzu SIL-30AC or Agilent Agilent 1200 LC high pressure liquid chromatography (Ultimate XB -C18 3.0*150mm chromatographic column or Xtimate C18 2.1*30mm chromatographic column).

Chiralpak IC-3 100×4.6mm I.D., 3um, Chiralpak AD-3 150×4.6mm I.D., 3um, Chiralpak AD-3 50×4.6mm I.D., 3um, Chiralpak AS-3 150×4.6mm were used for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100×4.6mm I.D., 3μm, ChiralCel OD-3 150×4.6mm I.D., 3um, Chiralcel OD-3 100×4.6mm I.D., 3μm, ChiralCel OJ-H 150×4.6mm I.D., 5um, Chiralcel OJ-3 150×4.6mm I.D., 3um column.

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

Column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier.

The chiral preparation column used DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).

The CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).

Kinase average inhibition rate and IC ₅₀ value were measured with NovoStar microplate reader (BMG Company, Germany).

The known starting materials of the present invention can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.

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

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

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

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

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

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

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

Unless otherwise specified in the examples, the temperature of the reaction is room temperature, which is 20° C. to 30° C.

The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in the reaction, the eluting agent system and the developing agent system of the column chromatography that the purified compound adopts and the thin-layer chromatography, the solvent The volume ratio is adjusted according to the polarity of the compound. Generally, water and acetonitrile are used as the mobile phase, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)- 1H-pyrazole-4-carboxamide 1

first step

5-hydrazinoisoquinoline 1b

Dissolve isoquinolin-5-amine (5.1g, 35.37mmol) in concentrated hydrochloric acid (50mL), add an aqueous solution (20mL) of sodium nitrite (3.66g, 53.06mmol) at 0°C, react for 30 minutes, dropwise Add concentrated hydrochloric acid solution (20mL) of stannous chloride (19.95g, 88.43mmol), react at room temperature for 3 hours, adjust pH to 12~14 with 20% aqueous sodium hydroxide solution, extract with ethyl acetate (30mL*3) , the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and extracted with ethyl acetate to obtain the title compound 1b (2.33 g, yield: 40.0%).

MS (ESI): m/z = 159.0 [M+H] ⁺ .

second step

1-(isoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 1d

5-Hydrazinoisoquinoline (2.33 g, 14.64 mmol) and ( Z )-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoic acid ethyl ester 1c ( 3.52g, 14.64mmol) was dissolved in ethanol (40mL), reacted at 60°C for 3 hours, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography with ethyl acetate to obtain the title compound 1d (2.56g , yield: 52.1%).

MS (ESI): m/z = 336.4 [M+H] ⁺ .

third step

5-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1 H -pyrazol-1-yl)isoquinoline 2-oxide 1e

Ethyl 1-(isoquinolin-5-yl)-5-(trifluoromethyl) -1H -pyrazole-4-carboxylate (2.56 g, 7.64 mmol) was dissolved in dichloromethane (30 mL), Add m-chloroperoxybenzoic acid (3.95g, 22.9mmol) at 0°C, react overnight at room temperature, wash with half-saturated sodium bisulfite solution (20mL*2) and potassium carbonate solution (20mL*2) successively, and dry the organic phase , concentrated in vacuo to give the title compound 1e (2.50 g, yield: 93.21%).

MS (ESI): m/z = 352.4 [M+H] ⁺ .

the fourth step

1-(1-Chloroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H -pyrazole-4-carboxylic acid ethyl ester 1f

5-(4-(Ethoxycarbonyl)-5-(trifluoromethyl) -1H -pyrazol-1-yl)isoquinoline 2-oxide (2.5g, 7.12mmol) was dissolved in chloroform (30mL ), add phosphorus oxychloride (1.33mL, 14.23mmol) at room temperature, react at 60°C for 3 hours, quench with water (20mL) under ice bath, concentrate the organic phase in vacuo, and use petroleum ether by silica gel column chromatography , ethyl acetate was extracted and purified to obtain the title compound 1f (1.96g, yield: 74.49%).

MS (ESI): m/z = 370.43 [M+H] ⁺ .

the fifth step

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H -pyrazole-4-carboxylic acid 1g

1-(1-chloroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1g, 2.71mmol) was dissolved in concentrated hydrochloric acid (15mL), 120 The reaction was carried out at °C for 3 hours, and concentrated in vacuo to obtain 1 g of the title compound (864 mg, yield: 98.83%).

MS (ESI): m/z = 324.4 [M+H] ⁺ .

step six

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)- 1H-pyrazole-4-carboxamide 1

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1 H -pyrazole-4-carboxylic acid (100mg, 0.31mmol) and 4-(Trifluoromethyl)pyrimidin-2-amine (50.46mg, 0.31mmol) was dissolved in pyridine (10mL), phosphorus oxychloride (0.058mL, 0.62mmol) was added at room temperature, and microwave reaction was performed at 120°C for 1 hour. Add saturated aqueous sodium bicarbonate (20 mL), extract with dichloromethane (20 mL*3), concentrate the organic phase in vacuo, and separate by high performance liquid chromatography to obtain the title compound 1 (12 mg, yield: 8.28%).

MS (ESI): m/z = 469.5 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ )δ 11.80(s,1H),11.62(s,1H),9.10(d, J =5.0Hz,1H),8.44(d, J =8.0Hz,1H), 8.42(s,1H),7.93(d, J =7.5Hz,1H),7.76(d, J =5.0Hz,1H),7.68(t, J =7.9Hz,1H),7.30-7.27(m,1H ),5.71(d, J =7.3Hz,1H).

Example 2

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)- 1H-pyrazole-4-carboxamide 2

first step

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)- 1H-pyrazole-4-carboxamide 2

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (120mg, 0.37mmol) and 6 -(Trifluoromethyl)pyrimidin-4-amine (60.55mg, 0.37mmol) was dissolved in pyridine (10mL), phosphorus oxychloride (0.069mL, 0.74mmol) was added at room temperature, and microwave reaction was carried out at 120°C for 20min. Add saturated aqueous sodium bicarbonate (20 mL), extract with dichloromethane (20 mL*3), concentrate the organic phase under reduced pressure, and separate by high performance liquid chromatography to obtain the title compound 2 (11 mg, yield: 6.33%).

MS (ESI): m/z = 469.5 [M+H] ⁺ .

1H NMR(400MHz,DMSO-d6)δ=12.18(s,1H),11.63(d,J=5.3Hz,1H),9.22(s,1H),8.56(d,J=7.8Hz,2H),8.44 (d,J=8.0Hz,1H),7.95(d,J=7.0Hz,1H),7.68(t,J=7.9Hz,1H),7.34-7.25(m,1H),5.69(d,J= 7.3Hz, 1H).

Example 3

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1H-pyrazole-4-carboxamide 3

first step

1-(1-hydrazinoisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 3c

Dissolve ethyl 1-(1-chloroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate 1f (200 mg, 0.54 mmol) in dioxane solution (12 mL), added hydrazine hydrate (3 mL) at room temperature, reacted at 70°C for 5 hours, and concentrated the reaction solution under reduced pressure to obtain the title compound 3a (225 mg, crude product).

MS (ESI): m/z = 366.5 [M+H] ⁺ .

second step

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 3e

Dissolve ethyl 1-(1-hydrazinoisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (225 mg, 0.62 mmol) in triethyl orthoformate (8 mL), reacted at 100°C for 1 hour, and concentrated the reaction solution under reduced pressure to obtain the title compound 3e (220 mg, yield: 95.1%).

MS (ESI): m/z = 376.5 [M+H] ⁺ .

third step

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 3f

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (220mg, 0.58mmol) was dissolved in concentrated hydrochloric acid (10mL), reacted at 120°C for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the title compound 3f (240mg, crude product).

MS (ESI): m/z = 348.4 [M+H] ⁺ .

the fourth step

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridine -4-yl)-1H-pyrazole-4-carboxamide 3

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (70mg , 0.20mmol) and 2-(trifluoromethyl)pyridin-4-amine 3g (32.68mg, 0.20mmol) were dissolved in pyridine (6mL), and phosphorus oxychloride (0.038mL, 0.40mmol) was added dropwise, room Warm reaction for 1 hour. Water (10 mL) was added, dichloromethane extracted (3*15 mL), the organic phase was concentrated under reduced pressure, and separated by high performance liquid chromatography to obtain the title compound 2 (27.1 mg, yield: 27.3%).

MS (ESI): m/z = 492.5 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ=11.28(br s,1H),9.36(s,1H),8.83(d,J=8.0Hz,1H),8.73(d,J=5.5Hz,1H ),8.60(s,1H),8.46(d,J=7.5Hz,1H),8.26(s,1H),7.99(quin,J=8.0Hz,3H),6.46(d,J=7.5Hz,1H ).

Example 4

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-N-(5-chloro-6-methoxypyridin-3-yl)-5- (Trifluoromethyl)-1H-pyrazole-4-carboxamide 4

first step

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-N-(5-chloro-6-methoxypyridin-3-yl)-5- (Trifluoromethyl)-1H-pyrazole-4-carboxamide 4

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 3f ( 71 mg, 0.20 mmol) and 5-chloro-6-methoxypyridin-3-amine 4a (32.42 mg, 0.20 mmol) were dissolved in pyridine (6 mL), and phosphorus oxychloride (0.038 mL, 0.41 mmol) was added dropwise , react at room temperature for 1 hour. Water (10 mL) was added, dichloromethane extracted (15 mL*3), the organic phase was concentrated under reduced pressure, and separated by high performance liquid chromatography to obtain the title compound 4 (5.5 mg, yield: 5.51%).

MS (ESI): m/z = 488.6 [M+H] ⁺ .

Example 5

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazole- 2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 5

first step

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazole- 2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 5

1-([1,2,4]triazolo[3,4-a]isoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 3f ( 70mg, 0.20mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine 5a (39.43mg, 0.20mmol) were dissolved in pyridine (6mL) and Add phosphorus oxychloride (0.038mL, 0.40mmol) dropwise, react at room temperature for 1 hour, add water (10mL), extract with dichloromethane (3*15mL), concentrate the organic phase under reduced pressure, and separate by high performance liquid chromatography. The title compound 5 (25 mg, yield: 23.6%) was obtained.

MS (ESI): m/z = 525.6 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ=11.28(br s,1H),11.47-11.05(m,1H),9.35(s,1H),8.93-8.79(m,2H),8.71-8.66( m,1H),8.61(s,1H),8.46(d,J=7.5Hz,1H),8.19(s,2H),8.08-7.92(m,2H),6.46(d,J=7.5Hz,1H ).

Example 6

1-(1-thiol-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 1H-pyrazole-4-carboxamide 6

first step

1-(1-thio-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 6b

1-(1-Chloroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 3a (200mg, 0.54mmol) and thiourea (45.3mg, 0.59mmol) was dissolved in ethanol (10mL), reacted at 80°C for 2 hours, added water (10mL) to the reaction solution, extracted with ethyl acetate (15mL*3), dried the organic phase, and concentrated under reduced pressure to obtain the title compound 6b (214mg, Crude).

MS (ESI): m/z = 368.4 [M+H] ⁺ .

second step

1-(1-thio-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 6c

1-(1-thio-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (214mg, 0.58mmol) Dissolve in concentrated hydrochloric acid (10 mL), react at 120°C for 1 hour, and concentrate the reaction solution under reduced pressure to obtain the title compound 6c (198 mg, crude product).

MS (ESI): m/z = 340.4 [M+H] ⁺ .

third step

1-(1-thiol-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 1H-pyrazole-4-carboxamide 6

1-(1-thio-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (51mg, 0.15mmol) and 2 -(Trifluoromethyl)pyridin-4-amine 3g (24.37mg, 0.15mmol) was dissolved in pyridine (6mL), phosphorus oxychloride (0.028mL, 0.30mmol) was added dropwise, and reacted at room temperature for 1 hour. Water (10 mL) was added, dichloromethane extracted (3*15 mL), the organic phase was concentrated under reduced pressure, and separated by high performance liquid chromatography to obtain the title compound 6 (17.2 mg, yield: 23.6%).

MS (ESI): m/z = 484.5 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ 13.62(s,1H),11.28(s,1H),9.02(d,J=5.5Hz,1H),8.72(d,J=5.5Hz,1H), 8.56(s,1H),8.24(d,J=2.0Hz,1H),8.08(dd,J=7.7,1.2Hz,1H),7.98(dd,J=5.4,2.0Hz,1H),7.80(t ,J=5.5Hz,1H),7.52(d,J=7.2Hz,1H),6.15(d,J=7.2Hz,1H).

Example 7

N-(5-chloro-6-methoxypyridin-3-yl)-1-(1-thio-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide 7

first step

N-(5-chloro-6-methoxypyridin-3-yl)-1-(1-thio-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide 7

1-(1-thiol-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 7a (65mg, 0.19mmol) and 5-Chloro-6-methoxypyridin-3-amine 4a (30.38mg, 0.19mmol) was dissolved in pyridine (6mL), phosphorus oxychloride (0.036mL, 0.38mmol) was added dropwise, and reacted at room temperature for 1 hour , added water (10mL), extracted with dichloromethane (3*15mL), concentrated the organic phase under reduced pressure, and separated by high performance liquid chromatography to obtain the title compound 7 (2mg, yield: 2.18%).

MS (ESI): m/z = 480.6 [M+H] ⁺ .

Example 8

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-thio-1,2-dihydroisoquinoline- 5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 8

first step

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-thio-1,2-dihydroisoquinoline- 5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 8

1-(1-thio-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 7a (60mg, 0.18mmol) and 5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine 5a (34.59 mg, 0.18 mmol) was dissolved in pyridine (6 mL), and phosphorus oxychloride was added dropwise (0.033mL, 0.35mmol), react at room temperature for 1 hour. Water (10 mL) was added, dichloromethane extracted (15 mL*3), the organic phase was concentrated under reduced pressure, and separated by high performance liquid chromatography to obtain the title compound 8 (4 mg, yield: 4.38%).

MS (ESI): m/z = 517.6 [M+H] ⁺ .

Example 9

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-5-yl)-5-(trifluoromethyl base)-1H-1,2,3-triazole-4-carboxamide 9

first step

5-Azidoisoquinoline 9b

Dissolve isoquinolin-5-amine 1a (1g, 6.94mmol) in acetonitrile (14mL), add tert-butyl nitrite (1.1g, 10.40mmol) and trimethylsilyl azide (1.2g, 10.40 mmol), after reacting for 1 hour, the reaction solution was concentrated, purified by silica gel column chromatography with ethyl acetate and n-hexane to obtain the title compound 9b (220 mg, yield: 19%).

MS (ESI): m/z = 171.2 [M+H] ⁺ .

second step

1-(isoquinolin-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 9c

5-Azidoisoquinoline 9b (220mg, 1.29mmol) and ethyl trifluoroacetylacetate (238mg, 1.29mmol) were dissolved in tetrahydrofuran (5mL), heated under reflux under nitrogen atmosphere for 20 hours, and depressurized It was purified by silica gel column chromatography with ethyl acetate and n-hexane to obtain the title compound 9c (300 mg, yield: 69%).

MS (ESI): m/z = 337.4 [M+H] ⁺ .

third step

1-(isoquinolin-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid 9d

1-(isoquinolin-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid ethyl ester 9c (100mg, 0.297mmol) was dissolved in ethanol (3mL ) and water (1 mL), reacted at 80°C for 2 hours, the reaction solution was concentrated under reduced pressure, the residue was added with 3 ml of concentrated hydrochloric acid, and then concentrated under reduced pressure to obtain the crude product of the title compound 9d , which was directly used in the next step without further purification .

MS (ESI): m/z = 309.1 [M+H] ⁺ .

the fourth step

N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinolin-5-yl)-5-(trifluoromethyl base)-1H-1,2,3-triazole-4-carboxamide 9

The crude 1-(isoquinolin-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid 9d from the previous step was dissolved in pyridine (4 mL), and then Add 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine 5a (64mg, 0.33mmol), add phosphorus oxychloride (114mg, 0.74mmol) at room temperature, React overnight at room temperature. After the reaction was complete, the organic phase was concentrated under reduced pressure, purified by C18 reverse-phase column chromatography, and lyophilized to obtain the title compound 9 (90 mg, two-step combined yield: 62%).

MS (ESI): m/z = 486.2 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ )δ 11.82(br s,1H),9.59(s,1H),9.09(d,J=2.4Hz,1H),8.80(d,J=2.0Hz,1H) ,8.64(d,J=6.0Hz,1H),8.56(d,J=8.4Hz,1H),8.32(d,J=6.8Hz,1H),8.20(s,2H),7.98(t,J= 8.0Hz, 1H), 7.29 (d, J=6.0Hz, 1H).

Example 10

N-(2-(difluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide 10

first step

2-(Difluoromethyl)pyridin-4-amine 10b

Dissolve 4-bromo-2-(difluoromethyl)pyridine (300mg, 1.44mmol) in aqueous ammonia (2mL) and N-methylpyrrolidone (NMP) (1mL), add cuprous oxide (41mg, 0.29mmol, The reaction was reacted in the microwave at 140 ° C for 1 hour. After the reaction was completed, 5 ml of ethyl acetate was added, and then washed twice with 5 ml of water and 5 ml of saturated NaCl aqueous solution, and the organic phase was concentrated under reduced pressure to obtain the title compound 10b (210 mg, crude product) , used directly in the next step without further purification.

MS (ESI) m/z: 145.3 [M+H] ⁺ .

second step

N-(2-(difluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide 10

2-(Difluoromethyl)pyridin-4-amine 10b (50 mg, 0.35 mmol) was dissolved in pyridine (3 mL), and 1-(1-oxo-1,2-dihydroisoquinoline-5 -yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (112mg, 0.35mmol), added phosphorus oxychloride (106mg, 0.69mmol) at room temperature, and stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, purified by C18 reverse-phase column chromatography, and lyophilized to obtain the title compound 10 (23.5 mg, yield: 15%).

MS (ESI) m/z: 450.6 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ )δ 11.64(s,1H),11.14(s,1H),8.63(d,J=5.6Hz,1H),8.53(s,1H),8.45(d,J =8.0Hz,1H),8.09(d,J=2.0Hz,1H),7.95(d,J=7.2Hz,1H),7.85(d,J=5.6Hz,1H),7.68(t,J=8.0 Hz, 1H), 7.34-7.27(m, 1H), 7.13-6.79(m, 1H), 5.66(d, J=7.6Hz, 1H).

Example 11

N-(Benzo[c][1,2,5]oxadiazol-5-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-( Trifluoromethyl)-1H-pyrazole-4-carboxamide 11

first step

Benzo[c][1,2,5]oxadiazol-5-amine 11b

Dissolve 5-bromobenzo[c][1,2,5]oxadiazole 11a (250mg, 1.25mmol) in aqueous ammonia (1.5mL) and N-methylpyrrolidone (1mL), add cuprous oxide (36mg , 0.25mmol, the reaction was reacted in microwave at 140°C for 1 hour. After the reaction was completed, 10ml of ethyl acetate was added, then washed twice with 10ml of water and 10ml of saturated NaCl aqueous solution, and the organic phase was concentrated to obtain the title compound 11b (180mg, crude product) was used directly in the next step without further purification.

MS (ESI) m/z: 136.3 [M+H] ⁺ .

second step

N-(Benzo[c][1,2,5]oxadiazol-5-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-( Trifluoromethyl)-1H-pyrazole-4-carboxamide 11

Dissolve benzo[c][1,2,5]oxadiazol-5-amine 11b (50mg, 0.37mmol) in pyridine (3mL), and add 1-(1-oxo-1,2-bis Hydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (119mg, 0.37mmol), added phosphorus oxychloride (113mg, 0.74mmol) at room temperature, After reacting at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, purified by C18 reverse-phase column chromatography, and lyophilized to obtain the title compound 11 (8.3 mg, yield: 5%).

MS (ESI): m/z = 441.6 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ )δ 11.65(br s,1H),11.13(s,1H),8.54(s,2H),8.45(d,J=8.0Hz,1H),8.13(d, J=9.6Hz, 1H), 7.95(d, J=7.2Hz, 1H), 7.76-7.64(m, 2H), 7.31(br s, 1H), 5.67(d, J=7.6Hz, 1H).

Example 12

5-cyclopropyl-1-(isoquinolin-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide 12

first step

(Z)-2-(Cyclopropyl)-3-ethoxyethyl acrylate 12c

At room temperature, dissolve ethyl 3-cyclopropyl-3-oxopropionate (0.945mL, 6.403mmol) in acetic anhydride (1.8mL, 19mmol), slowly add triethyl orthoformate (2mL, 12mmol ), stirred at 130°C for 4h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the title compound 12c (2.2 g, yield: 80%), which was directly used in the next reaction without purification.

second step

5-Cyclopropyl-1-(isoquinolin-5-yl)-1H-pyrazole-4-carboxylic acid ethyl ester 12d

5-Hydrazinoisoquinoline 1b (0.60g, 3.769mmol) and ethyl (Z)-2-(cyclopropyl)-3-ethoxyacrylate 12c (0.8g, 3.769mmol) were dissolved in ethanol ( 10 mL), stirred at 60°C for 3 hours until the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether, ethyl acetate) to obtain the title product 12d (120 mg, yield: 10%).

MS (ESI) m/z: 308.0 [M+H] ⁺ .

third step

5-cyclopropyl-1-(isoquinolin-5-yl)-1H-pyrazole-4-carboxylic acid 12e

At room temperature, compound 12d (50 mg, 0.163 mmol) was dissolved in methanol (2 mL) and water (1 mL), and sodium hydroxide (13 mg, 0.325 mmol) was added. The reaction liquid was heated to 65° C. and stirred for 3 hours until the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (10 mL), adjusted to pH=5 with 1N hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 12e (40 mg, yield: 88%).

MS (ESI) m/z: 280.1 [M+H] ⁺ .

¹ H NMR(400MHz,CD ₃ OD)δ=9.43(s,1H),8.52(d,J=6.0Hz,1H),8.37(d,J=8.4Hz,1H),8.14(s,1H), 8.01-7.94(m,1H),7.88(t,J=7.6Hz,1H),7.30(d,J=6.0Hz,1H),1.92-1.80(m,1H),0.80-0.55(m,4H) .

the fourth step

5-cyclopropyl-1-(isoquinolin-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide 12

At room temperature, compound 12e (20mg, 0.072mmol), 2-(trifluoromethyl)pyridin-4-amine 3g (11.61mg, 0.072mmol) and pyridine (56.64mg, 0.716mmol) were dissolved in dichloromethane (2mL ), adding phosphorus oxychloride (11 mg, 0.072 mmol). The reaction was stirred at 25°C for 1 hour, then warmed to 50°C and continued for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate solution (0.1 mL) and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by preparative HPLC (acetonitrile/water) to give the title compound 12 (6 mg, yield: 29%).

MS (ESI) m/z; 424.1 [M+H] ⁺ .

Example 13

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-(6-(2-oxopyrrolidin-1-yl)-5-(trifluoromethyl)pyridine -3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 13

first step

5-nitro-3-(trifluoromethyl)pyridin-2-amine 13b

3-(Trifluoromethyl)pyridin-2-amine 13a (1 g, 6.169 mmol) was dissolved in concentrated H ₂ SO ₄ (10 mL), cooled to 0° C., and concentrated HNO ₃ (0.309 mL, 7.402 mmol) was slowly added dropwise ). React at 0°C for 1 hour, then react at 25°C for 3h until the reaction is complete. The reaction solution was poured into ice water (20 mL), extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with water (30 mL x 3), brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate/petroleum ether) to obtain the title compound 13a (1.0 g, 78%).

¹ H NMR (400MHz, DMSO- d6 ) δ ppm 9.04 (d, J=2.4Hz, 1H), 8.38 (d, J=2.4Hz, 1H), 7.91 (s, 2H).

second step

1-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one 13d

5-Nitro-3-(trifluoromethyl)pyridin-2-amine 13b (500mg, 2.414mmol) was dissolved in acetonitrile (10mL), slowly added chlorobutyryl chloride (0.545mL, 4.828mmol) and di Isopropylethylamine (1.197mL, 7.243mmol) was reacted at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-30% ethyl acetate/petroleum ether) to obtain the title compound 13d (100 mg, yield: 15%).

¹ H NMR (400MHz, CDCl ₃ ) δ ppm 9.44(d, J=2.4Hz, 1H), 8.83(d, J=2.4Hz, 1H), 4.05(t, J=7.2Hz, 2H), 2.67-2.59 (m,2H), 1.29-1.23(m,2H).

third step

1-[5-Amino-3-(trifluoromethyl)pyridin-2-yl]pyrrolidin-2-one 13e

1-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-2-one 13d (100 mg, 0.363 mmol) was dissolved in methanol (10 mL), and Pd was added under argon atmosphere /C 10% (39 mg, 0.363 mmol). After hydrogen replacement, react in a hydrogen atmosphere (15 psi) at room temperature until the reaction is complete. The insoluble matter was filtered off and concentrated under reduced pressure to obtain the title compound 13e (50 mg, yield: 56%). The product was directly used in the next step without purification.

MS (ESI) m/z: 246.1 [M+H] ⁺ .

the fourth step

1-(1-oxo-1,2-1,2-dihydroisoquinolin-5-yl)-N-(6-(2-oxopyrrolidin-1-yl)-5-(trifluoro Methyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 13

1-[5-Amino-3-(trifluoromethyl)pyridin-2-yl]pyrrolidin-2-one 13e (35mg, 0.143mmol), 1-(1-oxo-1,2-di Hydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1 g (46.14 mg, 0.143 mmol) and pyridine (0.115 mL, 1.427 mmol) were dissolved in dichloromethane (5mL), phosphorus oxychloride (0.013mL, 0.143mmol) was slowly added dropwise. The reaction was stirred at room temperature until the reaction was complete. The reaction solution was poured into saturated sodium bicarbonate solution (20 mL), and extracted with dichloromethane (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (22-42% acetonitrile-water) to obtain the title compound 13 (7.1 mg, yield: 9%).

MS (ESI) m/z: 551.2 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ ppm 9.06(d, J =2.4Hz,1H),8.74(d, J =2.4Hz,1H),8.57(d, J =8.0Hz,1H),8.35( s,1H),7.87(d, J =6.8Hz,1H),7.75-7.64(m,1H),7.25(d, J =7.2Hz,1H),5.93(d, J =7.6Hz,1H), 3.96-3.83 (m, 2H), 2.64-2.55 (m, 2H), 2.30 (quin, J =7.6Hz, 2H).

¹⁹ F NMR: (400 MHz, CD ₃ OD) δ ppm -58.204, -63.608.

Example 14

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 1H-1,2,3-triazole-4-formamide 14

first step

5-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)isoquinoline 2-oxide 14b

Dissolve ethyl 1-(isoquinolin-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate 14a (250 mg, 0.74 mmol) in dichloro methane (5 mL), m-chloroperoxybenzoic acid (385 mg, 2.23 mmol) was added, and reacted at room temperature for 3 hours. The reaction solution was diluted with 10ml of dichloromethane, washed with 2mmol/L sodium bisulfite (10mL), then washed with saturated sodium bicarbonate solution (10mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was purified by silica gel column chromatography with the eluent system ethyl acetate/n-hexane to obtain the title compound 14b (200 mg, yield: 76%).

MS (ESI): m/z = 337 [M+H] ⁺ .

second step

1-(1-Chloroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazole-carboxylic acid ethyl ester 14c

Compound 14b (200 mg, 0.57 mmol) was dissolved in phosphorus oxychloride (5 mL), and heated to reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 14c (210 mg, yield: 100%), which was used directly in the next step without further purification.

MS (ESI): m/z = 371 [M+H] ⁺ .

third step

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid 14d

Compound 14c (200 mg, 0.54 mmol) was dissolved in concentrated hydrochloric acid (8 mL), and heated to reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by C18 reverse-phase column chromatography and lyophilized to obtain the title compound 14d (95 mg, yield: 54%).

MS (ESI): m/z = 325 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO- _d6 )11.73(s,2H),8.74(d,J=5.6Hz,1H),8.53(d,J=8.0Hz,1H),8.45(d,J=2.0Hz, 1H), 8.20-8.15(m, 2H), 7.75(t, J=7.9Hz, 1H), 7.31(d, J=7.2Hz, 1H), 5.80(d, J=7.2Hz, 1H).

the fourth step

1-(1-carbonyl-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H -1,2,3-triazole-4-formamide 14

Compound 14d (30mg, 0.09mmol) was dissolved in pyridine (3mL), then 2-(trifluoromethyl)pyridin-4-amine 3g (15mg, 0.09mmol) was added, and phosphorus oxychloride (28mg , 0.18mmol), reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, purified by C18 reverse-phase column chromatography, and lyophilized to obtain the title compound 14 (10 mg, yield: 23%).

MS (ESI): m/z = 469 [M+H] ⁺ .

Example 15

N-(5-chloro-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline- 5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 15

first step

5-Chloro-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-amino 15c

1-Cyclopropylpyrazole-4-boronic acid pinacol esters 15a and 15b (200 mg, 0.85 mmol) were dissolved in dioxane (3 mL), and [1,1'-bis(diphenylphosphine) di Ferrocene] palladium dichloride dichloromethane complex (70mg, 0.085mmol) and potassium carbonate (236mg, 1.71mmol), microwave reaction for 1 hour. After the reaction was completed, 10 ml of ethyl acetate was added to dilute, then washed with water (10 mL), and then added with saturated NaCl aqueous solution (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with the eluent system ethyl acetate/n-hexane to obtain the title compound 15c (80 mg, yield: 40%).

MS (ESI): m/z = 235 [M+H] ⁺ .

second step

N-(5-chloro-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(1-carbonyl-1,2-dihydroisoquinoline-5 -yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 15

Compound 15c (30mg, 0.13mmol) was dissolved in pyridine (3mL), and 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) was added -1H-pyrazole-4-carboxylic acid 1g (41mg, 0.13mmol), add phosphorus oxychloride (39mg, 0.26mmol) at room temperature, and react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, purified by C18 reverse phase column chromatography, and lyophilized to obtain the title compound 15 (12 mg, yield: 17%).

MS (ESI): m/z = 540 [M+H] ⁺ .

Example 16

N-[5-chloro-6-(2,5-dihydrofuran-3-yl)pyridin-3-yl]-1-(1-oxo-1,2-dihydroisoquinolin-5-yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 16

first step

N-[5-chloro-6-(2,5-dihydrofuran-3-yl)pyridin-3-yl]-1-(1-oxo-1,2-dihydroisoquinolin-5-yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 16

Dissolve 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (59mL, 0.18mmol) In dichloromethane (3 mL), 2-chloro-1-methylpyridin-1-ium iodide (116 mg, 0.458 mmol), diisopropylethylamine (0.25 mL, 1.53 mmol) and 5 -Chloro-6-(2,5-dihydrofuran-3-yl)pyridin-3-amine (30mg, 0.15mmol), reacted at 45°C for 12 hours, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography, The title compound 16 (4.1 mg, yield: 5.3%) was obtained.

MS (ESI): m/z = 502.1 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ 11.63(d,J=5.2Hz,1H),11.04(s,1H),8.77(d,J=2.4Hz,1H),8.50(s,1H),8.46 -8.40(m,3H),7.97-7.92(m,1H),7.94(d,J=6.8Hz,1H),7.67(t,J=8.0Hz,1H),7.32-7.27(m,1H), 7.00(t, J=2.0Hz, 1H), 5.65(d, J=7.2Hz, 1H), 5.07-4.99(m, 2H), 4.86(t, J=4.0Hz, 2H).

Example 17

N-(5-chloro-6-(tetrahydrofuran-3-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(tri Fluoromethyl)-1H-pyrazole-4-carboxamide 17

first step

N-(5-chloro-6-(tetrahydrofuran-3-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(tri Fluoromethyl)-1H-pyrazole-4-carboxamide 17

N-[5-chloro-6-(2,5-dihydrofuran-3-yl)pyridin-3-yl]-1-(1-oxo-1,2-dihydroisoquinoline-5- Base)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 16 (50mg, 0.1mmol) was dissolved in methanol (6mL), palladium carbon (10%, 20mg) was added at room temperature, hydrogen Under atmosphere, stir at room temperature for 40 minutes. Filter through celite. The filtrate was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to obtain the title compound 17 (4.5 mg, yield: 8.9%).

MS (ESI): m/z = 503.4 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d6)δ 8.71(s,1H),8.46-8.40(m,2H),8.34(d,1H),7.97-7.92(m,1H),7.68-7.64(m,1H ), 7.32-7.27(m,1H), 5.65(d,1H), 4.09-4.05(m,1H), 3.91-3.75(m,5H), 2.50-2.2.20(m,2H).

Example 18

N-(5-chloro-6-(tetrahydrofuran-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(tri Fluoromethyl)-1H-pyrazole-4-carboxamide 18

first step

3-[(N,N-di-tert-butoxycarbonyl)amino]-1-chloro-pyridine 18b

5-Chloropyridin-3-amine 18a (500 mg, 3.89 mmol) was dissolved in tetrahydrofuran (8 mL), di-tert-butyl dicarbonate (2.49 mL, 11.67 mmol) and p-dimethylaminopyridine (23 mg, 0.19mmol), react at room temperature for 12 hours. Pour the reaction solution into water (15mL), extract with ethyl acetate (15mL*2), combine the organic phases, wash with saturated aqueous sodium chloride solution (20mL*2), dry over anhydrous sodium sulfate, concentrate under reduced pressure, pass through a silica gel column Chromatography afforded the title compound 18b (800 mg, yield: 62.5%).

¹ H NMR (400MHz, CDCl ₃ ) δ 8.51(s, 1H), 8.33(s, 1H), 7.54(t, J=2.0Hz, 1H), 1.45(s, 18H).

second step

2-(2-Epoxypentyl)-3-chloro-5-[(N,N-di-tert-butoxycarbonyl)amino]-pyridine 18c

Dissolve 3-[(N,N-di-tert-butoxycarbonyl)amino]-1-chloro-pyridine 18b (200mg, 0.61mmol) in dimethylsulfoxide (2mL), add 4-methyl Benzene-1-sulfonic acid (0.078mL, 0.49mmol), stirred at room temperature for 20 minutes, added tetrahydrofuran (2mL, 24.41mmol), ammonium peroxodisulfate (0.35mL, 3.04mmol) and two [2-(2,4 -Difluorophenyl)-5-trifluoromethylpyridine][2-2"-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (68mg, 0.061mmol), the reaction solution Degassed for 10 minutes and sealed. Under blue light irradiation, the reaction mixture was stirred at room temperature for 3 hours, water (20 mL) was added, extracted with ethyl acetate (20 mL*2), the organic phases were combined, washed with saturated aqueous sodium chloride solution, anhydrous sulfuric acid Dry over sodium, concentrate under reduced pressure, and separate the crude product by high performance liquid chromatography to obtain the title compound 18c (40 mg, yield: 16%).

¹ H NMR (400MHz, CDCl ₃ ) δ 8.34(d, J=2.0Hz, 1H), 7.51(d, J=2.0Hz, 1H), 5.40(t, J=6.8Hz, 1H), 4.28-4.16( m,1H), 4.08-3.94(m,1H), 2.44-2.32(m,1H), 2.19-1.95(m,3H), 1.44(s,18H).

third step

5-Chloro-6-(tetrahydrofuran-2-yl)pyridin-3-amine 18d

2-(2-Epoxypentyl)-3-chloro-5-[(N,N-di-tert-butoxycarbonyl)amino]-pyridine 18c (30 mg, 0.075 mmol) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (1.5 mL, 20.19 mmol) was added under ice-cooling. After reacting at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure to obtain the title compound 18d (14 mg, yield: 93%).

¹ H NMR (400MHz, CDCl ₃ )δ 8.01(d, J=2.4Hz, 1H), 6.98(d, J=2.4Hz, 1H), 5.37-5.22(m, 1H), 4.14(q, J=7.2 Hz, 1H), 3.93(dt, J=5.6, 7.6Hz, 1H), 2.31-1.92(m, 4H).

the fourth step

N-(5-chloro-6-(tetrahydrofuran-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(tri Fluoromethyl)-1H-pyrazole-4-carboxamide 18

Dissolve 5-chloro-6-(tetrahydrofuran-2-yl)pyridin-3-amine 18d (10mg, 0.05mmol) in tetrahydrofuran (1mL), add sodium hydride (10mL, 0.25mL) under ice-cooling, and then add 1- (1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-formyl chloride 21h (25mg, 0.073mmol) in tetrahydrofuran (1mL), reacted at room temperature for 12 hours, added water (15mL), extracted with ethyl acetate (15mL*2), combined the organic phases, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product The title compound 18 (1.8 mg, yield: 7.4%) was obtained by separation by high performance liquid chromatography.

MS (ESI): m/z = 504.1 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ 11.62(d,J=5.2Hz,1H),10.96(s,1H),8.75(d,J=2.0Hz,1H),8.49(s,1H),8.46 -8.39(m,1H),8.34(d,J=2.0Hz,1H),7.94(d,J=7.2Hz,1H),7.67(t,J=8.0Hz,1H),7.32-7.25(m, 1H), 5.65(d, J=7.6Hz, 1H), 5.26(t, J=6.8Hz, 1H), 3.93(q, J=7.2 Hz, 1H), 3.86-3.77(m, 1H), 2.22- 2.15(m,2H),2.10-2.02(m,1H),2.00-1.92(m,1H).

Example 19

N-(5-chloro-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl) -5-(Trifluoromethyl)-1H-pyrazole-4-carboxamide 19

first step

1-(3-Chloro-5-nitropyridin-2-yl)pyrrolidin-2-one 19b

2-Bromo-3-chloro-5-nitropyridine 19a (3.0g, 12.63mmol) was dissolved in 1,4-dioxane (25mL), and pyrrolidin-2-one (1.95mL, 25.27 mmol), methyl[2-(methylamino)ethyl]amine (0.27mL, 2.53mmol), potassium phosphate (5.36g, 25.27mmol) and copper iodide (0.086mL, 2.53mmol). Under nitrogen atmosphere, react at 110°C for 12 hours, cool to room temperature, add water (50mL), extract with ethyl acetate (80mL*3), combine organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is Silica gel column chromatography gave the title compound (1.0 g, yield: 32%).

MS (ESI): m/z = 242.0 [M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ 9.18(d,J=2.4Hz,1H),8.58(d,J=2.4Hz,1H),4.05(t,J=7.2Hz,2H),2.65(t, J=8.0Hz, 2H), 2.30(q, J=7.6Hz, 2H).

second step

1-(5-Amino-3-chloropyridin-2-yl)pyrrolidin-2-one 19c

Dissolve 1-(3-chloro-5-nitropyridin-2-yl)pyrrolidin-2-one 19b (1.0g, 4.14mmol) in ethanol/water (20mL/5mL), add ammonium chloride ( 2.21g, 41.3mmol) and iron powder (1.16g, 20.6mmol), reacted at 90°C for 1 hour, cooled to room temperature, filtered through diatomaceous earth, and concentrated the filtrate under reduced pressure to obtain the title compound 19c (800mg, yield: 91.3%).

MS (ESI): m/z = 212.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d6)δ 7.75(d,J=2.8Hz,1H),7.08(d,J=2.8Hz,1H),5.79-5.67(m,2H),3.65(t,J= 7.2Hz, 2H), 2.41-2.33(m, 2H), 2.15-2.04(m, 2H).

third step

N-(5-chloro-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl) -5-(Trifluoromethyl)-1H-pyrazole-4-carboxamide 19

Dissolve 1-(5-amino-3-chloropyridin-2-yl)pyrrolidin-2-one 19c (61mg, 0.29mmol) in tetrahydrofuran (4mL), add sodium hydride (58mg, 1.46mmol) at 0°C And 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-formyl chloride 21h (100mg, 0.29mmol) tetrahydrofuran solution (4 mL). After reacting at room temperature for 1 hour, the reaction solution was stirred at 60°C for another 1 hour, cooled to room temperature, slowly added saturated aqueous ammonium chloride solution (30 mL) to quench the reaction, and extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to obtain the title compound 19 (55 mg, yield: 37%).

MS (ESI): m/z = 571.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- d6 )δ 11.63(s,1H),11.02(s,1H),8.71(d, J =2.4Hz,1H),8.50(s,1H),8.47-8.38(m, 2H), 7.94(d, J =6.8Hz, 1H), 7.67(t, J =7.6Hz, 1H), 7.29(d, J =7.2Hz, 1H), 5.65(d, J =7.2Hz, 1H) ,3.86-3.77(m,2H),2.49-2.43(m,2H),2.16(q, J =7.2Hz,2H).

Example 20

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)pyridin-2-yl)- 1H-pyrazole-4-carboxamide 20

first step

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)pyridin-2-yl)- 1H-pyrazole-4-carboxamide 20

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (60mg, 0.19mmol) and 3g (30mg, 0.19mmol) of 4- (trifluoromethyl)pyridin-2-amine was dissolved in pyridine (6mL), and phosphorus oxychloride (0.035mL, 0.37mmol) was added dropwise, reacted at room temperature for 1 hour, and added Water (10 mL), extracted with dichloromethane (15 mL*3), the organic phase was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to obtain the title compound 20 (31 mg, yield: 35%).

MS (ESI): m/z = 468.6 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ=11.68(s,1H),11.62(d,J=5.0Hz,1H),8.71(d,J=5.0Hz,1H),8.51(d,J= 7.0Hz, 2H), 8.44(d, J=8.0Hz, 1H), 7.94(d, J=7.5Hz, 1H), 7.67(t, J=7.8Hz, 1H), 7.59(d, J=5.0Hz ,1H),7.30~7.27(m,1H),5.72(d,J=7.3Hz,1H).

Example 21

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyridazin-4-yl) -1H-pyrazole-4-carboxamide 21

first step

Methyl 6-iodopyridazine-4-carboxylate 21b

To a mixture of methyl 6-chloropyridazine-4-carboxylate (2 g, 11.589 mmol) in hydroiodic acid (20 mL) was added sodium iodide (2.61 g, 17.384 mmol). Stir at 50°C for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was adjusted to pH=7 with saturated aqueous sodium bicarbonate and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound 21b (740 mg, yield: 87%).

MS (ESI) m/z = 264.9 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ ppm 9.52(d, J =1.6Hz, 1H), 8.30(d, J =2.0Hz, 1H), 3.95(s, 3H).

second step

Methyl 6-(trifluoromethyl)pyridazine-4-carboxylate 21d

Methyl 6-iodopyridazine-4-carboxylate (600mg, 2.273mmol) and 21c (639mg, 2.046mmol) were dissolved in N,N-dimethylformamide (5ml), and the mixture was under nitrogen atmosphere Microwave heated to 110°C for 4 hours. The reaction mixture was quenched slowly with water (10 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2) and water (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile solvent: 0~15% ethyl acetate/petroleum ether gradient 30ml/min) to obtain 6-(trifluoromethyl)pyridazine-4-carboxylic acid methyl ester 21d (210 mg, yield: 44.8%).

MS (ESI) m/z: 207.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.88 (d, J =1.6Hz, 1H), 8.35 (d, J =2.0Hz, 1H), 4.10 (s, 3H).

third step

6-(Trifluoromethyl)pyridazine-4-carboxylic acid 21e

To a mixture of methyl 6-(trifluoromethyl)pyridazine-4-carboxylate (270 mg, 1.310 mmol) in tetrahydrofuran (4 mL) and water (2 mL) was added lithium hydroxide (164 mg, 3.930 mmol). The mixture was stirred at 20°C for 1 hour, and the mixture was adjusted to pH=5 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-(trifluoromethyl)pyridazine-4-carboxylic acid 21e (220 mg, yield: 87% ).

MS (ESI) m/z = 193.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.84 (d, J=1.6Hz, 1H), 8.45 (d, J=2.0Hz, 1H).

the fourth step

tertiary butyl N-[6-(trifluoromethyl)pyridazin-4-yl]aminocarboxylate 21f

To a mixture of 6-(trifluoromethyl)pyridazine-4-carboxylic acid (210 mg, 1.093 mmol) in tert-butanol (5 ml) was added diphenylphosphoryl azide (DPPA) (0.284 ml, 1.312 mmol) and triethylamine (0.228ml, 1.640mmol). The mixture was stirred at 90°C for 12 hours. The reaction mixture was concentrated under reduced pressure, water (10 ml) was added, and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: 0~30% ethyl acetate/petroleum ether) to obtain N-[6-(trifluoromethyl)pyridazin-4-yl]aminocarboxylic acid Tributyl ester 21f (140 mg, yield: 43.79%).

MS (ESI) m/z = 264.1 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ ppm 9.18 (d, J =2.4Hz, 1H), 8.31 (d, J =2.4Hz, 1H), 7.17 (br s, 1H), 1.58 (s, 9H).

the fifth step

6-(trifluoromethyl)pyridazin-4-amine 21g

To a mixture of tert-butyl N-[6-(trifluoromethyl)pyridazin-4-yl]aminocarboxylate (140mg, 0.532mmol) in dichloromethane (2ml) was added trifluoroacetic acid (1ml) . Reaction at room temperature, TLC (PE/EA=3:1) showed that the reaction was complete. The reaction mixture was adjusted to pH=8 with 1N aqueous sodium hydroxide solution, extracted with dichloromethane (10 mL x 3), the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 6 -(trifluoromethyl)pyridazin-4-amine 21 g (100 mg, yield: 97%).

MS (ESI) m/z = 164.1 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ ppm 8.70 (d, J =2.4Hz, 1H), 7.03 (s, 2H), 6.97 (d, J =2.4Hz, 1H).

step six

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-formyl chloride 21h

0°C, to 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (100mg, 0.309 mmol) in dichloromethane (2ml) was added oxalyl chloride (0.040ml, 0.464mmol) and DMF (0.002ml, 0.031mmol). The mixture was stirred at 20°C for 1 hour and concentrated under reduced pressure to give 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole- 4-Formyl chloride (100 mg, yield: 94%) was directly used in the next step without further purification.

MS (ESI) m/z = 338.0 [M+H] ⁺ .

step seven

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[6-(trifluoromethyl)pyridazin-4-yl] -1H-pyrazole-4-carboxamide 21

To a solution of 21 g (25 mg, 0.153 mmol) of 6-(trifluoromethyl)pyridazin-4-amine in tetrahydrofuran (2 ml) was added sodium hydride (30.66 mg, 0.766 mmol) at 0°C. At 0°C, 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-formyl chloride was added for 21h (52.37 mg, 0.153mmol) in THF (2ml). The reaction was slowly quenched by adding saturated aqueous ammonium chloride (10 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (conditions: water (0.1% formic acid)-acetonitrile;) to give 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5- (Trifluoromethyl)-N-[6-(trifluoromethyl)pyridazin-4-yl]-1H-pyrazole-4-carboxamide 21 (6 mg, yield: 15%).

MS (ESI) m/z = 469.1 [M+H] ⁺ .

¹ H NMR: (400MHz,DMSO- d ₆ )δ ppm 11.66(d, J =5.6Hz,1H),11.57(s,1H),9.65(d, J =2.0Hz,1H),8.57(s,1H ),8.54-8.50(m,1H),8.45(d, J =8.0Hz,1H),7.98(d, J =7.6Hz,1H),7.73-7.64(m,1H),7.31(t, J = 6.8Hz, 1H), 5.65(d, J =7.2Hz, 1H).

Example 22

1-(1-thio-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyridazin-4-yl) -1H-pyrazole-4-carboxamide 22

first step

1-(1-thio-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyridazin-4-yl) -1H-pyrazole-4-carboxamide 22

1-(1-thio-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 7a (60mg, 0.18mmol) and 6-(Trifluoromethyl)pyridazin-4-amine 22a (28.84mg, 0.18mmol) was dissolved in pyridine (6mL), phosphorus oxychloride (0.033mL, 0.35mmol) was added at room temperature, and reacted at 60°C for 2 hours , cooled to room temperature, added saturated aqueous sodium bicarbonate solution (15mL), extracted with dichloromethane (15mL*3), the organic phase was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to obtain the title compound 22 (16mg, yield rate: 18%).

MS (ESI): m/z = 485.2 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ 9.64(d,J=2.4Hz,1H),9.02(d,J=8.4Hz,1H),8.58(s,1H),8.52(d,J=2.4 Hz, 1H), 8.10~8.08(m, 1H), 7.80(t, J=7.1Hz, 1H), 7.52(d, J=7.1Hz, 1H), 6.15(d, J=7.1Hz, 1H).

Example 23

N-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoro Methyl)-1H-pyrazole-4-carboxamide 23

first step

N-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoro Methyl)-1H-pyrazole-4-carboxamide 23

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (300mg, 0.93mmol) and 2-Chloro-6-(trifluoromethyl)pyridin-4-amine 23a (182.43mg, 0.93mmol) was dissolved in pyridine (10mL), and phosphorus oxychloride (0.17mL, 1.86mmol) was added at room temperature. React for 1 hour, add saturated aqueous sodium bicarbonate (20 mL), extract with dichloromethane (20 mL*3), and concentrate the organic phase under reduced pressure. The residue is separated by high performance liquid chromatography to obtain the title compound 23 (300 mg, yield: 64%).

MS (ESI): m/z = 502.6 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ 11.64(br d,J=5.2Hz,1H),11.41(br s,1H),8.54(s,1H),8.44(d,J=8.0Hz,1H ),8.17~8.10(m,2H),7.99~7.93(m,1H),7.67(t,J=8.0Hz,1H),7.32~7.27(m,1H),5.64(d,J=7.2Hz, 1H).

Example 24

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-4- base)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 24

first step

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-4- base)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 24

N-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(tri Fluoromethyl)-1H-pyrazole-4-carboxamide 23 (157mg, 0.31mmol) was dissolved in dioxane/water (12mL/4mL), and bisdibenzylideneacetone palladium (359.83mg, 0.63mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (26.57mg, 0.063mmol) and potassium hydroxide (35.11mg, 0.63mmol). Reaction was carried out at 115°C for 1 hour, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 24 (36 mg, yield: 23%).

MS (ESI): m/z = 484.3 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ 11.63(s,1H),11.07(s,1H),8.50(s,1H),8.44(d,J=8.0Hz,1H),7.94(d,J =6.8Hz, 1H), 7.67(t, J=7.8Hz, 1H), 7.63(s, 1H), 7.36-7.25(m, 2H), 5.65(d, J=7.3Hz, 1H).

Example 25

N-(Benzo[c][1,2,5]thiadiazol-5-yl-1-(1-oxo-1,2-dihydroisoquinolin-5-yl-5-trifluoromethane base)-1H-pyrazole-4-carboxamide 25

first step

N-(Benzo[c][1,2,5]thiadiazol-5-yl-1-(1-oxo-1,2-dihydroisoquinolin-5-yl-5-trifluoromethane base)-1H-pyrazole-4-carboxamide 25

Dissolve 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (50mg, 0.16mmol) In pyridine (3mL), add benzo[c][1,2,5]thiadiazol-5-amine 25a (28mg, 0.19mmol) and phosphorus oxychloride (47mg, 0.31mmol), room temperature reaction 2 Hour. The reaction solution was concentrated under reduced pressure, and purified by preparative high performance liquid chromatography to obtain the title compound 25 (24 mg, yield: 34%).

MS (ESI): m/z = 457.2 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- _d6 )δ 11.63(d,J=5.8Hz,1H),11.01(s,1H),8.66(d,J=1.6Hz,1H),8.53(s,1H),8.45 (d,J=8.0Hz,1H),8.12(d,J=9.4Hz,1H),7.98-7.87(m,2H),7.68(t,J=7.9Hz,1H),7.38-7.25(m, 1H), 5.68 (d, J=7.3Hz, 1H).

Example 26

N-(Benzo[c][1,2,5]oxadiazol-5-yl)-1-(1-thio-1,2-dihydroisoquinolin-5-yl)-5-( Trifluoromethyl)-1H-pyrazole-4-carboxamide 26

first step

N-(Benzo[c][1,2,5]oxadiazol-5-yl)-1-(1-sulfoxy-1,2-dihydroisoquinolin-5-yl)-5- (Trifluoromethyl)-1H-pyrazole-4-carboxamide 26

1-(1-thiol-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 7a (52mg, 0.15mmol) and Benzo[c][1,2,5]oxadiazol-5-amine 11b (31mg, 0.23mmol) was dissolved in pyridine (6mL), and phosphorus oxychloride (0.029mL, 0.31mmol) was added at room temperature. After the warm reaction is complete, add saturated aqueous sodium bicarbonate (15 mL), extract with dichloromethane (15 mL*3), and concentrate the organic phase under reduced pressure. The residue is purified by high performance liquid chromatography to obtain the title compound 26 (2.5 mg, yield rate: 3.5%).

MS (ESI): m/z = 457.2 [M+H] ⁺ .

Example 27

N-(1,3-dihydroisobenzofuran-5-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-trifluoromethyl-1H -Pyrazole-4-carboxamide 27

first step

N-(1,3-dihydroisobenzofuran-5-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-trifluoromethyl-1H -Pyrazole-4-carboxamide 27

Dissolve 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (50mg, 0.16mmol) In pyridine (3 mL), add 1,3-dihydroisobenzofuran-5-amine 27a (25 mg, 0.19 mmol) and phosphorus oxychloride (47 mg, 0.31 mmol), and react at room temperature for 2 hours. The reaction solution was concentrated and purified by reverse phase C18 column chromatography to obtain the title compound 27 (30 mg, yield: 44%).

MS (ESI): m/z = 441.3 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ 11.62(d,J=5.0Hz,1H),10.60(s,1H),8.46-8.41(m,2H),7.91(d,J=7.3Hz,1H ),7.76(s,1H),7.67(t,J=7.9Hz,1H),7.54(d,J=8.0Hz,1H),7.33-7.26(m,2H),5.67(d,J=7.3Hz ,1H),5.00(d,J=11.8Hz,4H).

Example 28

N-(3-chloro-4-(methylsulfinyl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl )-1H-pyrazole-4-carboxamide 28

first step

3-Chloro-4-methylsulfinylaniline 28b

Dissolve 2-chloro-1-methanesulfinyl-4-nitrobenzene 28a (300mg, 1.37mmol) in ethanol/water (10mL/2mL), add iron powder (381mg, 6.83mmol) and chloride at room temperature Ammonium (730mg, 13.66mmol), react at 90°C for 1 hour. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (15 mL), washed with water (15 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was passed through a silicone tube Purification by column chromatography afforded the title compound 28b (130 mg, yield: 50%).

MS (ESI): m/z = 190.0 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ 7.45(d,J=8.8Hz,1H),6.71(dd,J=2.0,8.4Hz,1H),6.64(d,J=2.0Hz,1H),5.95 (s,2H),2.66(s,3H).

second step

N-(3-chloro-4-(methylsulfonyl)phenyl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -1H-pyrazole-4-carboxamide 28

3-Chloro-4-methylsulfinylaniline 28b (130mg, 0.68mmol) was dissolved in tetrahydrofuran (1mL), and diisopropylethylamine (0.34mL, 2.056mmol) and 1-( 1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-formyl chloride (281mg, 0.82mmol) in tetrahydrofuran (1mL ), reacted overnight at room temperature, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound 28 (100 mg, yield: 26.5%).

MS (ESI): m/z = 495.0 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ 11.64(d,J=5.6Hz,1H),10.98(s,1H),8.49(s,1H),8.44(d,J=8.0Hz,1H),8.05 (d,J=2.0Hz,1H),7.96-7.90(m,2H),7.87-7.83(m,1H),7.67(t,J=8.0Hz,1H),7.30(dd,J=6.1,7.2 Hz, 1H), 5.66(d, J=7.2Hz, 1H), 2.80(s, 3H).

Example 29

N-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-( Trifluoromethyl)-1H-pyrazole-4-carboxamide 29

first step

5-Bromo-2-(trifluoromethyl)pyridin-4-amine 29a

2-(trifluoromethyl)pyridin-4-amine 3g (500mg, 3.084mmol) was dissolved in dichloromethane (10mL), and N-chlorobutanediimide (NBS) (548mg, 3.084mmol) was added at room temperature ), under nitrogen atmosphere, reacted at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound 29a (790 mg, yield: 95.6%).

MS (ESI): m/z = 241.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) 8.41 (s, 1H), 6.93 (s, 1H), 4.84 (s, 2H).

second step

5-methoxy-2-(trifluoromethyl)pyridin-4-amine 29b

Dissolve 2-bromo-5-(trifluoromethyl)aniline 29a (190mg, 0.792mmol) in methanol (10mL), add copper (123mg, 1.95mmol) and sodium methoxide (1216mg, 8.333mmol) at room temperature, 100 After reacting at ℃ for 18 hours, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound 29b (20 mg, yield: 5.3%).

MS (ESI): m/z = 193.1 [M+H] ⁺ .

third step

N-[5-methoxy-2-(trifluoromethyl)pyridin-4-yl]-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-( Trifluoromethyl)-1H-pyrazole-4-carboxamide 29

Mix 5-methoxy-2-(trifluoromethyl)pyridin-4-amine 29b (20mg, 0.104mmol) and 1-(1-oxo-1,2-dihydroisoquinolin-5-yl) -5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (33.65mg, 0.104mmol) was dissolved in pyridine (6mL), and phosphorus oxychloride (0.029mL, 0.312mmol) was added at room temperature, Reacted at 25°C for 16 hours, concentrated under reduced pressure, and the residue was separated and purified by high performance liquid chromatography to obtain the title compound 29 (7 mg, yield: 13.52%).

MS (ESI): m/z = 498.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- _d6 )δ 11.74-11.55(m,1H),10.60-10.29(m,1H),8.60(d,J=4.8Hz,2H),8.50-8.36(m,2H), 7.93(d, J=7.2Hz, 1H), 7.68(t, J=7.8Hz, 1H), 7.34-7.21(m, 1H), 5.78-5.75(m, 1H), 4.09(s, 3H).

Example 30

N-(6-Acetamido-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5- Trifluoromethyl-1H-pyrazole-4-carboxamide 30

first step

5-nitro-3-(trifluoromethyl)pyridin-2-amine 30b

2-Chloro-5-nitro-3-(trifluoromethyl)pyridine 30a (1g, 4.41mmol) was added into methanol solution of ammonia (7M, 9.46mL), reacted at room temperature for 14 hours, and the reaction solution was concentrated under reduced pressure. The residue was diluted with water (40 mL), extracted with ethyl acetate (40 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 30b (900 mg, yield: 98.4%).

¹ H NMR (400MHz, DMSO-d6) δ 9.05 (d, J=2.4Hz, 1H), 8.39 (d, J=2.8Hz, 1H), 8.09 (s, 2H).

second step

N-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetamide 30c

5-nitro-3-(trifluoromethyl)pyridin-2-amine 30b (0.19mL, 1.45mmol) was dissolved in dichloromethane (3mL), and triethylamine (0.40mL, 2.90mmol) was added at room temperature and p-dimethylaminopyridine (194mL, 1.59mmol), then add acetyl chloride (0.11mL, 1.59mmol) under ice-cooling, react at room temperature for 1 hour, add water (30mL) to the reaction solution, and extract with ethyl acetate (30mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound 30c (300mg, yield: 83%).

¹ H NMR (400MHz, DMSO-d6) δ 10.73(s, 1H), 9.47(d, J=2.4Hz, 1H), 8.84(d, J=2.8Hz, 1H), 2.14(s, 3H).

third step

N-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)acetamide 30d

Dissolve N-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetamide 30c (240mg, 0.96mmol) in ethanol/water (5mL/1.5mL), add chloride at room temperature Ammonium (0.042mL, 1.20mmol) and iron powder (0.034mL, 4.82mmol) were reacted at 90°C for 1 hour. Cool to room temperature, add water (50mL) to the reaction solution, extract with ethyl acetate (50mL*2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound 30d (200mg, yield: 94%).

¹ H NMR (400MHz, DMSO-d6) 9.62(s, 1H), 7.99(d, J=2.8Hz, 1H), 7.25(d, J=2.8Hz, 1H), 5.81(s, 2H), 1.91( s, 3H).

the fourth step

N-(6-Acetamido-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5- Trifluoromethyl-1H-pyrazole-4-carboxamide 30

Dissolve N-[5-amino-3-(trifluoromethyl)pyridin-2-yl]acetamide 30d (35mg, 0.16mmol) in tetrahydrofuran (3mL), add sodium hydride (17mg, 0.73mmol), after 10 minutes, add 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-formyl Chlorine 1g (50mg, 0.15mmol), under nitrogen atmosphere, react at room temperature for 2 hours, add ammonium chloride (10mL) under ice bath, extract with ethyl acetate (30mL*2), combine organic phases, dry over anhydrous sodium sulfate, After filtration, the filtrate was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to obtain the title compound 30 (8.6 mg, yield: 11%).

MS (ESI): m/z = 525.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6) 11.63(d, J=6.0Hz, 1H), 11.09(s, 1H), 10.16(s, 1H), 8.99(d, J=2.4Hz, 1H), 8.59( d,J=2.4Hz,1H),8.51(s,1H),8.44(d,J=8.0Hz,1H),7.95(d,J=6.8Hz,1H),7.67(t,J=8.0Hz, 1H), 7.36-7.23(m, 1H), 5.65(d, J=7.6Hz, 1H), 2.03(s, 3H).

Example 31

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-(6-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 31

first step

5-nitro-2-(pyrrolidin-1-yl)-3-(trifluoromethyl)pyridine 31c

2-Chloro-5-nitro-3-(trifluoromethyl)pyridine 31a (129mg, 0.57mmol) was dissolved in N,N-dimethylformamide (7mL), and tetrahydropyrrole 31b was added at room temperature ( 0.7mL, 0.85mmol) and cesium carbonate (371mg, 1.14mmol). React at room temperature for 3 hours, add water (15 mL) to the reaction solution, and extract with ethyl acetate (15 mL*3). The organic phases were combined, washed with saturated aqueous sodium chloride, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound 31c (100 mg, yield: 67%).

MS (ESI): m/z = 262.2 [M+H] ⁺ .

second step

6-(Pyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-3-amine 31d

Dissolve 5-nitro-2-(pyrrolidin-1-yl)-3-(trifluoromethyl)pyridine 31c (100mg, 0.38mmol) in ethanol/water (6mL/2mL), add iron powder ( 213mg, 3.8mmol) and ammonium chloride (206mg, 3.83mmol). React at 80°C for 2 hours, filter the reaction solution through diatomaceous earth, add water (15 mL) to the filtrate, and extract with ethyl acetate (15 mL*3). The organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound 31d (49 mg, yield: 55%).

MS (ESI): m/z = 232.2 [M+H] ⁺ .

third step

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-(6-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl )-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 31

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (68mg, 0.21mmol) 1g and 6-(Pyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-3-amine 31d (49mg, 0.21mmol) was dissolved in pyridine (5mL), and phosphorus oxychloride (0.42mmol, 0.04mL), reacted at room temperature for 1 hour, added saturated aqueous sodium bicarbonate (10mL), extracted with dichloromethane (10mL*3), concentrated the organic phase under reduced pressure, and separated and purified the residue by high performance liquid chromatography to obtain the title compound 31 (5.6 mg, yield: 4.93%).

MS (ESI): m/z = 537.3 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ 11.63(s,1H),10.64(s,1H),8.61(d,J=2.5Hz,1H),8.43(d,J=5Hz,2H),8.32 (d,J=2.5Hz,1H),7.94~7.92(m,1H),7.67(t,J=7.9Hz,1H),7.31~7.28(m,1H),5.64(d,J=7.3Hz, 1H), 3.52~3.49(m,4H), 1.93~1.89(m,4H).

Example 32

N-(2-(1,1-difluoroethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoro Methyl)-1H-pyrazole-4-carboxamide 32

first step

4-chloro-2-(1,l-difluoroethyl)pyridine 32b

Dissolve 1-(4-chloropyridin-2-yl)ethan-1-one 32a (0.24mL, 1.928mmol) in dichloromethane (5mL), add diethylaminosulfur trifluoride DAST under ice-cooling (2.54mL, 19mmol), react at 25°C for 12 hours. Add saturated aqueous sodium bicarbonate solution (30 mL), extract with dichloromethane (20 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography to obtain the title compound 32b (30 mg, yield: 8.7%).

¹ H NMR (400MHz, CDCl ₃ ) δ 8.55(d, J=5.2Hz, 1H), 7.68(d, J=2.0Hz, 1H), 7.38(dd, J=2.0, 5.2Hz, 1H), 2.02( t,J=18.8Hz,3H).

second step

tertiary butyl N-[2-(1,1-difluoroethyl)pyridin-4-yl]carbamate 32c

4-Chloro-2-(1,1-difluoroethyl)pyridine 32b (90 mg, 0.507 mmol) and tert-butyl carbamate (71 mg, 0.608 mmol) were dissolved in 1,4-dioxane (3 mL ), add 2-dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (16mg, 0.051mmol), cesium carbonate (247mg, 0.76mmol) and palladium acetate (11mg, 0.051mmol) at room temperature. Microwave reaction at 80°C for 2 hours, cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound 32c (130 mg, yield: 89%).

¹ H NMR (400MHz, CDCl ₃ )δ 8.46(d, J=5.6Hz, 1H), 7.62(d, J=2.0Hz, 1H), 7.46(dd, J=2.0, 5.6Hz, 1H), 7.14( br.s,1H),1.99(t,J=18.8Hz,4H),1.46(s,9H).

third step

2-(1,1-Difluoroethyl)pyridin-4-amine 32d

Dissolve tert-butyl N-[2-(1,1-difluoroethyl)pyridin-4-yl]carbamate (70mg, 0.271mmol) in dichloromethane (3mL), add three Fluoroacetic acid (1mL, 13.463mmol), reacted at 25°C for 12 hours, concentrated under reduced pressure, poured the residue into saturated aqueous sodium bicarbonate solution (15mL), extracted with dichloromethane (15mL*3), combined the organic phases, and Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound 32d (30 mg, yield: 69%).

¹ H NMR (400MHz, CDCl ₃ ) δ 8.26(d, J=6.0Hz, 1H), 6.89(d, J=2.4Hz, 1H), 6.57(d, J=3.2Hz, 1H), 2.07-2.01( m,3H).

the fourth step

N-(2-(1,1-difluoroethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoro Methyl)-1H-pyrazole-4-carboxamide 32

2-(1,1-difluoroethyl)pyridin-4-amine 32d (45mg, 0.285mmol) was dissolved in tetrahydrofuran (2mL), and sodium hydride (56mg, 1.423mmol) and 1 -(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-formyl chloride 21h (97.22mg, 0.285mmol) THF solution, react at 60°C for 12 hours, slowly add saturated ammonium chloride aqueous solution (10mL) dropwise to quench the reaction, extract with ethyl acetate (20mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and decompress the filtrate After concentration, the residue was separated and purified by high performance liquid chromatography to obtain the title compound 32 (11 mg, yield: 8.7%).

MS (ESI): m/z = 464.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- _d6 )δ 11.64(d,J=5.2Hz,1H),11.11(s,1H),8.61(d,J=5.6Hz,1H),8.52(s,1H),8.45 (d,J=8.0Hz,1H),8.08(d,J=2.0Hz,1H),7.95(d,J=6.4Hz,1H),7.85(dd,J=2.0,5.6Hz,1H),7.68 (t, J=8.0Hz, 1H), 7.30(dd, J=6.0, 7.2Hz, 1H), 5.66(d, J=7.2Hz, 1H), 2.01(t, J=19.2Hz, 3H).

Example 33

N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(tri Fluoromethyl)-1H-pyrazole-4-carboxamide 33

first step

3-Chloro-2-(difluoromethoxy)-5-nitropyridine 33c

3-Chloro-5-nitropyridin-2-ol 33a (354 mg, 2.03 mmol) was dissolved in acetonitrile (15 mL), and sodium hydride (219 mg, 5.48 mmol, 60%) was added at room temperature. Under nitrogen atmosphere, after reacting at room temperature for 10 minutes, 2,2-difluoro-2-(fluorosulfonyl)acetic acid 33b (632 mg, 3.55 mmol) was added, and the reaction was continued at room temperature for 20 minutes. Water (15 mL) was added under ice cooling, extracted with ethyl acetate (20 mL*3), the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound 33c (267 mg, yield: 58%).

second step

5-Chloro-6-(difluoromethoxy)pyridin-3-amine 33d

Dissolve 3-chloro-2-(difluoromethoxy)-5-nitropyridine 33c (267mg, 1.19mmol) in acetic acid (10mL), add iron powder (664mg, 11.89mmol) at room temperature, and react at room temperature After 3 hours, the reaction solution was concentrated under reduced pressure, dichloromethane (15 mL) was dissolved, filtered through diatomaceous earth, washed with saturated sodium bicarbonate solution, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound 33d (214 mg, yield: 92.5%).

MS (ESI): m/z = 195.1 [M+H] ⁺ .

third step

N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(tri Fluoromethyl)-1H-pyrazole-4-carboxamide 33

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (73mg, 0.23mmol) and 5-Chloro-6-(difluoromethoxy)pyridin-3-amine 33d (44mg, 0.23mmol) was dissolved in pyridine (7mL), and phosphorus oxychloride (0.042mL, 0.45mmol) was added at room temperature. React for 1 hour, add saturated aqueous sodium bicarbonate (10 mL), extract with dichloromethane (10 mL*3), and concentrate the organic phase under reduced pressure. The residue is separated by high performance liquid chromatography to obtain the title compound 33 (10.8 mg, yield :9%).

MS (ESI): m/z = 500.2 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ 11.63(s,1H),10.96(s,1H),8.50(d,J=2.4Hz,1H),8.49(s,1H),8.47(d,J =2.3Hz,1H),8.46~8.43(m,1H),7.95~7.93(m,1H),7.73(t,J=66.6Hz,1H),7.68(t,J=7.9Hz,1H),7.31 ~7.28(m,1H),5.64(d,J=7.4Hz,1H).

Example 34

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-(6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridin-3-yl) -5-Trifluoromethyl-1H-pyrazole-4-carboxamide 34

first step

(5-(trifluoromethyl)pyridin-3-yl)aminocarboxylic acid tert-butyl ester 34b

Dissolve 5-trifluoromethylpyridin-3-amine 34a (0.15mL, 1.23mmol) in tetrahydrofuran (3mL), add ditert-butyl dicarbonate (0.79mL, 3.70mmol) and p-dimethylamino Pyridine (7.5mg, 0.062mmol), react at room temperature for 16 hours, pour the reaction solution into water (20mL), extract with ethyl acetate (20mL*2), combine the organic phases, wash with saturated aqueous sodium chloride (20mL*2 ), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated and purified by silica gel column chromatography to obtain the title compound 34b (250 mg, yield: 77.2%).

¹ H NMR (400MHz, CDCl ₃ ) δ 8.61(d, J=2.0Hz, 1H), 8.55(s, 1H), 8.39(s, 1H), 7.26(s, 1H), 1.54(s, 9H).

second step

(6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridin-3-yl)tert-butyl carbamate 34c

Dissolve tert-butyl (5-(trifluoromethyl)pyridin-3-yl)aminocarboxylate 34b (180mg, 0.69mmol) in dimethylsulfoxide (2mL), add 4-methylbenzene at room temperature -1-sulfonic acid (0.088mL, 0.55mmol), tetrahydrofuran (3.38mL, 41.18mmol), O-[(sulfoperoxy)sulfo]diammonium oxide (0.40mL, 3.43mmol) and [4,4 ' -bis(1,1-dimethylethyl)-2,2 ' -bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2 -Pyridyl N]phenyl-C]iridium(III) hexafluorophosphate (77mg, 0.069mmol), under blue light irradiation, the reaction mixture was stirred at room temperature for 12 hours. Add water (30mL) to the reaction solution, extract with ethyl acetate (30mL*2), combine the organic phases, wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and the residue is subjected to silica gel column chromatography Separation and purification by method to obtain the title compound 34c (90 mg, yield: 39%).

¹ H NMR (400MHz, CDCl ₃ ) δ 8.85-8.70(m, 2H), 8.42(d, J=1.2Hz, 1H), 5.13(t, J=7.6Hz, 1H), 4.03(t, J=6.8 Hz, 2H), 2.53-2.42(m, 1H), 2.41-2.31(m, 1H), 2.14-2.06(m, 2H), 1.54(s, 9H).

third step

6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridin-3-amine 34d

Tert-butyl (6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridin-3-yl)carbamate 34c (80 mg, 0.24 mmol) was dissolved in dichloromethane (1.5 mL) , trifluoroacetic acid (0.5 mL, 6.73 mmol) was added under ice-cooling. React at room temperature for 1 hour, add saturated sodium bicarbonate solution (10 mL) under ice-cooling, extract with dichloromethane (30 mL*2), combine the organic phases, and concentrate the reaction solution under reduced pressure to obtain the title compound 34d (50 mg, yield: 89 %).

MS (ESI): m/z = 233.1 [M+H] ⁺ .

the fourth step

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-(6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridin-3-yl) -5-(Trifluoromethyl)-1H-pyrazole-4-carboxamide 34

Mix 6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridin-3-amine 34d (18 mg, 0.078 mmol) and 1-(1-oxo-1,2-dihydroisoquinoline- 5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-formyl chloride 21h (27.56mg, 0.085mmol) was dissolved in dichloromethane (2mL), and pyridine (0.063mL, 0.77mmol) and phosphorus oxychloride (0.022mL, 0.23mmol), reacted at room temperature for 1 hour, added saturated sodium bicarbonate solution (15mL), extracted with dichloromethane (15mL*2), combined the organic phases, saturated chlorinated Wash with aqueous sodium solution, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by high performance liquid chromatography to obtain the title compound 34 (4.9 mg, yield: 11%).

MS (ESI): m/z = 538.1 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ 11.62(d,J=5.6Hz,1H),10.61(s,1H),8.84(s,1H),8.50(s,1H),8.47-8.42(m, 2H),7.95(d,J=7.6Hz,1H),7.67(t,J=8.0Hz,1H),7.32-7.24(m,1H),5.69(d,J=6.4Hz,1H),5.33( t, J=6.8Hz, 1H), 4.04-3.96(m, 1H), 3.93-3.87(m, 1H), 2.33-2.22(m, 2H), 2.10-1.91(m, 2H).

Example 35

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-(6-(tetrahydrofuran-3-yl)-5-(trifluoromethyl)pyridin-3-yl) -5-Trifluoromethyl-1H-pyrazole-4-carboxamide 35

first step

2-(2,5-Dihydrofuran-3-yl)-5-nitro-3-(trifluoromethyl)pyridine 35c

2-Bromo-5-nitro-3-(trifluoromethyl)pyridine 35a (0.27mL, 1.85mmol) and 2-(2,5-dihydrofuran-3-yl)-4,4,5, 5-Tetramethyl-1,3,2-dioxaborane 35b (397mg, 2.03mmol) was dissolved in dioxane/water (4mL/0.6mL), and 1,1'-bis(di Tributylphosphine) (240mg, 0.369mmol) and potassium carbonate (765mg, 5.54mmol), reacted at 70°C for 4 hours under nitrogen atmosphere, added water (50mL) to the reaction solution, extracted with ethyl acetate (50mL*2) , the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the title compound 35c (300 mg, yield: 62%).

MS (ESI): m/z = 261.0 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 9.52(d, J=2.4Hz, 1H), 8.81(d, J=2.4Hz, 1H), 6.81-6.68(m, 1H), 5.19-5.15(m, 2H ), 5.02-4.97(m,2H).

second step

6-(oxolan-3-yl)-5-(trifluoromethyl)pyridin-3-amine 35d

Dissolve 2-(2,5-dihydrofuran-3-yl)-5-nitro-3-(trifluoromethyl)pyridine 35c (270 mg, 1.04 mmol) in methanol (3 mL), add palladium at room temperature Carbon (10%, 0.022mL, 0.21mmol), reacted at room temperature under hydrogen atmosphere for 1 hour, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound 35d (200mg, yield: 82%) .

¹ H NMR(400MHz,DMSO-d6)δ 8.14(d,J=2.4Hz,1H),7.18(d,J=2.4Hz,1H),5.69(s,2H),3.98-3.87(m,2H) ,3.84-3.77(m,1H),3.65-3.52(m,2H),2.21-2.05(m,2H).

third step

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-[6-(oxo-3-yl)-5-(trifluoromethyl)pyridin-3-yl ]-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 35

6-(oxolan-3-yl)-5-(trifluoromethyl)pyridin-3-amine 35d (35 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride ( 82mg, 2.06mmol), after 10 minutes, add 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4- Formyl chloride was reacted for 21h (88mg, 0.26mmol), under nitrogen atmosphere, at 60°C for 1 hour, cooled to room temperature, the reaction solution was added with saturated sodium bicarbonate solution (20mL), extracted with dichloromethane (30 mL*3), The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by high performance liquid chromatography to obtain the title compound 35 (24.3 mg, yield: 17.5%).

MS (ESI): m/z = 538.2 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d6)δ 11.62(s,1H),11.05(s,1H),9.08(d,J=2.0Hz,1H),8.55-8.51(m,1H),8.49(s, 1H), 8.44(d, J=8.0Hz, 1H), 7.94(d, J=7.2Hz, 1H), 7.67(t, J=7.6Hz, 1H), 7.29(d, J=7.2Hz, 1H) ,5.65(d,J=7.6Hz,1H),4.10-4.02(m,1H),4.02-3.94(m,1H),3.90-3.82(m,1H),3.79-3.71(m,2H),2.28 -2.20(m,2H).

Example 36

1-(1-oxo-1,2-dihydrophthalazin-5-yl)-5-(trifluoromethyl)-N-(2-trifluoromethylpyridin-4-yl)-1H-pyridine Azole-4-carboxamide 36

first step

3-Hydroxy-4-nitro-2,3-dihydro-1H-isoindol-1-one 36b

4-Nitro-2,3-dihydro-1H-isoindole-1,3-dione 36a (5g, 26.02mmol) was dissolved in dichloromethane/methanol (50mL/50mL), and hydroboration was added at room temperature Sodium (0.88g, 26.02mmol), react at room temperature for 6 hours, add saturated aqueous sodium bicarbonate (40mL) to quench the reaction, stir for 20 minutes, extract the aqueous phase with ethyl acetate (100mL*2), combine the organic phases, and Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound 36b (3.8 g, yield: 75%).

MS (ESI): m/z = 195.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- d6 )δ 9.31(s,1H),8.32(dd, J =0.8,8.0Hz,1H),8.03(d, J =6.8Hz,1H),7.84-7.80(m, 1H), 6.64(d, J =8.8Hz, 1H), 6.35(d, J =8.8Hz, 1H).

second step

3-Hydroxy-4-nitro-1,3-dihydro-2-benzofuran-1-one 36c

Add 3-hydroxy-4-nitro-2,3-dihydro-1H-isoindol-1-one 36b (3.8g, 19.57mmol) into concentrated hydrochloric acid (30mL), react at 90°C for 12 hours, cool to room temperature warm, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound 36c (2.6 g, yield: 68%).

MS (ESI): m/z = 196.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d6)δ 8.53(dd,J=0.7,8.0Hz,1H),8.49(s,1H),8.27(d,J=7.2Hz,1H),7.96(t,J= 7.6Hz, 1H), 7.07(s, 1H).

third step

5-nitro-1,2-dihydrophthalazin-1-one 36d

Dissolve 3-hydroxy-4-nitro-1,3-dihydro-2-benzofuran-1-one 36c (2.6g, 13.32mmol) in ethanol (20mL), add hydrazine hydrate solution (186mL , 3.54mmol), reacted at 80°C for 4 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 36d (1.6g, yield: 62%).

MS (ESI): m/z = 192.1 [M+H] ⁺ .

the fourth step

5-Amino-1,2-dihydrophthalazin-1-one 36e

5-Nitro-1,2-dihydrophthalazin-1-one 36d (1.6g, 8.37mmol) was dissolved in methanol (20mL), under a nitrogen atmosphere, palladium carbon (10%, 0.84mmol) was added, and the reaction The system was replaced with hydrogen three times, and reacted at room temperature under 15 psi for 12 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound 36d (2.3 g, yield: 95%).

MS (ESI): m/z = 162.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d6)δ 12.36(s,1H),8.47(s,1H),7.49-7.39(m,1H),7.31(d,J=7.8Hz,1H),6.99(dd, J=1.0,8.0Hz,1H),6.26(s,2H).

the fifth step

5-hydrazino-1,2-dihydrophthalazin-1-one 36f

5-Amino-1,2-dihydrophthalazin-1-one 36e (300mg, 1.86mmol) was added to concentrated hydrochloric acid (5mL), and an aqueous solution of sodium nitrite (0.149mL, 2.792mmol) was added under ice cooling ( 4 mL), reacted in ice bath for 0.5 hours, then added dropwise a concentrated hydrochloric acid solution (8 mL) of tin dichloride (1050 mg, 4.65 mmol), and reacted at room temperature for 5 hours. The reaction solution was adjusted to pH 12-14 with 20% aqueous sodium hydroxide solution, extracted with ethyl acetate (50mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 36f (240 mg, yield: 72.7%).

MS (ESI): m/z = 177.1 [M+H] ⁺ .

step six

1-(1-oxo-1,2-dihydrophthalazin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 36h

Dissolve 5-hydrazino-1,2-dihydrophthalazin-1-one 36f (240 mg, 1.36 mmol) in ethanol (6 mL), add ( Z )-2-(ethoxymethylene) at room temperature -4,4,4-Trifluoro-3-oxobutyric acid ethyl ester 1c (0.26mL, 1.36mmol), reacted at 60°C for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain The title compound 36h (50 mg, yield: 10%).

MS (ESI): m/z = 353.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d6)δ 13.02(s,1H),8.47(d,J=7.6Hz,1H),8.45(s,1H),8.18-8.13(m,1H),8.06-8.00( m, 1H), 7.75(s, 1H), 4.35(q, J=7.2Hz, 2H), 1.33(t, J=7.2Hz, 3H).

step seven

1-(1-oxo-1,2-dihydrophthalazin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 36i

1-(1-oxo-1,2-dihydrophthalazin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 36h (40mg, 0.11mmol) Dissolve in tetrahydrofuran/water (6mL/2mL), add lithium hydroxide aqueous solution (0.016mL, 0.57mmol) at room temperature, react at 50°C for 6 hours, concentrate the reaction solution under reduced pressure, then add 1N hydrochloric acid solution to adjust the pH value to 2 -3, extracted with ethyl acetate (20 mL*2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure to obtain the title compound 36i (30 mg, yield: 81%).

MS (ESI): m/z = 325.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d6)δ 13.45(s,1H),13.02(s,1H),8.47(d,J=8.0Hz,1H),8.39(s,1H),8.14(d,J= 7.0Hz, 1H), 8.06-7.99(m, 1H), 7.71(s, 1H).

eighth step

1-(1-oxo-1,2-dihydrophthalazin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H -Pyrazole-4-carboxamide 36

1-(1-oxo-1,2-dihydrophthalazin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 36i (20mg, 0.062mmol), 2 -(Trifluoromethyl)pyridin-4-amine 3g (10.0mg, 0.062mmol) and pyridine (0.050mL, 0.62mmol) were dissolved in dichloromethane (2mL), and phosphorus oxychloride (0.006mL, 0.062mmol), reacted at room temperature for 1 hour, added water (10mL), extracted with dichloromethane (10mL*3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to HPLC Chromatography gave the title compound 36 (2.6 mg, yield: 9%).

MS (ESI): m/z = 469.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d6)δ 13.07(s,1H),11.24(s,1H),8.72(d,J=5.6Hz,1H),8.57(s,1H),8.50(d,J= 7.8Hz,1H),8.23(d,J=1.6Hz,1H),8.19(d,J=7.2Hz,1H),8.09-8.03(m,1H),7.97(dd,J=1.6,5.6Hz, 1H), 7.64(s, 1H).

Example 37

1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-N-(2-trifluoromethylpyridin-4-yl)-1H- Pyrazole-4-carboxamide 37

first step

8-(2-(Diphenylmethylene)hydrazino)quinazolin-4(3H)-one 37c

8-Bromo-3,4-dihydroquinazolin- 4-one 37a (500 mg, 2.22 mmol) and (diphenylmethylene)hydrazine 37b (436 mg, 2.22 mmol) were dissolved in toluene (5 mL), Add sodium 2-methylpropane-2-ate (355mg, 3.70mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (230mg, 0.37mmol) and palladium acetate (41mg, 0.19mmol) at room temperature mmol), under a nitrogen atmosphere, reacted at 80°C for 12 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound 37c (200 mg, yield: 31.7%).

MS (ESI): m/z = 341.1 [M+H] ⁺ .

second step

5-hydrazino-1,2-dihydroquinazolin-1-one 37d

Dissolve 8-(2-(diphenylmethylene)hydrazino)quinazolin-4(3H)-one 37c (180 mg, 0.53 mmol) in ethanol (5 mL), add hydrogen chloride (0.50 mL, 4.23 mmol), reacted for 16 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain the title compound 37d (240 mg).

MS (ESI): m/z = 177.1 [M+H] ⁺ .

third step

1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 37f

Dissolve 5-hydrazino-1,2-dihydroquinazolin-1-one 37d (240mg, 1.36mmol) in ethanol (6ml), add (Z)-2-(ethoxymethylene )-4,4,4-trifluoro-3-oxobutanoic acid ethyl ester 1c (0.14mL, 0.74mmol), reacted at 60°C for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography, The title compound 37f (100 mg, yield: 38%) was obtained.

MS (ESI): m/z = 353.1 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ 10.35-10.03(m,1H),8.50(dd,J=1.6,8.4Hz,1H),8.27-8.24(m,1H),8.02(s,1H),7.92 (dd, J=1.6, 7.6Hz, 1H), 7.70-7.66(m, 1H), 4.45-4.38(m, 2H), 1.42(t, J=7.2Hz, 3H).

the fourth step

1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 37g

1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 37f (78mg, 0.22mmol ) was dissolved in tetrahydrofuran/water (3mL/1mL), lithium hydroxide (0.031mL, 1.11mmol) was added at room temperature, reacted at 50°C for 6 hours, saturated aqueous sodium bicarbonate solution (20mL) was added to the reaction solution, and extracted with dichloromethane (30mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 37g (60mg, yield: 83%) of the title compound.

MS (ESI): m/z = 325.0 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ 8.31-8.27(m,1H),8.17(s,1H),8.12-8.08(m,1H),7.57-7.52(m,1H),7.44-7.40(m, 1H), 7.02(s, 1H).

the fifth step

1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]- 1H-pyrazole-4-carboxamide 37

37g (60mg, 0.18mmol) of 1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 2-(Trifluoromethyl)pyridin-4-amine 3g (30mg, 0.18mmol) and pyridine (0.150mL, 1.85mmol) were dissolved in dichloromethane (8mL), and phosphorus oxychloride (0.05mL, 0.55 mmol), react at room temperature for 1 hour, add the reaction solution into saturated sodium bicarbonate (15ml), and extract with dichloromethane (30mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to obtain the title compound 37 (18.4 mg, yield: 21.2%).

MS (ESI): m/z = 469.1 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ 11.26-11.07(m,1H),8.70(d,J=5.6Hz,1H),8.51-8.46(m,1H),8.39-8.35(m,1H), 8.24(d, J=1.6Hz, 1H), 8.14(s, 1H), 8.11-8.07(m, 1H), 8.01-7.97(m, 1H), 7.72(t, J=7.6Hz, 1H).

Example 38

N-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-( Trifluoromethyl)-1H-pyrazole-4-carboxamide 38

first step

2-methoxy-6-(trifluoromethyl)pyridin-4-amine 38b

Sodium methoxide in methanol (2mL, 30% wt) was added to 2-chloro-6-(trifluoromethyl)pyridin-4-amine 38a (100mg, 0.51mmol), microwaved at 100°C for 1h, cooled to room temperature Finally, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), and the organic phase was concentrated under reduced pressure to obtain the title compound 38b (100 mg, crude product).

MS (ESI): m/z = 193.1 [M+H] ⁺ .

second step

N-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-( Trifluoromethyl)-1H-pyrazole-4-carboxamide 38

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (60mg, 0.19mmol) and 2-Methoxy-6-(trifluoromethyl)pyridin-4-amine 38b (53mg, 0.28mmol) was dissolved in pyridine (7mL), phosphorus oxychloride (0.035mL, 0.38mmol) was added at room temperature, and the reaction After 2 hours, add saturated aqueous sodium bicarbonate (15 mL), extract with dichloromethane (15 mL*3), concentrate the organic phase under reduced pressure, and separate the residue by high performance liquid chromatography to obtain the title compound 38 (15 mg, yield: 16 %).

MS (ESI): m/z = 498.3 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ 11.56(s,1H),11.10(s,1H),8.45(s,1H),8.37(d,J=8.0Hz,1H),7.94~7.81(m ,1H),7.71(d,J=1.6Hz,1H),7.60(t,J=7.8Hz,1H),7.41(d,J=1.6Hz,1H),7.22(m,1H),5.58(d ,J=7.4Hz,1H),3.85(s,3H).

Example 39

N-(1-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1-(1-oxo-1,2-dihydroiso Quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 39

first step

4-Amino-6-(trifluoromethyl)pyridin-2-ol 39a

2-Chloro-6-(trifluoromethyl)pyridin-4-amine 38a (440mg, 2.24mmol) was dissolved in 1,4-dioxane/water (15mL/5mL), and dibenzylidene was added at room temperature Palladium acetonate (128.7mg, 0.22mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (190mg, 0.44mmol) and potassium hydroxide (251mg, 4.49mmol) . React at 115°C for 1 hour, concentrate the reaction solution under reduced pressure, add water (20mL) to the residue, and extract with ethyl acetate (20mL*2), adjust the pH value of the aqueous phase to 2~3 with hydrochloric acid (3M), After extraction (20 mL*2), the aqueous phase was concentrated under reduced pressure to obtain the title product 39a (122 mg, yield: 30%).

MS (ESI): m/z = 179.4 [M+H] ⁺ .

second step

4-Amino-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one 39b

4-Amino-6-(trifluoromethyl)pyridin-2-ol 39a (122 mg, 0.62 mmol) was dissolved in ethanol (8 mL), potassium carbonate (128 mg, 0.93 mmol) and iodomethane (0.039 mL, 0.62mmol). React at 70°C for 3 hours, cool to room temperature, add water (15 mL), extract with ethyl acetate (10 mL*3), combine the organic phases, and concentrate under reduced pressure to obtain the title compound 39b (48 mg, yield: 40%).

MS (ESI): m/z = 193.0 [M+H] ⁺ .

third step

N-(1-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1-(1-oxo-1,2-dihydroiso Quinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 39

4-Amino-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one 39b (48mg, 0.25mmol) and 1-(1-oxo-1,2-dihydroiso Quinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1g (80mg, 0.25mmol) was dissolved in pyridine (6mL), and phosphorus oxychloride ( 0.047mL, 0.5mmol), react at room temperature for 2 hours. The reaction solution was added with water (10mL), extracted with dichloromethane (10mL*3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to obtain the title compound 39 (9.6mg, yield: 7.7% ).

MS (ESI): m/z = 498.2 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d6)δ 11.64(s,1H),10.90(s,1H),8.49(s,1H),8.44(d,J=8.0Hz,1H),7.94(d,J= 7.5Hz, 1H), 7.68(t, J=7.9Hz, 1H), 7.34-7.27(m, 1H), 7.24(d, J=2.2Hz, 1H), 7.15(d, J=2.2Hz, 1H) ,5.64(d,J=7.3Hz,1H),3.48(s,3H).

Example 40

1-(8-oxo-7,8-dihydro-2,7-naphthyridin-4-yl)-5-(trifluoromethyl)-N-(2-trifluoromethylpyridin-4-yl )-1H-pyrazole-4-carboxamide 40

first step

4-Methyl-5-nitropyridine-3-carbonitrile 40b

3-Bromo-4-methyl-5-nitropyridine 40a (3g, 13.824mmol) was dissolved in N,N-dimethylformamide (6mL), and zinc cyanide (1.5g, 12.943 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.8g, 1.383mmol) and tridibenzylideneacetone dipalladium (0.63g, 0.691mmol), nitrogen Under the atmosphere, react with microwave at 130°C for 1 hour, cool to room temperature, add water (40mL), extract with ethyl acetate (30mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The compound was separated by silica gel column chromatography to obtain the title compound 40b (1.3 g, yield: 79%).

MS (ESI): m/z = 164.1 [M+H] ⁺ .

second step

4-[(E)-2-(Dimethylamino)vinyl]-5-nitropyridine-3-carbonitrile 40c

4-Methyl-5-nitropyridine-3-carbonitrile 40b (1.3g, 7.969mmol) was dissolved in dichloromethane (10mL), and N,N-dimethylformamide-dimethyl Acetal (2 mL, 15.93 mmol) was reacted at 40°C for 12 hours, and the reaction solution was concentrated under reduced pressure to obtain the title compound 40c (1 g, yield: 57%).

third step

5-nitro-1,2-dihydro-2,7-naphthyridin-1-one 40d

Add 4-[(E)-2-(dimethylamino)vinyl]-5-nitropyridine-3-carbonitrile 40c (1g, 4.583mmol) into acetic acid (30mL), add hydrogen bromide at room temperature acid (18 mL, 4.383 mmol). Under nitrogen atmosphere, react at 60°C for 5 hours, add the reaction solution into saturated aqueous sodium bicarbonate solution (60mL), extract with ethyl acetate (40mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and depressurize the filtrate After concentration, the residue was separated and purified by silica gel column chromatography to obtain the title compound 40d (460 mg, yield: 55%).

MS (ESI): m/z = 192.0 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d6)δ 12.18(s,1H),9.54(s,1H),9.43(s,1H),7.74(dd,J=6.4,7.2Hz,1H),7.06(d, J=7.2Hz, 1H).

the fourth step

5-Amino-1,2-dihydro-2,7-naphthyridin-1-one 40e

Dissolve 5-nitro-1,2-dihydro-2,7-naphthalen-1-one 40d (400mg, 2.093mmol) in methanol (6mL), add palladium on carbon (10%, 221mg, 0.208mmol ), under hydrogen (15psi) atmosphere, reacted at 25°C for 3 hours, filtered through celite, and concentrated the filtrate under reduced pressure to obtain the title compound 40e (200mg, yield: 59%).

MS (ESI): m/z = 162.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- _d6 )δ 11.40(s,1H),8.54(s,1H),8.06(s,1H),7.28(d,J=7.6Hz,1H),6.67(d,J= 7.2Hz, 1H), 5.79(s, 2H).

the fifth step

5-hydrazino-1,2-dihydro-2,7-naphthyridin-1-one 40f

Dissolve 5-amino-1,2-dihydro-2,7-naphthyridin-1-one 40e (100mg, 0.621mmol) in concentrated hydrochloric acid (2mL), add sodium nitrite (0.05mg, 0.931mmol) in an aqueous solution (2mL), stirred at 0°C for 0.5 hours, then added dropwise a solution of tin protochloride dihydrate (350mg, 1.551mmol) in concentrated hydrochloric acid (2mL), reacted at room temperature for 3 hours, and then reacted with 20% hydrogen Aqueous sodium oxide solution was used to adjust the reaction solution to pH=12~14, extracted with ethyl acetate (30mL*2), and the aqueous phase was lyophilized to obtain the title compound 40f (100mg, yield: 91%).

MS (ESI): m/z = 177.1 [M+H] ⁺ .

step six

1-(8-oxo-7,8-dihydro-2,7-naphthyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 40g

Dissolve 5-hydrazino-1,2-dihydro-2,7-naphthyridin-1-one 40f (80mg, 0.454mmol) in ethanol (5mL), add (Z)-2-(ethoxy Methylene)-4,4,4-trifluoro-3-oxobutanoic acid ethyl ester 1c (0.132mL, 0.681mmol), react at 60°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain 40 g (36 mg, yield: 22%) of the title compound.

MS (ESI): m/z = 353.1 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- _d6 )δ 12.01(s,1H),9.48(s,1H),8.97(s,1H),8.47(s,1H),7.53(d,J=7.2Hz,1H) , 5.82(d, J=7.2Hz, 1H), 4.34(q, J=7.2Hz, 2H), 1.32(t, J=7.2Hz, 3H).

step seven

1-(8-oxo-7,8-dihydro-2,7-naphthyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 40h

With 1-(8-oxo-7,8-dihydro-2,7-naphthyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 40g ( 36mg, 0.102mmol) was dissolved in tetrahydrofuran/water (3mL/1mL), lithium hydroxide (21mg, 0.51mmol) was added at room temperature, and reacted at 50°C for 4 hours. The reaction solution was adjusted to pH 2-3 with 1N hydrochloric acid solution, and extracted with ethyl acetate (20mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 40h (22mg, yield: 66%).

MS (ESI): m/z = 325.1 [M+H] ⁺ .

eighth step

1-(8-oxo-7,8-dihydro-2,7-naphthyridin-4-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridine-4 -yl]-1H-pyrazole-4-carboxamide 40

1-(8-oxo-7,8-dihydro-2,7-naphthyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 40h (20mg, 0.062mmol), 2-(trifluoromethyl)pyridin-4-amine 3g (10mg, 0.062mmol) and pyridine (0.05mL, 0.617mmol) were dissolved in dichloromethane (4mL), and phosphorus oxychloride was added at room temperature (0.006mL, 0.062mmol), reacted at room temperature for 1 hour, added water (10mL), extracted with dichloromethane (10mL*3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was Separation by high performance liquid chromatography gave the title compound 40 (1.7 mg, yield: 5.8%).

MS (ESI): m/z = 469.1 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ 12.02(s,1H),11.25(s,1H),9.50(s,1H),8.97(s,1H),8.71(d,J=5.6Hz,1H) ,8.58(s,1H),8.22(s,1H),7.97(br d,J=5.6Hz,1H),7.59(br d,J=7.2Hz,1H),5.77(d,J=7.2Hz, 1H).

biological test

In vitro assays include assays that determine cell morphology, protein expression and/or cytotoxicity, enzyme inhibitory activity, and/or subsequent functional consequences of treatment of cells with compounds of the invention. Alternatively or additionally to in vitro assays can be used to quantify the ability of an inhibitor to bind to a protein or nucleic acid molecule within a cell.

Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/target molecule complex, and determining the amount of radiolabel bound. Alternatively or in addition, inhibitor binding can be determined by running competition experiments in which new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. for determining the present invention as Detailed conditions of exemplary systems for compounds of MALT1 inhibitors are set forth in the Biological Examples below.

Such assays are exemplary and not intended to limit the scope of the invention. The skilled practitioner will understand that conventional assays can be modified to develop equivalent or other assays that can be used to equally assess activity or otherwise characterize compounds and/or compositions as described herein.

Test example 1 MALT1 biochemical protease assay

Using tetrapeptide (Ac-LRSR-MCA, PEPTIDE INSTITUTE) as substrate and full-length MALT1 protein (Strep-MALT1(1-824)-Myc/DDK, ORIGENE TP314639) purified from mammalian cell HEK293T, in vitro assay Assessment of MALT1 protease activity. The tetrapeptide LRSR is coupled to AMC (7-amino-4-methylcoumarin) and provides a quenched fluorescent substrate for the MALT1 protease. Cleavage of AMC from arginine residues results in increased coumarin fluorescence measured at 450 nm (excitation 360 nm). The composition of the final detection buffer is 5.625nM MALT1 protein, 2.5μM Ac-LRSR-MCA, 20mM HEPES, 10mM KCl, 1.5mM MgCl‧6H2O, 1mM 2Na(EDTA‧2Na), 0.01% TritonX-100, 1M citric acid Trisodium Citrate Dihydrate, and 10 mM DTT. Test compounds dissolved in 100% DMSO were added to a 384-well plate (Greiner-781086) at 200 nL per well using Echo. The highest concentration of each test compound was 10 μM or 1 μM, 3-fold serial dilution, and the tested concentration range was from 10 μM to 0.2 nM. Control wells in assay buffer without enzyme were used as low controls (LC), and vehicle (1% DMSO) wells with enzyme reaction but no compound treatment were used as high controls (HC). Compounds were incubated with MALT1 enzyme and substrate for 15 hours at room temperature. Fluorescence was then measured at excitation 360 nm and emission 450 nm using Envision. XLfit was used _to fit the inhibition curve and calculate the IC ₅₀ value, which is shown in Table 1.

_IC50 values (Z prime > 0.5) were calculated using the following formula:

LC = median of low control values

Low control: reaction without MALT1 enzyme

HC = median of high control values

High control: vehicle control without compound

Inhibition %=100-[(sample-LC)/(HC-LC)×100]

Curve fitting formula: fit=(A+((B-A)/(1+((C/x)^D))))

A: Min(Bottom), B: Max(Top), C: IC ₅₀ (inflection point), D: Slope (Hill value)

Experimental results: IC ₅₀ values of the disclosed compounds on the inhibition of MALT1 biochemical protease, A: IC ₅₀ value<100nm; B: 100nm<IC ₅₀ value<600nm; C: 600nm<IC ₅₀ value<1000nm; D: 1000nm< _IC50 values.

The structure of the reference compound is as follows, which can be obtained by referring to WO2018119036A:

Test Example 2 Determination of Intratumor Drug Concentration

Inoculate 0.2mL (5 x ¹⁰⁶ cells) of OCI-Ly3 cells (human diffuse large B-cell lymphoma cells, WuXi AppTec Pharmaceutical Technology Co., Ltd.) (plus Matrigel, volume ratio 1:1) subcutaneously into each female On the right back of NOG mice (6-8 weeks old, weighing 18-22g, Shanghai Weitong Lihua Experimental Animal Technology Co., Ltd.), the average volume of tumors reached 230mm ³ and began to be administered in groups.

After 28 consecutive days of dosing, plasma and tumor samples were collected at 0, 2, 4, and 8 hours after the last dose. The plasma and intratumoral concentrations of the compounds were quantitatively analyzed by LC-MS/MS with an AB API4000 mass spectrometer. (Chromatographic column: Raptor Biphenyl 2.7μm 50×2.1mm; mobile phase: A 0% acetonitrile aqueous solution (0.1% formic acid), B 100% acetonitrile aqueous solution (0.1% formic acid); quantitative method: internal standard method).

Plasma sample preparation:

Dilute the analyte stock solution with 50% acetonitrile in water to obtain the desired working solution series concentration. Add 3 μL of working solution (5, 10, 20, 50, 100, 500, 1000, 5000, 10000 ng/mL) to 30 μL of blank NOG mouse plasma to reach 0.5~1000 ng/mL (0.5, 1, 2, 5, 10 , 50, 100, 500, 1000ng/mL) calibration standard, the total volume is 33μL (standard sample). 1 ng/mL, 2 ng/mL, 50 ng/mL, and 800 ng/mL plasma QC samples were prepared separately from the QC samples used for the calibration curve. These QC samples were prepared on the day of analysis following the same method as the calibration standards.

In 200 μL of internal standard mixture containing acetonitrile, 33 μL of standard samples, 33 μL of quality control samples and 33 μL of plasma samples collected after administration (plasma 30 μL, blank solution 3 μL) were added for protein precipitation. Samples were then vortexed for 30 s. After centrifugation at 4000 rpm at 4°C for 15 minutes, the supernatant was diluted 3 times with water, and 20 μL of the diluted supernatant was injected into the LC/MS/MS system for quantitative analysis.

Tumor sample preparation:

Dilute the analyte stock solution with 50% acetonitrile in water to obtain the desired working solution series concentration. Add 3 μL of working solution (5, 10, 20, 50, 100, 500, 1000, 5000, 10000 ng/mL) to 30 μL of blank NOG mouse tumors to reach 0.5–1000 ng/mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000ng/mL) calibration standards, total 33μL (standard sample). Prepare 4 quality control samples for tumors, respectively 1ng/mL, 2ng/mL, 50 ng/mL and 800ng/mL, independent of the samples used for the calibration curve. These QC samples were prepared on the day of analysis following the same method as the calibration standards.

In 200 μL of acetonitrile mixture containing internal standard, 33 μL of standard samples, 33 μL of quality control samples and 33 μL of tumor samples collected after administration (30 μL of tumor homogenate, 3 μL of blank solution) were added for protein precipitation. Samples were then vortexed for 30 s. After centrifugation at 4000 rpm at 4°C for 15 min, the supernatant was diluted 3 times with water, and 20 μL of the diluted supernatant was injected into the LC/MS/MS system for quantitative analysis. The results are summarized in Table 3 and Table 4.

The results showed that compound 11 had a higher intratumoral/plasma concentration ratio.

Claims (16)

A compound represented by formula III or a pharmaceutically acceptable salt thereof,

in, Y ₁ is CR ₁₄ ; Y ₂ is N; Ring C is selected from optionally substituted by 1-3 R ₁₃

R ₁₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 3-6 membered Heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro , cyano, amino substituents are substituted; R ₁₂ is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, the naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms optionally replaced by 1-3 R Substituted by _12a , the R _12a is selected from side oxygen, thio, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, Cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 ring Alkoxy, 3-6-membered heterocyclic group, 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl Substituents of group, isobutyl group, nitro group, cyano group and amino group; R ₁₃ is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl, -NHCOR _13a , -COR _13b , -SO ₂ R _13c , -SOCH ₃ ; where the C _1-6 alkyl, C _3-6 cycloalkyl, C _{1- 6} alkoxy, C _3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, Substituents of n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino; R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl; The proviso is that the compound shown in formula III does not include the following compounds:

A compound represented by formula III or a pharmaceutically acceptable salt thereof,

in, Y ₁ is CR ₁₄ ; Y ₂ is N; Ring C is selected from optionally substituted by 1-3 R ₁₃

R ₁₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 member heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, 5-6 member Heterocyclic group, 3-6 membered heteroaryl group optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro , cyano, amino substituents are substituted; R ₁₂ is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, the naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms optionally replaced by 1-3 R Substituted by _12a , the R _12a is selected from side oxygen, thio, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, Cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 ring Alkoxy, 3-6-membered heterocyclic group, 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl Substituents of group, isobutyl group, nitro group, cyano group and amino group; R ₁₃ is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 members Heterocyclyl, 3-6 membered heteroaryl, -NHCOR _13a , -COR _13b , -SO ₂ R _13c ; where the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy , C _3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, Substituents of isopropyl, n-butyl, isobutyl, nitro, cyano, amino; R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl; The proviso is that the compound shown in formula III does not include the following compounds:

The compound shown in formula III as described in claim 1 or 2 or a pharmaceutically acceptable salt thereof, which is formula III-a, formula III-b, formula III-c, formula III-d, formula III-e, formula A compound represented by III-h or formula III-j or a pharmaceutically acceptable salt thereof,

The compound shown in the preferred formula III-h

; in, n is an integer selected from 0-3, R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ are as defined in Claim 1. The compound represented by formula III or a pharmaceutically acceptable salt thereof as described in Claim 1 or 2, which is a compound represented by formula III-i or a pharmaceutically acceptable salt thereof,

in, n is an integer selected from 0-3, R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ are as defined in Claim 1. The compound shown in formula III or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4, wherein R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, halogen, Nitro, cyano, hydroxyl; preferred R ₁₄ is selected from hydrogen, methyl, cyclopropyl, halogen, nitro, cyano, hydroxyl; more preferred R ₁₄ is selected from hydrogen. The compound represented by formula III or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein each R ₁₃ is independently selected from trifluoromethyl, hydrogen, halogen; preferably R ₁₃ is independently selected from trifluoromethyl. A compound of formula III or a pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 5, wherein each R ₁₃ is independently selected from nitro, cyano, halogen, -NHCOR _13a , -COR _13b , -SO ₂ R _13c , -SOCH ₃ ; R _13a , R _13b and R _13c are independently selected from amino, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, p-methylphenyl. The compound represented by formula III or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein each R ₁₃ is independently selected from methyl, methoxy, trifluoromethyl, trifluoromethyl Oxy, difluoromethoxy, -SOCH ₃ , halogen, cyano; preferably R ₁₃ is selected from trifluoromethyl. The compound represented by formula III or a pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 8, wherein n is selected from an integer of 0-2, preferably n is selected from an integer of 1-2, more preferably n is 1. The compound represented by formula III or a pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 9, wherein, R ₁₂ is selected from 1-side oxygen-1,2-dihydroisoquinolin-5-yl, 1-thiol-1,2-dihydroisoquinolin-5-yl, preferably 1-side oxygen-1 ,2-Dihydroisoquinolin-5-yl; The 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thiol-1,2-dihydroisoquinolin-5-yl is optionally substituted by 1-3 R _12a , The R _12a is selected from C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _3-6 cycloalkyl, nitro, cyano, halogen, containing 1-3 3-6 membered heterocyclic group containing heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy , C _3-6 cycloalkoxy, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally selected from 1-3 Halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino substituents. The compound represented by formula III or a pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 9, wherein, R ₁₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen; wherein the C _{1 -6} alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 selected from halogen, methyl, ethyl, cyclopropyl, Substituents of n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl; Preferably R ₁₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, nitro, cyano, halogen; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 selected from halogen, methyl, ethyl, cyclopropyl Substituents of radical, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl; More preferably R ₁₁ is selected from hydrogen, cyclopropyl, trifluoromethyl. The compound represented by formula III or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 11, which is selected from:

An isotopic substitution of the compound represented by formula III or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 12, preferably, the isotopic substitution is deuterium atom substitution. A pharmaceutical composition comprising the compound shown in formula III as described in any one of claim items 1 to 12 or a pharmaceutically acceptable salt thereof or an isotope substitution as described in claim item 13 and a pharmaceutically acceptable excipient . A compound shown in formula III as described in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or an isotope substitution as described in claim 13 or a pharmaceutical composition as described in claim 14 in the preparation Use in medicine for preventing and/or treating disorders related to MALT1. A compound shown in formula III as described in any one of claim items 1-12 or a pharmaceutically acceptable salt thereof or an isotope substitution as described in claim item 13 or a pharmaceutical composition as described in claim item 14 Use in the preparation of medicines for preventing and/or treating autoimmune diseases, inflammatory diseases, cancers and tumors.