CN117120427A

CN117120427A - MALT1 inhibitor and preparation method and application thereof

Info

Publication number: CN117120427A
Application number: CN202280027175.4A
Authority: CN
Inventors: 李云飞; 王艳辉; 贾云静; 刘彪; 张瑱; 林晓燕
Original assignee: Shanghai Tuojie Biomedical Technology Co ltd
Current assignee: Shanghai Tuojie Biomedical Technology Co ltd
Priority date: 2021-06-18
Filing date: 2022-06-17
Publication date: 2023-11-24
Also published as: WO2022262855A1; TW202317537A

Abstract

Discloses a MALT1 inhibitor, a preparation method and application thereof. Specifically, a compound shown in a formula III, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound serving as a MALT1 inhibitor in preventing and/or treating autoimmune diseases, inflammatory diseases, cancers and tumors are disclosed.

Description

MALT1 inhibitor and preparation method and application thereof

Technical Field

The present disclosure relates to a MALT1 inhibitor, a preparation method thereof, a pharmaceutical composition containing the same, and use thereof for preventing and/or treating autoimmune diseases, inflammatory diseases, cancers, and tumors.

Background

The mucosa-associated tissue lymphoma ectopic protein1 (MALT 1) is an important protein molecule upstream of NF- κB signaling pathway, and forms a complex CBM with B-cell chronic lymphocytic leukemia/lymphoma protein (B-cell chronic lymphocyticleukemia/lymphoma10, BCL 10) and membrane-associated guanylate kinase 1 (caspase-recruitment domain (CARD) containing membrane-associated guanylatekinase protein1, CARMA 1) containing caspase recruitment structure, which transmits the near-end antigen receptor protein signal to IκB kinase (IKK) and thus activates NF- κB signaling pathway. Excessive activation of MALT1-NF- κB signaling pathway is closely related to inflammation and tumor development.

Disclosure of Invention

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

Wherein:

ring a is selected from 9-15 membered heteroaryl groups containing 1-4 heteroatoms;

preferably, ring A is selected from the group consisting of 1-oxo-1, 2-dihydroisoquinolin-5-yl, 1-thio-1, 2-dihydroisoquinolin-5-yl, quinolin-5-yl, isoquinolin-5-yl, thieno [2,3-c]Pyridin-4-yl, naphthyl,

R ₁ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a nitro group, a cyano group, a halogen, a 3-6 membered heterocyclic group, a 3-6 membered heteroaryl group; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

R ₂ selected from hydrogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, -COR _2a 、-SO ₂ R _2b 、-NHCOR _2c A hydroxyl group; the C is _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy, oxo;

R _2a 、R _2b 、R _2c Each independently selected from amino, C _1-6 Alkyl, phenyl, p-methylphenyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, hydroxy;

R ₃ selected from hydrogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, -COR _3a 、-SO ₂ R _3b 、-NHCOR _3c The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

R _3a 、R _3b 、R _3c each independently selected from amino, C _1-6 Alkyl, phenyl, p-methylphenyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, hydroxy;

R ₄ and R is ₅ Each independently selected from C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, hydroxy, methanesulfonyl; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryl optionally substituted with 1-3 substituents selected from halogenSubstituents such as methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and hydroxy;

With the proviso that the compound of formula I does not include the following:

in a second aspect, the present disclosure also provides compounds of formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or a pharmaceutically acceptable salt thereof,

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

In some embodiments, R in a compound represented by formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-I, I-j, I-k, or a pharmaceutically acceptable salt thereof ₂ Selected from hydrogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, -COR _2a 、-SO ₂ R _2b 、-NHCOR _2c Nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, hydroxy; the C is _1-6 Alkyl, C _3-6 Cycloalkyl radicals、C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy, oxo;

R _2a 、R _2b 、R _2c each independently selected from amino, C _1-6 Alkyl, phenyl, p-methylphenyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, hydroxy.

In some embodiments, R in a compound represented by formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-I, I-j, I-k, or a pharmaceutically acceptable salt thereof ₂ Selected from hydrogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, -COR _2a 、-SO ₂ R _2b 、-NHCOR _2c Cyano, halogen, 3-6 membered heterocyclyl; the C is _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy, 3-6 membered heterocyclyl is optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy, oxo;

R _2a 、R _2b 、R _2c each independently selected from amino, C _1-6 Alkyl, phenyl, p-methylphenyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl.

In some embodiments, R in a compound represented by formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-I, I-j, I-k, or a pharmaceutically acceptable salt thereof ₂ Selected from hydrogen, C _1-6 Alkyl, cyano, halogen, 3-6 membered heterocyclyl, -COR _2a 、-NHCOR _2c The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-6 Alkyl, 3-6 membered heterocyclyl optionally substituted with 1-3 substituents selected from halogen; r is R _2a 、R _2c Each independently selected from amino, C _1-6 An alkyl group; preferably R ₂ Selected from hydrogen, trifluoromethyl, cyano, halogen, 3-6 membered heterocyclyl, -CONH ₂ 、-NHCOCH ₃ 。

In some embodiments, R in a compound represented by formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-I, I-j, I-k, or a pharmaceutically acceptable salt thereof ₁ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, nitro, cyano, halogen; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

preferably R ₁ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, nitro, cyano, halogen; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy.

More preferably R ₁ Selected from hydrogen, cyclopropyl, trifluoromethyl.

In some embodiments, R in a compound represented by formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-I, I-j, I-k, or a pharmaceutically acceptable salt thereof ₃ Selected from hydrogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, -COR _3a 、-SO ₂ R _3b 、-NHCOR _3c The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

R _3a 、R _3b 、R _3c each independently selected from amino, C _1-6 Alkyl, phenyl, p-methylphenyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, hydroxy.

In some embodiments, R in a compound represented by formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-I, I-j, I-k, or a pharmaceutically acceptable salt thereof ₃ Selected from hydrogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

preferably R ₃ Selected from hydrogen, C _1-6 Alkyl, C _1-6 An alkoxy group; the C is _1-6 Alkyl, C _1-6 Alkoxy is optionally substituted with 1-3 substituents selected from halogen;

more preferably R ₃ Selected from halogen-substituted C _1-6 An alkyl group;

most preferably R ₃ Is trifluoromethyl.

In some embodiments, R in a compound represented by formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-I, I-j, I-k, or a pharmaceutically acceptable salt thereof ₄ And R is ₅ Independently selected from C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, amino, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, hydroxy, methanesulfonyl; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxy;

preferably R ₄ And R is ₅ Independently selected from C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, amino, halogen, hydroxy, methanesulfonyl; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxy;

More preferably R ₄ And R is ₅ Independently selected from C _1-6 Alkyl, C _3-6 Cycloalkyl, nitro, cyano, amino, halogen, hydroxy, methanesulfonyl; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxy;

most preferably R ₄ And R is ₅ Independently selected from methyl, ethyl, methoxy, cyclopropyl, nitro, cyano, amino, halogen, hydroxy, methanesulfonyl; wherein the methyl, ethyl, methoxy and cyclopropyl are optionally substituted by 1-3 substituents selected from halogen, nitro, cyano, amino and hydroxy.

In certain embodiments, R ₄ Independently selected from halogen, C _1-6 Alkyl, C _1-6 An alkoxy group.

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

in a fourth aspect, the present disclosure also provides a compound as shown in formula II or a pharmaceutically acceptable salt thereof,

wherein:

ring B is selected from 9-15 membered heteroaryl groups containing 1-4 heteroatoms;

preferably, ring B is selected from the group consisting of 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, naphthyl,

R ₆ And R is ₁₀ Each independently selected from C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, hydroxy, methanesulfonyl; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocycylAryl is optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxy;

R ₇ selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a nitro group, a cyano group, a halogen, a hydroxy group, a 3-6 membered heterocyclic group, a 3-6 membered heteroaryl group; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

R ₈ selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a nitro group, a cyano group, a halogen, a 3-6 membered heterocyclic group, a 3-6 membered heteroaryl group, a hydroxyl group; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₉ 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, -O-3-6 membered heterocyclyl, -COR _9a 、-SO ₂ R _9b 、 -NH-CO-CH ₃ The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, -O-3-6 membered heterocyclyl, 3-6 membered heteroaryl, -NH-CO-CH ₃ Optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, oxo;

R _9a 、R _9b and R is _9c Each independently selected from amino, C _1-6 Alkyl, phenyl, p-methylphenyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, hydroxy;

with the proviso that the compound of formula II does not include the following:

in certain embodiments, a compound represented by formula II:

wherein:

preferably, ring B is selected from the group consisting of 1-oxo-1, 2-dihydroisoquinolin-5-yl, 1-thio-1, 2-dihydroisoquinolin-5-yl, quinoxalin-5-yl, isoquinolin-5-yl, naphthyl, thieno [2,3-c ] ]Pyridin-4-yl, naphthyl,

R ₆ And R is ₁₀ Each independently selected from C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, hydroxy, methanesulfonyl; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxy;

R ₈ selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a nitro group, a cyano group, a halogen, a 3-6 membered heterocyclic group, a 3-6 membered heteroaryl group, a hydroxyl group; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryl groups are optionally substituted with 1-3 groups selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, aminoIs substituted by a substituent of (2);

R ₉ 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 said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

in a 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 a pharmaceutically acceptable salt thereof,

preferably of formula II-a;

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

In certain embodiments, R in a compound represented by formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or a pharmaceutically acceptable salt thereof ₉ 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 said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy, 3-6 membered heterocyclyl is optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, oxo;

preferably R ₉ Selected from hydrogen, C _1-6 Alkyl, C _1-6 An alkoxy group; the C is _1-6 Alkyl, C _1-6 Alkoxy groups are optionally substituted with 1-3 halogens.

In certain embodiments, R in a compound represented by formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or a pharmaceutically acceptable salt thereof ₉ Selected from 3-6 membered heterocyclyl, -COR _9a 、-SO ₂ R _9b 、 Wherein the 3-6 membered heterocyclic group is optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R _9a 、R _9b and R is _9c Each independently selected from amino, C _1-6 Alkyl, phenyl, p-methylphenyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, hydroxy.

In certain embodiments, a compound of formula II-d or formula II-g, or a pharmaceutically acceptable salt thereof, wherein

R _9a 、R _9b and R is _9c Each independently of the otherIs selected from amino, C _1-6 Alkyl, phenyl, p-methylphenyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, hydroxy;

preferably R ₉ Selected from trifluoromethyl and triazole.

In certain embodiments, R in a compound represented by formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or a pharmaceutically acceptable salt thereof ₉ Selected from the group consisting of

In certain embodiments, R in a compound represented by formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or a pharmaceutically acceptable salt thereof ₉ Selected from C _1-6 Alkoxy, triazole, difluoromethyl, -NH-CO-CH ₃ 、 Difluoromethoxy.

In certain embodiments, R in a compound represented by formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or a pharmaceutically acceptable salt thereof ₉ Selected from the group consisting of-NH-CO-CH ₃ 、-OCHF ₂ 、 Difluoromethoxy, trifluoromethoxy,

In certain embodiments, R in a compound represented by formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or a pharmaceutically acceptable salt thereof ₉ Selected from trifluoromethyl.

In certain embodiments, R in a compound represented by formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or a pharmaceutically acceptable salt thereof ₉ Selected from difluoromethyl.

In certain embodiments, R in a compound represented by formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or a pharmaceutically acceptable salt thereof ₈ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, hydroxy; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heteroaryl optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

preferably R ₈ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, hydroxy; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heteroaryl optionallySubstituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, nitro, cyano, amino;

more preferably R ₈ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, nitro, cyano, halogen, hydroxy; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, nitro, cyano, amino;

more preferably R ₈ Selected from hydrogen, 1-3 halogen substituted alkyl, halogen;

most preferably R ₈ Selected from chlorine.

In certain embodiments, R in a compound represented by formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or a pharmaceutically acceptable salt thereof ₆ And R is ₁₀ Each independently selected from C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, amino, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, hydroxy, methanesulfonyl; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxy;

Preferably R ₆ And R is ₁₀ Each independently selected from C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, amino, halogen, hydroxy, methanesulfonyl; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 groups selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino,A substituent of a hydroxyl group;

more preferably R ₆ And R is ₁₀ Each independently selected from C _1-6 Alkyl, C _3-6 Cycloalkyl, nitro, cyano, amino, halogen, hydroxy, methanesulfonyl; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxy;

most preferably R ₆ And R is ₁₀ Each independently selected from methyl, ethyl, methoxy, cyclopropyl, nitro, cyano, amino, halogen, hydroxy, methanesulfonyl; wherein the methyl, ethyl, methoxy and cyclopropyl are optionally substituted by 1-3 substituents selected from halogen, nitro, cyano, amino and hydroxy.

In certain embodiments, R in a compound represented by formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or a pharmaceutically acceptable salt thereof ₇ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, nitro, cyano, halogen; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

preferably R ₇ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, nitro, cyano, halogen; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 groups selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopropylSubstituents for oxo, nitro, cyano, amino, and hydroxy.

More preferably R ₇ Selected from hydrogen, cyclopropyl, trifluoromethyl.

In certain embodiments, R in a compound represented by formula II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or a pharmaceutically acceptable salt thereof ₇ Is trifluoromethyl.

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

wherein:

Y ₁ is CR (CR) ₁₄ Or N;

Y ₂ is CR (CR) ₁₅ Or N;

1) When Y is ₁ Is CR (CR) ₁₄ And Y is ₂ In the case of the number N,

ring C is selected from optionally 1-3R ₁₃ Substituted

2) When Y is ₁ Is N and Y ₂ Is CR (CR) ₁₅ In the time-course of which the first and second contact surfaces,

ring C is selected from optionally 1-3R ₁₃ Substituted 6-10 membered aryl, 5-10 membered heteroaryl;

3) When Y is ₁ 、Y ₂ When the two are both N, the two are all N,

ring C is selected from the group consisting of optionally 1 to 3R ₁₃ Substituted 6-10 membered aryl, 5-10 membered heteroaryl;

each R ₁₃ Independently selected from C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy group,C _3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, -NHCOR _13a 、-COR _13b 、-SO ₂ R _13c 、-SOR _13c The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₁ selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a nitro group, a cyano group, a halogen, a 3-6 membered heterocyclic group, a 3-6 membered heteroaryl group; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₂ Selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, optionally substituted with 1-3R _12a Substituted, the R _12a Selected from oxo, thio, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R _13a 、R _13b and R is _13c Each independently selected from amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, phenyl, p-methylphenyl;

R ₁₄ 、R ₁₅ each independently selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, halogen, nitro, cyano, hydroxy;

with the proviso that the compound of formula III does not include the following:

in certain embodiments, a compound of formula III or a pharmaceutically acceptable salt thereof,

wherein:

Y ₁ is CR (CR) ₁₄ Or N;

Y ₂ is CR (CR) ₁₅ Or N;

1) When Y is ₁ Is CR (CR) ₁₄ And Y is ₂ In the case of the number N,

ring C is selected from optionally 1-3R ₁₃ Substituted

3) When Y is ₁ 、Y ₂ When the two are both N, the two are all N,

each R ₁₃ 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 heterocyclyl, 3-6 membered heteroaryl, -NHCOR _13a 、-COR _13b 、-SO ₂ R _13c The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₂ selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, optionally substituted with 1-3R _12a Substituted, the R _12a Selected from oxo, thio, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl; the C is _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, 3-6 membered heterogeniesThe cyclic group, 3-6 membered heteroaryl is optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

wherein:

Y ₁ is CR (CR) ₁₄ ；

Y ₂ Is N;

ring C is selected from optionally 1-3R ₁₃ Substituted

R ₁₃ 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 heterocyclyl, 3-6 membered heteroaryl, -NHCOR _13a 、-COR _13b 、-SO ₂ R _13c 、-SOCH ₃ The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryl groups are optionally substituted with 1-3 groups selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, iso-propylSubstituents such as butyl, nitro, cyano and amino are substituted;

R ₁₄ selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, halogen, nitro, cyano, hydroxy;

wherein:

Y ₁ is CR (CR) ₁₄ ；

Y ₂ Is N;

ring C is selected from optionally 1-3R ₁₃ Substituted

R ₁₁ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a nitro group, a cyano group, a halogen, a 3-6 membered heterocyclic group, a 3-6 membered heteroaryl group; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 5-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₃ 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 heterocyclyl, 3-6 membered heteroaryl, -NHCOR _13a 、-COR _13b 、-SO ₂ R _13c The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

in a seventh aspect, the present disclosure also provides a compound of 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 III-m, or a pharmaceutically acceptable salt thereof,

preferred are compounds of the formula III-h

Wherein:

n is selected from the integers from 0 to 3,

R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ as defined in formula III.

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

wherein:

n is selected from the integers from 0 to 3,

R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ as defined in formula III.

In certain embodiments, a compound represented by formula III, III-a, III-b, III-c, III-d, III-e, III-h, III-i, or a pharmaceutically acceptable salt thereof, R ₁₄ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, halogen, nitro, cyano, hydroxy; preferably R ₁₄ Selected from hydrogenMethyl, cyclopropyl, halogen, nitro, cyano, hydroxy; more preferably R ₁₄ Selected from hydrogen.

In certain embodiments, a compound represented by 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 Independently selected from trifluoromethyl, hydrogen, halogen; preferably R ₁₃ Independently selected from trifluoromethyl.

In certain embodiments, a compound represented by 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 Independently selected from C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryl is optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino.

In certain embodiments, a compound represented by 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 Independently selected from nitro, cyano, halogen, -NHCOR _13a 、-COR _13b 、-SO ₂ R _13c 、-SO R _13c Wherein R is _13a 、R _13b And R is _13c Independently selected from amino, C _1-6 Alkyl, C _3-6 Cycloalkyl groups.

In certain embodiments, a compound represented by 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 Independently selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, -SOCH ₃ Halogen, cyano.

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

ring C, R ₁₁ 、R ₁₂ 、R ₁₅ As defined in formula III.

In certain embodiments, in a compound of formula III, formula III-f, or a pharmaceutically acceptable salt thereof, R ₁₅ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, halogen, nitro, cyano, hydroxy; preferably R ₁₅ Selected from hydrogen, methyl, cyclopropyl, halogen, nitro, cyano, hydroxy; more preferably R ₁₅ Selected from hydrogen.

In certain embodiments, ring C is selected from the group consisting of compounds represented by formulas III, III-a, III-b, III-C, III-d, III-e, III-f, III-g, III-h, or pharmaceutically acceptable salts thereof, optionally substituted with 1-3R ₁₃ Substituted 6-10 membered aryl, 5-10 membered heteroaryl;

each R ₁₃ 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 heterocyclyl, 3-6 membered heteroaryl, -NHCOR _13a 、-COR _13b 、-SO ₂ R _13c 、SOR _13c The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R _13a 、R _13b and R is _13c Each independently selected from amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, phenyl,para-methylphenyl;

preferably, the method comprises the steps of,

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

each R ₁₃ 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 heterocyclyl containing 1-3 heteroatoms, 3-6 membered heteroaryl containing 1-3 heteroatoms, -NHCOR _13a 、-COR _13b 、-SO ₂ R _13c 、SOR _13c The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group containing 1-3 heteroatoms, a 3-6 membered heteroaryl group containing 1-3 heteroatoms optionally substituted with 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;

R _13a 、R _13b and R is _13c Each independently selected from amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, phenyl, p-methylphenyl.

In certain embodiments, ring C is selected from the group consisting of compounds represented by formulas III, III-a, III-b, III-C, III-d, III-e, III-f, III-g, III-h, or pharmaceutically acceptable salts thereof, optionally substituted with 1-3R ₁₃ Substituted phenyl, pyridine, pyridazine, pyrazine, pyrimidine,Preferably ring C is selected from the group consisting of optionally 1 to 3R ₁₃ Substituted

Each R ₁₃ Independently selected from C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cyclic alkoxy, nitro, cyano, halogen, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone,Triazole, -NHCOR _13a 、-COR _13b 、-SO ₂ R _13c 、SOR _13c The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cyclic alkoxy, tetrahydrofuran ketone, pyrrolidine, pyrrolidone, triazole,Optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R _13a 、R _13b and R is _13c Each independently selected from amino, methyl, cyclopropyl, phenyl, p-methylphenyl.

In certain embodiments, R in a compound represented by formula III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, or a pharmaceutically acceptable salt thereof ₁₂ Selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, optionally substituted with 1-3R _12a Substituted, the R _12a Selected from oxo, thio, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals 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 is _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group containing 1-3 heteroatoms, a 3-6 membered heteroaryl group containing 1-3 heteroatoms optionally substituted with 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.

In certain embodiments, R in a compound represented by formula III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, or a pharmaceutically acceptable salt thereof ₁₂ Selected from the group consisting of 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,

The 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,Optionally by 1-3R _12a Substituted, the R _12a Selected from C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals 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 is _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group, the 3-6 membered heterocyclic group containing 1-3 hetero atoms, the 3-6 membered heteroaryl group containing 1-3 hetero atoms are optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino.

In certain embodiments, R in a compound represented by formula III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, or a pharmaceutically acceptable salt thereof ₁₂ Selected from the group consisting ofThe saidOptionally by 1-3R _12a Substituted, the R _12a Selected from C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals 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 is _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group, the 3-6 membered heterocyclic group containing 1-3 hetero atoms, the 3-6 membered heteroaryl group containing 1-3 hetero atoms are optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino.

In certain embodiments, R in a compound represented by formula III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, or a pharmaceutically acceptable salt thereof ₁₁ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, nitro, cyano, halogen; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

preferably R ₁₁ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, nitro, cyano, halogen; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy.

More preferably R ₁₁ Selected from hydrogen, cyclopropyl, trifluoromethyl.

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

wherein:

X ₁ 、X ₂ independently selected from C, O, N, X ₃ Selected from C, N or a bond; preferably X ₁ Selected from N, X ₂ Selected from C, X ₃ Selected from N;

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

R ₁₈ selected from oxo, thio, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals 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 is _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group containing 1-3 heteroatoms, a 3-6 membered heteroaryl group containing 1-3 heteroatoms optionally substituted with 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 selected from integers from 0 to 3;

R ₁₆ selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a nitro group, a cyano group, a halogen, a 3-6 membered heterocyclic group, a 3-6 membered heteroaryl group; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₇ Selected from optionally 1-3R _17a Substituted 6-10 membered aryl, 5-10 membered heteroaryl;

each R _17a 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 heterocyclyl, 3-6 membered heteroaryl, -NHCOR _17b 、-COR _17c 、-SO ₂ R _17d、 -SOR _17d The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R _17b 、R _17c and R is _17d Each independently selected from amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, phenyl, p-methylphenyl.

In certain embodiments, ring D is selected from the group consisting of 1-oxo-1, 2-dihydroisoquinolin-5-yl, 1-thioxo-1, 2-dihydroisoquinolin-5-yl, quinolin-5-yl, and isoquinolin-5-yl in the compound represented by formula IV or a pharmaceutically acceptable salt thereofLin-5-yl, naphthyl, thieno [2,3-c ]]Pyridin-4-yl,

R ₁₈ Selected from C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals 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 is _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group containing 1-3 heteroatoms, a 3-6 membered heteroaryl group containing 1-3 heteroatoms optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

m is selected from integers from 0 to 3.

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

m is selected from integers from 0 to 3.

In certain embodiments, a compound of formula IV or a pharmaceutically acceptable salt thereof, R ₁₇ Selected from optionally 1-3R _17a Substituted 6-10 membered aryl, 5-10 membered heteroaryl;

each R _17a 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 heterocyclyl, 3-6 membered heteroaryl, -NHCOR _17b 、-COR _17c 、-SO ₂ R _17d 、-SOR _17d The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R _17b 、R _17c And R is _17d Each independently selected from amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, phenyl, p-methylphenyl;

preferably, R ₁₇ Selected from optionally 1-3R _17a Substituted phenyl, naphthyl, 3-6 membered heteroaryl containing 1-3 heteroatoms;

each R _17a 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 heterocyclyl containing 1-3 heteroatoms, 3-6 membered heteroaryl containing 1-3 heteroatoms, -NHCOR _17b 、-COR _17c 、-SO ₂ R _17d 、-SOR _17d The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group containing 1-3 heteroatoms, a 3-6 membered heteroaryl group containing 1-3 heteroatoms optionally substituted with 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;

In certain embodiments, a compound of formula IV or a pharmaceutically acceptable salt thereof, R ₁₇ Selected from optionally 1-3R _17a Substituted phenyl, pyridine, pyridazine, pyrazine, pyrimidine,

Each R _17a Independently selected from C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cyclic alkoxy, nitro, cyano, halogen, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone,Triazole, -NHCOR _17b 、 -COR _17c 、-SO ₂ R _17d 、-SOR _17d The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cyclic alkoxy, tetrahydrofuran ketone, pyrrolidine, pyrrolidone, triazole,Optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R _17b 、R _17c and R is _17d Each independently selected from amino, methyl, cyclopropyl, phenyl, p-methylphenyl.

In certain embodiments, a compound of formula IV or a pharmaceutically acceptable salt thereof, R ₁₇ Selected from optionally 1-3R _17a Substituted pyridines;

each R _17a Independently selected from C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cyclic alkoxy, nitro, cyano, halogen, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone,Triazole, -NHCOR _17b 、-COR _17c 、-SO ₂ R _17d 、-SOR _17d The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cyclic alkoxy, tetrahydrofuran ketone, pyrrolidine, pyrrolidone, triazole,Optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R _17b 、R _17c And R is _17d Each independently selected from amino, methyl, cyclopropyl, phenyl, p-methylphenyl;

preferably, the method comprises the steps of,

R ₁₇ selected from optionally 1-3R _17a Substituted

Each R _17a Independently selected from halogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, nitroCyano, 1-3 halogen substituted C _1-6 An alkyl group.

In certain embodiments, a compound of formula IV or a pharmaceutically acceptable salt thereof, R ₁₆ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, nitro, cyano, halogen; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

preferably R ₁₆ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, nitro, cyano, halogen; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

more preferably R ₁₆ Selected from hydrogen, cyclopropyl, trifluoromethyl.

In a tenth aspect, the present disclosure also provides a compound of the formula,

in an eleventh aspect, the present disclosure also provides an isotopic substitution of the compound as set forth in the first to tenth aspects, preferably wherein the isotopic substitution is deuterium atom substitution.

In a twelfth aspect, the present disclosure also provides a pharmaceutical composition comprising a compound according to the first to eleventh aspects or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition is in a unit dose of 0.001mg to 1000mg.

In certain embodiments, the pharmaceutical composition comprises 0.01 to 99.99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the foregoing compound or pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the foregoing compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical compositions comprise 1% to 99% of the foregoing compounds, or pharmaceutically acceptable salts thereof. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the foregoing compound or a pharmaceutically acceptable salt thereof.

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

In a thirteenth aspect, the present disclosure also provides a method of preventing and/or treating a condition associated with MALT1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the first to eleventh aspects or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the twelfth aspect.

The MALT 1-related disorders include, but are not limited to, autoimmune diseases, inflammatory diseases, cancers, tumors, etc., such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitis diseases, hematopoietic primary cancers or solid tumors, including chronic myelogenous leukemia, non-hodgkin's lymphoma, and other B-cell lymphomas.

The present disclosure also provides a method of preventing and/or treating an autoimmune disease, inflammatory disease, cancer, tumor comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in the first to eleventh aspects or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in the twelfth aspect.

Such autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vascular inflammatory diseases, such as hematopoietic primary cancers or solid tumors, including chronic myelogenous leukemia, non-hodgkin's lymphoma and other B-cell lymphomas.

The present disclosure also provides the use of a compound according to the first to eleventh aspects or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the twelfth aspect in the manufacture of a medicament for the prevention and/or treatment of a MALT 1-related disorder.

The present disclosure also provides the use of a compound according to the first to eleventh aspects or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the twelfth aspect for the manufacture of a medicament for the prevention and/or treatment of autoimmune diseases, inflammatory diseases, cancers, tumors.

The present disclosure also provides a compound according to the first to eleventh aspects or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the twelfth aspect for use in the prevention and/or treatment of a MALT 1-related disorder.

The present disclosure also provides the use of a compound according to the first to eleventh aspects or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the twelfth aspect for the prevention and/or treatment of autoimmune diseases, inflammatory diseases, cancers, tumors.

The compound or the pharmaceutically acceptable salt or the pharmaceutical composition thereof has good inhibiting effect on MALT1 and IC with inhibiting activity on MALT1 ₅₀ IC having a value of 0.01 to 1000nM, inhibiting activity of certain compounds against MALT1 ₅₀ An IC50 value of 0.01 to 500nM for the inhibitory activity of certain compounds against MALT1, an IC50 value of 0.01 to 300nM for the inhibitory activity of certain compounds against MALT1 enzyme ₅₀ IC having a value of 0.01 to 200nM and inhibiting activity of certain compounds against MALT1 enzyme ₅₀ IC having a value of 0.01 to 100nM, inhibiting activity of certain compounds against MALT1 enzyme ₅₀ Value of<IC of inhibitory Activity of certain Compounds against MALT1 enzyme 100nM ₅₀ Value of<50nM。

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

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

Optically active (R) -and (S) -isomers and 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 may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).

In the chemical structure of the compounds of the invention, the bondIndicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structureMay beOr at the same time contain Two configurations. In the chemical structure of the compounds of the present disclosure, the bond The configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are included.

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

Tautomers are structural isomers of organic compounds that are readily interconvertible by chemical reactions known as tautomerization. This reaction often results in the formal migration of hydrogen atoms or protons, accompanied by a transition between single bonds and adjacent double bonds. Some common tautomers are: ketone-enols, lactams-lactams. Examples of lactam-lactam balances are between a and B as shown below,

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

Any isotopically-labeled derivative of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or an isomer thereof, is covered by the present disclosure. Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, and the like. They can be respectively isotopically substituted with ² H(D)、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁵ S、 ³⁶ Cl and Cl ¹²⁵ I, etc. Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium (i.e., at least 45% deuterium incorporation) having an abundance that is at least 3000 times greater than the natural abundance of deuterium (which is 0.015%).

The present disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds. Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, tridentate borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

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

Term interpretation:

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"pharmaceutically acceptable excipients" include, but are not limited to, any auxiliary agent, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent that has been approved by the U.S. food and drug administration for use in humans or livestock animals.

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 is also meant to be an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method of administration, the route and dosage, and the severity of the side effects. An effective amount may be the maximum dose or regimen that avoids significant side effects or toxic effects.

"alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, and various branched isomers thereof, and the like. The alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, 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, said 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 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

"alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. For example "C _2-6 Alkenyl "means alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups 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, substituents may be substituted at any useful point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxy, oxo, 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, said 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 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

"alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or alkynes containing aliphatic hydrocarbon groups. Such as ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl. Alkynyl groups may be substituted or unsubstituted and when substituted, substituents may be substituted at any useful point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxy, oxo, 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, said 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 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. 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, independently selected from halogen, deuterium, hydroxy, oxo, 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, said 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 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, aloneAnd is selected from halogen, deuterium, hydroxy, oxo, 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, said 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 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "cycloalkenyl" refers to partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. The cycloalkenyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, 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, said 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 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, 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 ring atoms are selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2), but does not include-O-; a ring moiety of O-S-or-S-S-, the remaining ring atoms being carbon . Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:

etc.

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

etc.

The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, 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, said 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 groupsOptionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, 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 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached 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 groups independently selected from halogen, deuterium, hydroxy, oxo, 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, said 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 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups may be 5 to 12 membered or 5 to 10 membered, more preferably 5 or 6 membered. Non-limiting examples of which 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, wherein the ring attached 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 groups independently selected from halogen, deuterium, hydroxy, oxo, 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, said 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 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, 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, said 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 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, 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 defined above.

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

The term "hydroxy" refers to an-OH group.

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

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

The term "oxo" refers to an =o substituent.

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

Detailed Description

The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

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

As the measurement of High Performance Liquid Chromatography (HPLC), shimadzu LC-20A systems, shimadzu LC-2010HT series, shimadzu DGU-20A5R, shimadzu LC-30AD, shimadzu SIL-30AC or Agilent 1200 LC high pressure liquid chromatograph (Ultimate XB-C18.0 x 150mm column or Xtimate C18.1 x 30mm column) was used.

Chiral HPLC analysis was performed using Chiralpak IC-3X 4.6mm I.D.,3um, chiralpak AD-3X 50.4.6 mm I.D.,3um, chiralpak AS-3X 4.6mm I.D.,3 μm, chiralCel OD-3 150×4.6mm I.D.,3um, chiralCel OD-3 100×4.6mm I.D.,3 μm, chiralCel OJ-H150×4.6mm I.D.,5um, chiralCel OJ-3 150×4.6mm I.D.,3um column.

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Column chromatography generally uses 100-200 mesh, 200-300 mesh or 300-400 mesh of yellow sea silica gel as a carrier.

Chiral preparative columns used DAICEL CHIRALPAK IC (250 mm. Times.30 mm,10 um) or Phenomnex-Amylose-1 (250 mm. Times.30 mm,5 um).

The CombiFlash flash rapid prep instrument used CombiFlash Rf150 (teldyne ISCO).

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

The known starting materials of the present invention may be synthesized using or following methods known in the art, or may be purchased from the companies ABCR GmbH & Co.KG, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples uses Thin Layer Chromatography (TLC), a developing agent used in the reaction, a system of column chromatography eluent used for purifying the compound and a developing agent system of thin layer chromatography, the volume ratio of the solvent is adjusted according to the polarity of the compound, water and acetonitrile are generally used as mobile phases, and small amounts of alkaline or acidic reagents such as triethylamine and acetic acid may 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

Isoquinolin-5-amine (5.1 g,35.37 mmol) was dissolved in concentrated hydrochloric acid (50 mL), aqueous solution (20 mL) of sodium nitrite (3.66 g,53.06 mmol) was added at 0deg.C, after 30 minutes of reaction, concentrated hydrochloric acid solution (20 mL) of stannous chloride (19.95 g,88.43 mmol) was added dropwise, reaction was carried out at room temperature for 3 hours, pH was adjusted to 12-14 with 20% aqueous sodium hydroxide solution, ethyl acetate was extracted (30 mL. Times.3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with ethyl acetate to give 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 ethyl (Z) -2- (ethoxymethylene) -4, 4-trifluoro-3-oxobutanoate 1c (3.52 g,14.64 mmol) were dissolved in ethanol (40 mL), reacted at 60℃for 3 hours, concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography eluting with ethyl acetate to give the title compound 1d (2.56 g, yield: 52.1%).

MS(ESI)：m/z＝336.4[M+H] ⁺ 。

Third step

5- (4- (ethoxycarbonyl) -5- (trifluoromethyl) -1H-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), m-chloroperoxybenzoic acid (3.95 g,22.9 mmol) was added at 0 ℃ and reacted overnight at room temperature, washed successively with half-saturated sodium hydrogen sulfite solution (20 mL x 2) and potassium carbonate solution (20 mL x 2), and the organic phase dried and concentrated in vacuo to give the title compound 1e (2.50 g, yield: 93.21%).

MS(ESI)：m/z＝352.4[M+H] ⁺ 。

Fourth step

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

5- (4- (ethoxycarbonyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl) isoquinoline 2-oxide (2.5 g,7.12 mmol) was dissolved in chloroform (30 mL), phosphorus oxychloride (1.33 mL,14.23 mmol) was added at room temperature, reacted for 3 hours at 60℃and quenched with water (20 mL) under ice bath, and the organic phase was concentrated in vacuo and purified by silica gel column chromatography eluting with petroleum ether, ethyl acetate to give the title compound 1f (1.96 g, yield: 74.49%).

MS(ESI)：m/z＝370.43[M+H] ⁺ 。

Fifth step

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

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

MS(ESI):m/z＝324.4[M+H] ⁺ 。

Sixth step

1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid (100 mg,0.31 mmol) and 4- (trifluoromethyl) pyrimidin-2-amine (50.46 mg,0.31 mmol) were dissolved in pyridine (10 mL), phosphorus oxychloride (0.058 mL,0.62 mmol) was added at room temperature and the mixture was subjected to microwave reaction at 120℃for 1 hour. Saturated aqueous sodium bicarbonate (20 mL) was added, dichloromethane extracted (20 mL x 3) and the organic phase concentrated in vacuo and separated by high performance liquid chromatography to give the title compound 1 (12 mg, yield: 8.28%).

MS(ESI):m/z＝469.5[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.80(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) -1H-pyrazole-4-carboxylic acid (120 mg,0.37 mmol) and 6- (trifluoromethyl) pyrimidin-4-amine (60.55 mg,0.37 mmol) were dissolved in pyridine (10 mL), phosphorus oxychloride (0.069 mL,0.74 mmol) was added at room temperature and the mixture was subjected to microwave reaction at 120℃for 20min. Saturated aqueous sodium bicarbonate (20 mL) was added, dichloromethane extracted (20 mL x 3), and the organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography to give 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) pyridin-4-yl) -1H-pyrazole-4-carboxamide 3

First step

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

1- (1-chloroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid ethyl ester 1f (200 mg,0.54 mmol) was dissolved in dioxane solution (12 mL), hydrazine hydrate (3 mL) was added at room temperature, reaction was carried out at 70℃for 5 hours, and the reaction solution was concentrated under reduced pressure to give 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

1- (1-hydrazinoisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid ethyl ester (225 mg,0.62 mmol) was dissolved in triethyl orthoformate (8 mL), and the reaction solution was concentrated under reduced pressure at 100℃for 1 hour to give 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 (220 mg,0.58 mmol) was dissolved in concentrated hydrochloric acid (10 mL), reacted at 120℃for 1 hour, and the reaction solution was concentrated under reduced pressure to give the title compound 3f (240 mg, crude product).

MS(ESI)：m/z＝348.4[M+H] ⁺ 。

Fourth step

1- ([ 1,2,4] triazolo [3,4-a ] isoquinolin-7-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid (70 mg,0.20 mmol) and 3g (32.68 mg,0.20 mmol) of 2- (trifluoromethyl) pyridin-4-amine were dissolved in pyridine (6 mL), phosphorus oxychloride (0.038 mL,0.40 mmol) was added dropwise and reacted at room temperature for 1 hour. Water (10 mL) was added, dichloromethane extraction (3X 15 mL) and the organic phase concentrated under reduced pressure and separated by high performance liquid chromatography to give 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) -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), phosphorus oxychloride (0.038 mL,0.41 mmol) was added dropwise and reacted at room temperature for 1 hour. Water (10 mL) was added, dichloromethane (15 mL. Times.3) was extracted, the organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography to give 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-triazol-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) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid 3f (70 mg,0.20 mmol) and 5-chloro-6- (2H-1, 2, 3-triazol-2-yl) pyridin-3-amine 5a (39.43 mg,0.20 mmol) were dissolved in pyridine (6 mL), phosphorus oxychloride (0.038 mL,0.40 mmol) was added dropwise, reacted at room temperature for 1 hour, water (10 mL) was added, dichloromethane extraction (3X 15 mL) and the organic phase concentrated under reduced pressure, separated by high performance liquid chromatography to give the title compound 5 (25 mg, yield: 23.6%).

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-thio-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 (200 mg,0.54 mmol) and thiourea (45.3 mg,0.59 mmol) were dissolved in ethanol (10 mL), reacted at 80℃for 2 hours, the reaction solution was added with water (10 mL), extracted with ethyl acetate (15 mL. Times.3), and the organic phase was dried and concentrated under reduced pressure to give the title compound 6b (214 mg, 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 (214 mg,0.58 mmol) was dissolved in concentrated hydrochloric acid (10 mL), reacted at 120℃for 1 hour, and the reaction solution was concentrated under reduced pressure to give the title compound 6c (198 mg, crude product).

MS(ESI)：m/z＝340.4[M+H] ⁺ 。

Third step

1- (1-thio-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid (51 mg,0.15 mmol) and 3g (24.37 mg,0.15 mmol) of 2- (trifluoromethyl) pyridin-4-amine were dissolved in pyridine (6 mL), phosphorus oxychloride (0.028 mL,0.30 mmol) was added dropwise and reacted at room temperature for 1 hour. Water (10 mL) was added, dichloromethane extraction (3X 15 mL) and the organic phase concentrated under reduced pressure and separated by high performance liquid chromatography to give 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 )δ13.62(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

1- (1-thio-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid 7a (65 mg,0.19 mmol) and 5-chloro-6-methoxypyridine-3-amine 4a (30.38 mg,0.19 mmol) were dissolved in pyridine (6 mL), phosphorus oxychloride (0.036 mL,0.38 mmol) was added dropwise, reacted at room temperature for 1 hour, water (10 mL) was added, dichloromethane extraction (3X 15 mL) and the organic phase concentrated under reduced pressure and separated by high performance liquid chromatography to give the title compound 7 (2 mg, 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-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxamide 8

First step

1- (1-thio-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid 7a (60 mg,0.18 mmol) and 5-chloro-6- (2H-1, 2, 3-triazol-2-yl) pyridin-3-amine 5a (34.59 mg,0.18 mmol) were dissolved in pyridine (6 mL), phosphorus oxychloride (0.033 mL,0.35 mmol) was added dropwise and reacted at room temperature for 1 hour. Water (10 mL) was added, dichloromethane (15 mL. Times.3) was extracted, the organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography to give 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) -1H-1,2, 3-triazole-4-carboxamide 9

First step

5-azidoisoquinoline 9b

Isoquinolin-5-amine 1a (1 g,6.94 mmol) was dissolved in acetonitrile (14 mL), tert-butyl nitrite (1.1 g,10.40 mmol) and trimethyl silicon azide (1.2 g,10.40 mmol) were added at 0deg.C, after reaction for 1 hour, the reaction solution was concentrated and purified by silica gel column chromatography eluting with ethyl acetate and n-hexane to give 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 (220 mg,1.29 mmol) and ethyl trifluoroacetoacetate (238 mg,1.29 mmol) were dissolved in tetrahydrofuran (5 mL), heated under reflux for 20 hours under nitrogen, and purified by silica gel column chromatography eluting with ethyl acetate and n-hexane to give 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

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

MS(ESI)：m/z＝309.1[M+H] ⁺ 。

Fourth step

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), then 5-chloro-6- (2H-1, 2, 3-triazol-2-yl) pyridin-3-amine 5a (64 mg,0.33 mmol) was added, phosphorus oxychloride (114 mg,0.74 mmol) was added at room temperature and reacted overnight at room temperature. After the completion of the reaction, the organic phase was concentrated under reduced pressure, purified by C18 reverse phase column chromatography and lyophilized to give 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 )δ11.82(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

4-bromo-2- (difluoromethyl) pyridine (300 mg,1.44 mmol) was dissolved in aqueous ammonia (2 mL) and N-methylpyrrolidone (NMP) (1 mL), cuprous oxide (41 mg,0.29 mmol) was added, and the reaction was reacted at 140℃for 1 hour under microwaves after completion of the reaction, 5mL ethyl acetate was added, and then the organic phase was concentrated under reduced pressure, washing twice with 5mL water and 5mL saturated aqueous NaCl solution, respectively, to give the title compound 10b (210 mg, crude product) which was used directly in the next step without further purification.

MS(ESI)m/z：145.3[M+H] ⁺ 。

Second step

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

MS(ESI)m/z：450.6[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.64(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＝8.0Hz,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

5-bromobenzo [ c ] [1,2,5] oxadiazole 11a (250 mg,1.25 mmol) was dissolved in ammonia (1.5 mL) and N-methylpyrrolidone (1 mL), cuprous oxide (36 mg,0.25 mmol) was added, and the reaction was reacted at 140℃for 1 hour under microwaves.

MS(ESI)m/z：136.3[M+H] ⁺ 。

Second step

Benzo [ C ] [1,2,5] oxadiazol-5-amine 11b (50 mg,0.37 mmol) was dissolved in pyridine (3 mL), 1g (119 mg,0.37 mmol) of 1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid was further added, phosphorus oxychloride (113 mg,0.74 mmol) was added at room temperature, the reaction solution was concentrated under reduced pressure and purified by C18 reverse phase column chromatography and lyophilized to give the title compound 11 (8.3 mg, yield: 5%).

MS(ESI)：m/z＝441.6[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.65(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- (Cyclopropionyl) -3-ethoxyacrylic acid ethyl ester 12c

Ethyl 3-cyclopropyl-3-oxopropionate (0.945 mL,6.403 mmol) was dissolved in acetic anhydride (1.8 mL,19 mmol) at room temperature, triethyl orthoformate (2 mL,12 mmol) was slowly added dropwise and stirred at 130℃for 4h. After completion of the reaction, the reaction solution was concentrated under reduced pressure to give the title compound 12c (2.2 g, yield: 80%) which was 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 (0.60 g,3.769 mmol) and ethyl (Z) -2- (cyclopropoyl) -3-ethoxyacrylate 12c (0.8 g,3.769 mmol) were dissolved in ethanol (10 mL) and stirred at 60℃for 3 hours until the reaction was complete. The reaction solution was cooled to room temperature, concentrated under reduced pressure to give a crude product, and the residue was purified by silica gel column chromatography with an eluent system (petroleum ether, ethyl acetate) to give 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

Compound 12d (50 mg,0.163 mmol) was dissolved in methanol (2 mL) and water (1 mL) at room temperature, and sodium hydroxide (13 mg,0.325 mmol) was added. The reaction solution was heated to 65℃and stirred for 3 hours until the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (10 mL), ph=5 was adjusted 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. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 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)。

Fourth step

Compound 12e (20 mg,0.072 mmol), 2- (trifluoromethyl) pyridin-4-amine 3g (11.61 mg,0.072 mmol) and pyridine (56.64 mg, 0.710 mmol) were dissolved in dichloromethane (2 mL) at room temperature and phosphorus oxychloride (11 mg,0.072 mmol) was added. The reaction was stirred at 25℃for 1 hour, then warmed to 50℃and continued for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate solution (0.1 mL) and concentrated under reduced pressure to give 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) pyridin-3-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxamide 13

First step

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

3- (trifluoromethyl) pyridine-2-amine 13a (1 g,6.169 mmol) was dissolved in concentrated H ₂ SO ₄ (10 mL) of the mixture was cooled to 0℃and concentrated HNO was slowly added dropwise ₃ (0.309 mL,7.402 mmol). The reaction was carried out at 0℃for 1 hour, followed by 25℃for 3 hours until completion. The reaction was poured into ice water (20 mL) and extracted with ethyl acetate (30 mL. Times.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 column chromatography on silica gel (0 to 20% ethyl acetate/petroleum ether) to give the title compound 13a (1.0 g, 78%).

¹ H NMR(400MHz,DMSO-d6)δppm 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 (500 mg,2.414 mmol) was dissolved in acetonitrile (10 mL), chlorobutyryl chloride (0.545 mL, 4.8238 mmol) and diisopropylethylamine (1.197mL, 7.243 mmol) were slowly added dropwise and reacted at 25℃for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0.about.30% ethyl acetate/petroleum ether) to give the title compound 13d (100 mg, yield: 15%).

¹ H NMR(400MHz,CDCl ₃ )δppm 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, 0.803 mmol) was dissolved in methanol (10 mL) and Pd/C10% (39 mg, 0.803 mmol) was added under argon. After hydrogen displacement, the reaction was completed at room temperature under a hydrogen atmosphere (15 psi). Insoluble matter was filtered off, and concentrated under reduced pressure to give the title compound 13e (50 mg, yield: 56%), which was used in the next step without purification.

MS(ESI)m/z：246.1[M+H] ⁺ 。

Fourth step

1- [ 5-amino-3- (trifluoromethyl) pyridin-2-yl ] pyrrolidin-2-one 13e (35 mg,0.143 mmol), 1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid 1g (46.14 mg,0.143 mmol) and pyridine (0.115 mL,1.427 mmol) were dissolved in dichloromethane (5 mL) and phosphorus oxychloride (0.013 mL,0.143 mmol) was slowly added dropwise. The reaction was stirred at room temperature until the reaction was complete. The reaction was poured into saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (30 mL. Times.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 give the title compound 13 (7.1 mg, yield: 9%).

MS(ESI)m/z：551.2[M+H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δppm 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:(400MHz,CD ₃ OD)δppm-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-carboxamide 14

First step

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

1- (isoquinolin-5-yl) -5- (trifluoromethyl) -1H-1,2, 3-triazole-4-carboxylic acid ethyl ester 14a (250 mg,0.74 mmol) was dissolved in dichloromethane (5 mL), and 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 methylene chloride, further washed with 2mmol/L sodium hydrogensulfite (10 mL), further washed with saturated sodium hydrogencarbonate solution (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system of ethyl acetate/n-hexane to give 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 at reflux for 3 h. The reaction solution was concentrated under reduced pressure to give the title compound 14c (210 mg, yield: 100%) which was used 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 at reflux for 6 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by C18 reverse phase column chromatography and freeze-dried to give 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)。

Fourth step

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

Compound 14d (30 mg,0.09 mmol) was dissolved in pyridine (3 mL), 3g (15 mg,0.09 mmol) of 2- (trifluoromethyl) pyridin-4-amine was added thereto, phosphorus oxychloride (28 mg,0.18 mmol) was added thereto at room temperature, and the reaction was continued at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, purified by C18 reverse phase column chromatography, and lyophilized to give 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-dihydroisoquinolin-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 (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (70 mg,0.085 mmol) and potassium carbonate (236 mg,1.71 mmol) were added and reacted for 1 hour by microwaves. After completion of the reaction, 10mL of ethyl acetate was added to dilute, and then washed with water (10 mL), and then with saturated aqueous NaCl solution (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system of ethyl acetate/n-hexane to give 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-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxamide 15

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

1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid 1g (59 mL,0.18 mmol) was dissolved 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 (30 mg,0.15 mmol) were added at room temperature, reacted for 12 hours at 45℃and concentrated under reduced pressure, the residue was purified by high performance liquid chromatography to give the title compound 16 (4.1 mg, yield: 5.3%).

MS(ESI)：m/z＝502.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ11.63(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- (trifluoromethyl) -1H-pyrazole-4-carboxamide 17

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 (50 mg,0.1 mmol) was dissolved in methanol (6 mL), palladium on carbon (10%, 20 mg) was added at room temperature, and the mixture was stirred at room temperature under a hydrogen atmosphere for 40 minutes. Filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to give the title compound 17 (4.5 mg, yield: 8.9%).

MS(ESI)：m/z＝503.4[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ8.71(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- (trifluoromethyl) -1H-pyrazole-4-carboxamide 18

First step

3- [ (N, N-Di-t-Butoxycarbonyl) amino ] -1-chloro-pyridine 18b

5-chloropyridin-3-amine 18a (500 mg,3.89 mmol) was dissolved in tetrahydrofuran (8 mL), and di-tert-butyl dicarbonate (2.49 mL,11.67 mmol) and p-dimethylaminopyridine (23 mg,0.19 mmol) were added at room temperature and reacted at room temperature for 12 hours. The reaction solution was poured into water (15 mL), extracted with ethyl acetate (15 ml×2), the organic phases were combined, washed with saturated aqueous sodium chloride (20 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to give the title compound 18b (800 mg, yield: 62.5%).

¹ H NMR(400MHz,CDCl ₃ )δ8.51(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

3- [ (N, N-Di-t-Butoxycarbonyl) amino ] -1-chloro-pyridine 18b (200 mg,0.61 mmol) was dissolved in dimethyl sulfoxide (2 mL), 4-methylbenzene-1-sulfonic acid (0.078 mL,0.49 mmol) was added at room temperature, stirred at room temperature for 20 minutes, tetrahydrofuran (2 mL,24.41 mmol), ammonium peroxodisulfate (0.35 mL,3.04 mmol) and bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine ] [2-2 "-bis (4-t-butylpyridine) ] iridium bis (hexafluorophosphoric acid) salt (68 mg,0.061 mmol) were added, and the reaction solution was degassed for 10 minutes and sealed. The reaction mixture was stirred at room temperature for 3 hours under irradiation of blue light, water (20 mL) was added, extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography to give the title compound 18c (40 mg, yield: 16%).

¹ H NMR(400MHz,CDCl ₃ )δ8.34(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-t-butoxycarbonyl) amino ] -pyridine 18c (30 mg,0.075 mmol) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL,20.19 mmol) was added under ice-bath. The reaction was carried out at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to give the title compound 18d (14 mg, yield: 93%).

¹ H NMR(400MHz,CDCl ₃ )δ8.01(d,J＝2.4Hz,1H),6.98(d,J＝2.4Hz,1H),5.37-5.22(m,1H),4.14(q,J＝7.2Hz,1H),3.93(dt,J＝5.6,7.6Hz,1H),2.31-1.92(m,4H)。

Fourth step

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

MS(ESI)：m/z＝504.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ11.62(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＝7.2Hz,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 (3.0 g,12.63 mmol) was dissolved in 1, 4-dioxane (25 mL), and pyrrolidin-2-one (1.95 mL,25.27 mmol), methyl [2- (methylamino) ethyl ] amine (0.27 mL,2.53 mmol), potassium phosphate (5.36 g,25.27 mmol) and copper iodide (0.086 mL,2.53 mmol) were added at room temperature. The reaction was carried out at 110℃for 12 hours under nitrogen, cooled to room temperature, water (50 mL) was added, ethyl acetate was extracted (80 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the title compound (1.0 g, yield: 32%).

MS(ESI)：m/z＝242.0[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ9.18(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

1- (3-chloro-5-nitropyridin-2-yl) pyrrolidin-2-one 19b (1.0 g,4.14 mmol) was dissolved in ethanol/water (20 mL/5 mL), ammonium chloride (2.21 g,41.3 mmol) and iron powder (1.16 g,20.6 mmol) were added at room temperature and reacted for 1 hour at 90℃cooled to room temperature and filtered through celite with suction and the filtrate concentrated under reduced pressure to give the title compound 19c (800 mg, yield: 91.3%).

MS(ESI)：m/z＝212.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ7.75(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

1- (5-amino-3-chloropyridin-2-yl) pyrrolidin-2-one 19c (61 mg,0.29 mmol) was dissolved in tetrahydrofuran (4 mL) and sodium hydride (58 mg,1.46 mmol) and a solution of 1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carbonyl chloride 21H (100 mg,0.29 mmol) in tetrahydrofuran (4 mL) were added at 0deg.C. After 1 hour at room temperature, the reaction mixture was stirred for another 1 hour at 60 ℃, cooled to room temperature, quenched by slow addition of saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL x 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 give the title compound 19 (55 mg, yield: 37%).

MS(ESI)：m/z＝571.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ11.63(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) -1H-pyrazole-4-carboxylic acid 1g (60 mg,0.19 mmol) and 4- (trifluoromethyl) pyridin-2-amine 3g (30 mg,0.19 mmol) were dissolved in pyridine (6 mL), phosphorus oxychloride (0.035 mL,0.37 mmol) was added dropwise, reacted for 1 hour at room temperature, water (10 mL) was added, dichloromethane extraction (15 mL. Times.3) and the organic phase was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to give 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

6-iodopyridazine-4-carboxylic acid methyl ester 21b

To a mixture of methyl 6-chloropyridazine-4-carboxylate (2 g,11.589 mmol) and hydroiodic acid (20 ml) was added sodium iodide (2.61 g, 17.284 mmol). Stirring is carried out for 12 hours at 50℃under nitrogen. 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 )δppm 9.52(d,J＝1.6Hz,1H),8.30(d,J＝2.0Hz,1H),3.95(s,3H)。

Second step

6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester 21d

Methyl 6-iodopyridazine-4-carboxylate (600 mg,2.273 mmol) and 21c (639 mg,2.046 mmol) were dissolved in N, N-dimethylformamide (5 ml) and the mixture was microwave heated to 110℃under a nitrogen atmosphere for 4 hours. The reaction mixture was slowly quenched 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 (flow agent: 0 to 15% ethyl acetate/petroleum ether gradient 30 ml/min) to give methyl 6- (trifluoromethyl) pyridazine-4-carboxylate 21d (210 mg, yield: 44.8%).

MS(ESI)m/z：207.0[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ9.88(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, 3.930mmol). The mixture was stirred at 20 ℃ 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. Times.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 )δppm 9.84(d,J＝1.6Hz,1H),8.45(d,J＝2.0Hz,1H)。

Fourth step

N- [6- (trifluoromethyl) pyridazin-4-yl ] aminocarboxylic acid tert-butyl ester 21f

To a mixture of 6- (trifluoromethyl) pyridazine-4-carboxylic acid (210 mg,1.093 mmol) in tert-butanol (5 ml) was added diphenyl azide phosphate (DPPA) (0.284 ml,1.312 mmol) and triethylamine (0.228 ml,1.640 mmol). The mixture was stirred at 90℃for 12 hours. The reaction mixture was concentrated under reduced pressure, water (10 ml) was added, and extracted with ethyl acetate (10 ml×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 to 30% ethyl acetate/petroleum ether) to give tert-butyl N- [6- (trifluoromethyl) pyridazin-4-yl ] aminocarboxylate 21f (140 mg, yield: 43.79%).

MS(ESI)m/z＝264.1[M+H] ⁺ 。

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

Fifth step

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

To a mixture of tert-butyl N- [6- (trifluoromethyl) pyridazin-4-yl ] aminocarboxylate (140 mg,0.532 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml). The reaction was at room temperature and TLC (PE/ea=3:1) showed complete reaction. The reaction mixture was adjusted to ph=8 with 1N aqueous sodium hydroxide solution, extracted with dichloromethane (10 ml×3), and 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 21g of 6- (trifluoromethyl) pyridazin-4-amine (100 mg, yield: 97%).

MS(ESI)m/z＝164.1[M+H] ⁺ 。

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

Sixth step

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

Oxalyl chloride (0.040 ml, 0.460 mmol) and DMF (0.002ml, 0.031 mmol) were added to a mixture of 1g (100 mg,0.309 mmol) of 1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid in dichloromethane (2 ml) at 0deg.C. The mixture was stirred at 20℃for 1 hour, and concentrated under reduced pressure to give 1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carbonyl chloride (100 mg, yield: 94%), which was used in the next step without further purification.

MS(ESI)m/z＝338.0[M+H] ⁺ 。

Seventh step

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 6- (trifluoromethyl) pyridazin-4-amine 21g (25 mg,0.153 mmol) in tetrahydrofuran (2 ml) was added sodium hydride (30.66 mg,0.766 mmol) at 0 ℃. A solution of 1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carbonyl chloride in tetrahydrofuran (2 ml) was added at 0deg.C for 21H (52.37 mg,0.153 mmol). Saturated aqueous ammonium chloride (10 mL) was added to slowly stop the reaction. The aqueous layer was extracted with ethyl acetate (20 mL. Times.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 (condition: water (0.1% formic acid) -acetonitrile; 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 )δppm 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) -1H-pyrazole-4-carboxylic acid 7a (60 mg,0.18 mmol) and 6- (trifluoromethyl) pyridazin-4-amine 22a (28.84 mg,0.18 mmol) were dissolved in pyridine (6 mL), phosphorus oxychloride (0.033 mL,0.35 mmol) was added at room temperature, reacted for 2 hours at 60℃cooled to room temperature, saturated aqueous sodium bicarbonate solution (15 mL) was added, dichloromethane extraction (15 mL. Times.3) and the organic phase was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to give the title compound 22 (16 mg, yield: 18%).

MS(ESI)：m/z＝485.2[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ9.64(d,J＝2.4Hz,1H),9.02(d,J＝8.4Hz,1H),8.58(s,1H),8.52(d,J＝2.4Hz,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- (trifluoromethyl) -1H-pyrazole-4-carboxamide 23

First step

1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid 1g (300 mg,0.93 mmol) and 2-chloro-6- (trifluoromethyl) pyridin-4-amine 23a (182.43 mg,0.93 mmol) were dissolved in pyridine (10 mL), phosphorus oxychloride (0.17 mL,1.86 mmol) was added at room temperature, reacted for 1 hour at room temperature, saturated aqueous sodium bicarbonate solution (20 mL) was added, dichloromethane extraction (20 mL. Times.3) was performed, the organic phase was concentrated under reduced pressure and the residue was separated by high performance liquid chromatography to give the title compound 23 (300 mg, yield: 64%).

MS(ESI)：m/z＝502.6[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.64(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-dihydropyridin-4-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxamide 24

First step

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

MS(ESI)：m/z＝484.3[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.63(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-trifluoromethyl) -1H-pyrazole-4-carboxamide 25

First step

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

MS(ESI)：m/z＝457.2[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO- _d6 )δ11.63(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-thioxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxamide 26

1- (1-thio-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid 7a (52 mg,0.15 mmol) and benzo [ c ] [1,2,5] oxadiazol-5-amine 11b (31 mg,0.23 mmol) were dissolved in pyridine (6 mL), phosphorus oxychloride (0.029 mL,0.31 mmol) was added at room temperature, after the reaction was complete at room temperature, saturated aqueous sodium bicarbonate solution (15 mL) was added, dichloromethane extraction (15 mL. Times.3) and the organic phase was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography to give title compound 26 (2.5 mg, yield: 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

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

MS(ESI)：m/z＝441.3[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.62(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-pyrrole-4-carboxamide 28

First step

3-chloro-4-methylsulfinylaniline 28b

2-chloro-1-methylsulfinyl-4-nitrobenzene 28a (300 mg,1.37 mmol) was dissolved in ethanol/water (10 mL/2 mL), and iron powder (3831 mg,6.83 mmol) and ammonium chloride (730 mg,13.66 mmol) were added at room temperature and reacted at 90℃for 1 hour. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (15 mL), washed with water (15 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 28b (130 mg, yield: 50%).

MS(ESI)：m/z＝190.0[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ7.45(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 (130 mg,0.68 mmol) was dissolved in tetrahydrofuran (1 mL), diisopropylethylamine (0.34 mL,2.056 mmol) and a solution of 1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carbonyl chloride (281mg, 0.82 mmol) in tetrahydrofuran (1 mL) were added at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give the title compound 28 (100 mg, yield: 26.5%).

MS(ESI)：m/z＝495.0[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ11.64(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＝6.1,7.2Hz,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 (500 mg,3.084 mmol) was dissolved in dichloromethane (10 mL), N-chlorosuccinimide (NBS) (268 mg,3.084 mmol) was added at room temperature and reacted at room temperature under nitrogen atmosphere for 16 hours, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give the title compound 29a (790 mg, yield: 95.6%).

MS(ESI)：m/z＝241.0[M+H] ⁺ 。

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

Second step

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

2-bromo-5- (trifluoromethyl) aniline 29a (190 mg,0.792 mmol) was dissolved in methanol (10 mL), copper (123 mg,1.95 mmol) and sodium methoxide (1216 mg,8.333 mmol) were added at room temperature, the reaction was reacted at 100℃for 18 hours, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give 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

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

MS(ESI)：m/z＝498.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO- _d6 )δ11.74-11.55(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 (1 g,4.41 mmol) was added to aqueous ammonia in methanol (7M, 9.46 mL), reacted at room temperature for 14 hours, the reaction concentrated under reduced pressure, the residue diluted with water (40 mL), extracted with ethyl acetate (40 mL. Times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the title compound 30b (900 mg, yield: 98.4%).

¹ H NMR(400MHz,DMSO-d6)δ9.05(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 (0.19 mL,1.45 mmol) was dissolved in dichloromethane (3 mL), triethylamine (0.40 mL,2.90 mmol) and p-dimethylaminopyridine (194 mL,1.59 mmol) were added at room temperature, then acetyl chloride (0.11 mL,1.59 mmol) was added under ice-bath, reacted for 1 hour at room temperature, water (30 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL. Times.2), the organic phases combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure and the residue purified by silica gel column chromatography to give the title compound 30c (300 mg, yield: 83%).

¹ H NMR(400MHz,DMSO-d6)δ10.73(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

N- (5-nitro-3- (trifluoromethyl) pyridin-2-yl) acetamide 30c (240 mg,0.96 mmol) was dissolved in ethanol/water (5 mL/1.5 mL) and ammonium chloride (0.042 mL,1.20 mmol) and iron powder (0.034 mL,4.82 mmol) were added at room temperature and reacted at 90℃for 1 hour. Cooled to room temperature, water (50 mL) was added to the reaction, extracted with ethyl acetate (50 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 30d (200 mg, 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)。

Fourth step

N- [ 5-amino-3- (trifluoromethyl) pyridin-2-yl ] acetamide 30d (35 mg,0.16 mmol) was dissolved in tetrahydrofuran (3 mL), sodium hydride (17 mg,0.73 mmol) was added under ice-bath, after 10 min 1g (50 mg,0.15 mmol) of 1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxamide chloride was added, reaction was carried out at room temperature under nitrogen atmosphere for 2 hours, ammonium chloride (10 mL) was added under ice-bath, ethyl acetate extraction (30 mL. Times.2) and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to give 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 (129 mg,0.57 mmol) was dissolved in N, N-dimethylformamide (7 mL), and tetrahydropyrrole 31b (0.7 mL,0.85 mmol) and cesium carbonate (375 mg,1.14 mmol) were added at room temperature. The reaction was carried out at room temperature for 3 hours, water (15 mL) was added to the reaction mixture, and extraction was carried out with ethyl acetate (15 mL. Times.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 give 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

5-nitro-2- (pyrrolidin-1-yl) -3- (trifluoromethyl) pyridine 31c (100 mg,0.38 mmol) was dissolved in ethanol/water (6 mL/2 mL) and iron powder (213 mg,3.8 mmol) and ammonium chloride (206 mg,3.83 mmol) were added at room temperature. The reaction was carried out at 80℃for 2 hours, the reaction mixture was filtered through celite, water (15 mL) was added to the filtrate, and extraction was carried out with ethyl acetate (15 mL. Times.3). The organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give 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) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid (68 mg,0.21 mmol) 1g and 6- (pyrrolidin-1-yl) -5- (trifluoromethyl) pyridin-3-amine 31d (49 mg,0.21 mmol) were dissolved in pyridine (5 mL), phosphorus oxychloride (0.42 mmol,0.04 mL) was added at room temperature, reacted for 1 hour at room temperature, saturated aqueous sodium bicarbonate solution (10 mL) was added, dichloromethane extraction (10 mL. Times.3) and the organic phase was concentrated under reduced pressure and the residue was isolated and purified by high performance liquid chromatography to give title compound 31 (5.6 mg, yield: 4.93%).

MS(ESI)：m/z＝537.3[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.63(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- (trifluoromethyl) -1H-pyrazole-4-carboxamide 32

First step

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

1- (4-Chloropyridin-2-yl) ethan-1-one 32a (0.24 mL,1.928 mmol) was dissolved in methylene chloride (5 mL), and diethylaminosulfur trifluoride DAST (2.54 mL,19 mmol) was added thereto with ice-bath, and reacted at 25℃for 12 hours. Saturated aqueous sodium bicarbonate (30 mL) was added, extracted with dichloromethane (20 mL x 3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 32b (30 mg, yield: 8.7%).

¹ H NMR(400MHz,CDCl ₃ )δ8.55(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

N- [2- (1, 1-difluoroethyl) pyridin-4-yl ] carbamic acid tert-butyl ester 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), and 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (16 mg,0.051 mmol), cesium carbonate (247 mg,0.76 mmol) and palladium acetate (11 mg,0.051 mmol) were added at room temperature. Microwave reaction at 80℃for 2 hours, cooling to room temperature, concentrating under reduced pressure, and separating and purifying the residue by silica gel column chromatography to give the title compound 32c (130 mg, yield: 89%).

¹ H NMR(400MHz,CDCl ₃ )δ8.46(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

Tert-butyl N- [2- (1, 1-difluoroethyl) pyridin-4-yl ] carbamate (70 mg, 0.271mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL,13.463 mmol) was added under ice-bath, reacted for 12 hours at 25℃concentrated under reduced pressure, the residue was poured into saturated aqueous sodium bicarbonate solution (15 mL), extracted with dichloromethane (15 mL. Times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the title compound 32d (30 mg, yield: 69%).

¹ H NMR(400MHz,CDCl ₃ )δ8.26(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)。

Fourth step

2- (1, 1-difluoroethyl) pyridin-4-amine 32d (45 mg, 0.284 mmol) was dissolved in tetrahydrofuran (2 mL), sodium hydride (56 mg,1.423 mmol) and a solution of 1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxamide 21H (97.22 mg, 0.284 mmol) in tetrahydrofuran were added at 0 ℃ under nitrogen atmosphere, the reaction was quenched at 60 ℃ for 12 hours, saturated aqueous ammonium chloride solution (10 mL) was slowly added dropwise, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated and purified by high-performance liquid chromatography to give the title compound 32 (11 mg, yield: 8.7%).

MS(ESI)：m/z＝464.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO- _d6 )δ11.64(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- (trifluoromethyl) -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,5.48mmol, 60%) was added at room temperature. After 10 minutes at room temperature under nitrogen, 33b (630 mg,3.55 mmol) of 2, 2-difluoro-2- (fluorosulfonyl) acetic acid was added and the reaction was continued at room temperature for 20 minutes. Water (15 mL) was added in ice bath, ethyl acetate was extracted (20 mL. Times.3), the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give the title compound 33c (267 mg, yield: 58%).

Second step

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

3-chloro-2- (difluoromethoxy) -5-nitropyridine 33c (267 mg,1.19 mmol) was dissolved in acetic acid (10 mL), iron powder (264 mg,11.89 mmol) was added at room temperature, the reaction was carried out at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, methylene chloride (15 mL) was dissolved and filtered through celite, the saturated sodium bicarbonate solution was washed, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give the title compound 33d (214 mg, yield: 92.5%).

MS(ESI)：m/z＝195.1[M+H] ⁺ 。

Third step

1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid 1g (73 mg,0.23 mmol) and 5-chloro-6- (difluoromethoxy) pyridin-3-amine 33d (44 mg,0.23 mmol) were dissolved in pyridine (7 mL), phosphorus oxychloride (0.042 mL,0.45 mmol) was added at room temperature and reacted for 1 hour at room temperature, saturated aqueous sodium bicarbonate solution (10 mL) was added, dichloromethane extraction (10 mL. Times.3) was performed, the organic phase was concentrated under reduced pressure and the residue was separated by high performance liquid chromatography to give the title compound 33 (10.8 mg, yield: 9%).

MS(ESI)：m/z＝500.2[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.63(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

5-trifluoromethylpyridin-3-amine 34a (0.15 mL,1.23 mmol) was dissolved in tetrahydrofuran (3 mL), di-tert-butyl dicarbonate (0.79 mL,3.70 mmol) and p-dimethylaminopyridine (7.5 mg,0.062 mmol) were added at room temperature, reacted for 16 hours at room temperature, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases combined, washed with saturated aqueous sodium chloride (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound 34b (250 mg, yield: 77.2%).

¹ H NMR(400MHz,CDCl ₃ )δ8.61(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) carbamic acid tert-butyl ester 34c

Tert-butyl (5- (trifluoromethyl) pyridin-3-yl) aminocarboxylate 34b (180 mg,0.69 mmol) was dissolved in dimethyl sulfoxide (2 mL), 4-methylbenzene-1-sulfonic acid (0.088 mL,0.55 mmol), tetrahydrofuran (3.38 mL,41.18 mmol), O- [ (sulfoperoxy) sulfo ] diammonium oxide (0.40 mL,3.43 mmol) and [4,4' -bis (1, 1-dimethylethyl) -2,2' -bipyridyl N1, N1' ] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl N ] phenyl-C ] iridium (III) (77 mg,0.069 mmol) were added at room temperature and the reaction mixture was stirred at room temperature under blue light irradiation for 12 hours. The reaction solution was added with water (30 mL), extracted with ethyl acetate (30 ml×2), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give the title compound 34c (90 mg, yield: 39%).

¹ H NMR(400MHz,CDCl ₃ )δ8.85-8.70(m,2H),8.42(d,J＝1.2Hz,1H),5.13(t,J＝7.6Hz,1H),4.03(t,J＝6.8Hz,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) and trifluoroacetic acid (0.5 mL,6.73 mmol) was added under ice-bath. The reaction was carried out at room temperature for 1 hour, saturated sodium bicarbonate solution (10 mL) was added in ice bath, dichloromethane extraction (30 mL x 2), the organic phases were combined, and the reaction solution was concentrated under reduced pressure to give the title compound 34d (50 mg, yield: 89%).

MS(ESI)：m/z＝233.1[M+H] ⁺ 。

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

6- (tetrahydrofuran-2-yl) -5- (trifluoromethyl) pyridin-3-amine 34d (18 mg,0.078 mmol) and 1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxamide 21H (27.56 mg,0.085 mmol) were dissolved in dichloromethane (2 mL), pyridine (0.063 mL,0.77 mmol) and phosphorus oxychloride (0.022 mL,0.23 mmol) were added at room temperature and reacted for 1 hour at room temperature, saturated sodium bicarbonate solution (15 mL) was added, extracted with dichloromethane (15 mL. Times.2), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure and the residue was separated and purified by high-performance liquid chromatography to give title compound 34 (4.9 mg, yield: 11%).

MS(ESI)：m/z＝538.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ11.62(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 (0.27 mL,1.85 mmol) and 2- (2, 5-dihydrofuran-3-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane 35b (397 mg,2.03 mmol) were dissolved in dioxane/water (4 mL/0.6 mL), 1' -bis (di-t-butylphosphine) (240 mg,0.369 mmol) and potassium carbonate (765 mg,5.54 mmol) were added at room temperature, reacted at 70℃for 4 hours under nitrogen atmosphere, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL. Times.2), the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to give the title compound 35c (300 mg, yield: 62%).

MS(ESI)：m/z＝261.0[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ9.52(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- (Oxazol-3-yl) -5- (trifluoromethyl) pyridin-3-amine 35d

2- (2, 5-Dihydrofuran-3-yl) -5-nitro-3- (trifluoromethyl) pyridine 35c (270 mg,1.04 mmol) was dissolved in methanol (3 mL), palladium on carbon (10%, 0.022mL,0.21 mmol) was added at room temperature, the reaction was reacted under a hydrogen atmosphere at room temperature for 1 hour, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound 35d (200 mg, yield: 82%).

¹ H NMR(400MHz,DMSO-d6)δ8.14(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- (Oxetan-3-yl) -5- (trifluoromethyl) pyridin-3-amine 35d (35 mg,0.16 mmol) was dissolved in tetrahydrofuran (3 mL), sodium hydride (82 mg,2.06 mmol) was added under ice-bath, after 10 min 1- (1-oxo-1, 2-dihydro-isoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carbonyl chloride 21H (88 mg,0.26 mmol) was added, reaction was carried out at 60℃for 1H under nitrogen atmosphere, cooled to room temperature, the reaction solution was added to saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by high performance liquid chromatography to give the title compound 35 (24.3 mg, 17.5%).

MS(ESI)：m/z＝538.2[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ11.62(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-dihydro-phthalazin-5-yl) -5- (trifluoromethyl) -N- (2-trifluoromethylpyridin-4-yl) -1H-pyrazole-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 (5 g,26.02 mmol) was dissolved in dichloromethane/methanol (50 mL/50 mL), sodium borohydride (0.88 g,26.02 mmol) was added at room temperature, reacted for 6 hours at room temperature, quenched by adding saturated aqueous sodium bicarbonate (40 mL), stirred for 20 minutes, the aqueous phase extracted with ethyl acetate (100 mL. Times.2), the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the title compound 36b (3.8 g, yield: 75%).

MS(ESI)：m/z＝195.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ9.31(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

3-hydroxy-4-nitro-2, 3-dihydro-1H-isoindol-1-one 36b (3.8 g,19.57 mmol) is added to concentrated hydrochloric acid (30 mL), reacted at 90℃for 12 hours, cooled to room temperature, the reaction solution concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography to give the title compound 36c (2.6 g, yield: 68%).

MS(ESI)：m/z＝196.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ8.53(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-dihydro-phthalazin-1-one 36d

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

MS(ESI)：m/z＝192.1[M+H] ⁺ 。

Fourth step

5-amino-1, 2-dihydro-phthalazin-1-one 36e

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

MS(ESI)：m/z＝162.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ12.36(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)。

Fifth step

5-hydrazino-1, 2-dihydro-phthalazin-1-one 36f

5-amino-1, 2-dihydro-phthalazin-1-one 36e (300 mg,1.86 mmol) was added to concentrated hydrochloric acid (5 mL), an aqueous solution (4 mL) of sodium nitrite (0.149 mL,2.792 mmol) was added under ice bath, and the mixture was reacted under ice bath for 0.5 hours, followed by dropwise addition of 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 was adjusted to pH 12-14 with 20% aqueous sodium hydroxide, extracted with ethyl acetate (50 mL. Times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 36f (240 mg, yield: 72.7%).

MS(ESI)：m/z＝177.1[M+H] ⁺ 。

Sixth step

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

5-hydrazino-1, 2-dihydro-phthalazin-1-one 36f (240 mg,1.36 mmol) was dissolved in ethanol (6 mL), ethyl (Z) -2- (ethoxymethylene) -4, 4-trifluoro-3-oxobutanoate 1c (0.26 mL,1.36 mmol) was added at room temperature, the reaction was reacted at 60℃for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the title compound 36h (50 mg, yield: 10%).

MS(ESI)：m/z＝353.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ13.02(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)。

Seventh step

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

Ethyl 1- (1-oxo-1, 2-dihydro-phthalazin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylate (40 mg,0.11 mmol) was dissolved in tetrahydrofuran/water (6 mL/2 mL), aqueous lithium hydroxide solution (0.016 mL,0.57 mmol) was added at room temperature, reacted at 50℃for 6 hours, the reaction solution was concentrated under reduced pressure, then 1N hydrochloric acid solution was added to adjust pH to 2-3, extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 36i (30 mg, yield: 81%).

MS(ESI)：m/z＝325.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ13.45(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-dihydro-phthalazin-5-yl) -5- (trifluoromethyl) -N- [2- (trifluoromethyl) pyridin-4-yl ] -1H-pyrazole-4-carboxamide 36

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

MS(ESI)：m/z＝469.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ13.07(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), and sodium 2-methylpropan-2-carboxylate (355 mg,3.70 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (230 mg,0.37 mmol) and palladium acetate (41 mg,0.19 mmol) were added at room temperature to react for 12 hours under nitrogen atmosphere at 80 ℃. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give 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

8- (2- (diphenylmethylene) hydrazino) quinazolin-4 (3H) -one 37c (180 mg,0.53 mmol) was dissolved in ethanol (5 mL), and hydrogen chloride (0.50 mL,4.23 mmol) was added at room temperature to react for 16 hours. The reaction solution was filtered and concentrated under reduced pressure to give 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

5-hydrazino-1, 2-dihydroquinazolin-1-one 37d (240 mg,1.36 mmol) was dissolved in ethanol (6 ml), ethyl (Z) -2- (ethoxymethylene) -4, 4-trifluoro-3-oxobutanoate 1c (0.14 ml,0.74 mmol) was added at room temperature, the reaction was reacted at 60℃for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the title compound 37f (100 mg, yield: 38%).

MS(ESI)：m/z＝353.1[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ10.35-10.03(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)。

Fourth step

1- (4-oxo-3, 4-dihydro-quinazolin-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 (78 mg,0.22 mmol) was dissolved in tetrahydrofuran/water (3 mL/1 mL), lithium hydroxide (0.031 mL,1.11 mmol) was added at room temperature, reacted at 50℃for 6 hours, saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 37g (60 mg, yield: 83%).

MS(ESI)：m/z＝325.0[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.31-8.27(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)。

Fifth step

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

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

MS(ESI)：m/z＝469.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ11.26-11.07(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 (2 mL,30% wt) was added to 2-chloro-6- (trifluoromethyl) pyridin-4-amine 38a (100 mg,0.51 mmol), microwaved at 100 ℃ for 1h, cooled to room temperature, water (10 mL) was added to the reaction, extracted with ethyl acetate (10 mL x 3), and the organic phase concentrated under reduced pressure to give the title compound 38b (100 mg, crude).

MS(ESI)：m/z＝193.1[M+H] ⁺ 。

Second step

1- (1-oxo-1, 2-dihydroisoquinolin-5-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid 1g (60 mg,0.19 mmol) and 2-methoxy-6- (trifluoromethyl) pyridin-4-amine 38b (53 mg,0.28 mmol) were dissolved in pyridine (7 mL), phosphorus oxychloride (0.035 mL,0.38 mmol) was added at room temperature and reacted for 2 hours, saturated aqueous sodium bicarbonate solution (15 mL) was added, dichloromethane extraction (15 mL. Times.3) and the organic phase was concentrated under reduced pressure and the residue was separated by high performance liquid chromatography to give the title compound 38 (15 mg, yield: 16%).

MS(ESI)：m/z＝498.3[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.56(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-dihydroisoquinolin-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 (440 mg,2.24 mmol) was dissolved in 1, 4-dioxane/water (15 mL/5 mL) and bis (dibenzylideneacetone palladium (128.7 mg,0.22 mmol), 2-di-tert-butyl phosphino-2 ',4',6' -triisopropylbiphenyl (190 mg,0.44 mmol) and potassium hydroxide (251 mg,4.49 mmol) were added at room temperature. The reaction was carried out at 115℃for 1 hour, the reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and extracted with ethyl acetate (20 mL. Times.2), the aqueous phase was adjusted to pH 2 to 3 with hydrochloric acid (3M), and extracted with ethyl acetate (20 mL. Times.2), and the aqueous phase was concentrated under reduced pressure to give 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) and potassium carbonate (128 mg,0.93 mmol) and methyl iodide (0.039 mL,0.62 mmol) were added at room temperature. The reaction was carried out at 70℃for 3 hours, cooled to room temperature, water (15 mL) was added, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and concentrated under reduced pressure to give the title compound 39b (48 mg, yield: 40%).

MS(ESI)：m/z＝193.0[M+H] ⁺ 。

Third step

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

MS(ESI)：m/z＝498.2[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ11.64(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 (3 g, 13.823 mmol) was dissolved in N, N-dimethylformamide (6 mL), zinc cyanide (1.5 g,12.943 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (0.8 g,1.383 mmol) and dibenzylideneacetone dipalladium (0.63 g,0.691 mmol) were added at room temperature, and the reaction was carried out under a microwave atmosphere at 130℃for 1 hour under nitrogen atmosphere, cooled to room temperature, water (40 mL) was added, extracted with ethyl acetate (30 mL. Times.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 silica gel column chromatography to give 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 (1.3 g,7.969 mmol) was dissolved in dichloromethane (10 mL), N-dimethylformamide-dimethylacetal (2 mL,15.93 mmol) was added at room temperature, the reaction was continued at 40℃for 12 hours, and the reaction solution was concentrated under reduced pressure to give the title compound 40c (1 g, yield: 57%).

Third step

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

4- [ (E) -2- (dimethylamino) vinyl ] -5-nitropyridine-3-carbonitrile 40c (1 g,4.583 mmol) was added to acetic acid (30 mL) and hydrobromic acid (18 mL,4.383 mmol) was added at room temperature. The reaction was carried out at 60℃under nitrogen atmosphere for 5 hours, the reaction solution was added to a saturated aqueous sodium hydrogencarbonate solution (60 mL), extracted with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give the title compound 40d (460 mg, yield: 55%).

MS(ESI)：m/z＝192.0[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ12.18(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)。

Fourth step

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

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

MS(ESI)：m/z＝162.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO- _d6 )δ11.40(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)。

Fifth step

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

5-amino-1, 2-dihydro-2, 7-naphthyridin-1-one 40e (100 mg,0.621 mmol) was dissolved in concentrated hydrochloric acid (2 mL), an aqueous solution (2 mL) of sodium nitrite (0.05 mg,0.931 mmol) was added at 0 ℃, stirred at 0 ℃ for 0.5 hours, then a concentrated hydrochloric acid (2 mL) solution of stannous chloride dihydrate (350 mg, 1.5531 mmol) was added dropwise, the reaction was allowed to react at room temperature for 3 hours, the reaction solution was adjusted to ph=12 to 14 with 20% aqueous sodium hydroxide solution, extracted (30 mL x 2) with ethyl acetate, and lyophilized in aqueous phase to give the title compound 40f (100 mg, yield: 91%).

MS(ESI)：m/z＝177.1[M+H] ⁺ 。

Sixth step

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

5-hydrazino-1, 2-dihydro-2, 7-naphthyridin-1-one 40f (80 mg,0.454 mmol) was dissolved in ethanol (5 mL), and ethyl (Z) -2- (ethoxymethylene) -4, 4-trifluoro-3-oxobutanoate 1c (0.132 mL,0.681 mmol) was added at room temperature to react at 60℃for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 40g (36 mg, yield: 22%) of the title compound.

MS(ESI)：m/z＝353.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO- _d6 )δ12.01(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)。

Seventh step

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

40g (36 mg,0.102 mmol) of ethyl 1- (8-oxo-7, 8-dihydro-2, 7-naphthyridin-4-yl) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylate (3 mL/1 mL) was dissolved in tetrahydrofuran/water, and lithium hydroxide (21 mg,0.51 mmol) was added at room temperature to react at 50℃for 4 hours. The reaction was adjusted to pH 2-3 with 1N hydrochloric acid solution and extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 40h (22 mg, 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) pyridin-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 (20 mg,0.062 mmol), 2- (trifluoromethyl) pyridin-4-amine 3g (10 mg,0.062 mmol) and pyridine (0.05 mL, 0.611 mmol) were dissolved in dichloromethane (4 mL), phosphorus oxychloride (0.006mL, 0.062 mmol) was added at room temperature, reacted at room temperature for 1H, water (10 mL) was added, extracted with dichloromethane (10 mL. Times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue isolated by high performance liquid chromatography to give the title compound 40 (1.7 mg, yield: 5.8%).

MS(ESI)：m/z＝469.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ12.02(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 testing

In vitro assays include assays that determine cell morphology, protein expression and/or cytotoxicity, enzyme inhibition activity, and/or subsequent functional consequences of treating cells with a compound of the invention. An alternative or in addition to in vitro assays may 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 radiolabeled binding. Alternatively or in addition, inhibitor binding may be determined by running competition experiments, in which the new inhibitors are incubated with purified proteins or nucleic acids that bind to known radioligands. The detailed conditions for an exemplary system for assaying compounds of the invention as MALT1 inhibitors are set forth in the biological examples below.

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

Test example 1 MALT1 Biochemical protease assay

MALT1 protease activity was assessed in an in vitro assay using tetrapeptides (Ac-LRSR-MCA, PEPTIDE INSTUTE) as substrates and full length MALT1 protein (Strep-MALT 1 (1-824) -Myc/DDK, ORIGENE TP 314639) purified from mammalian cells HEK 293T. Tetrapeptides LRSR are coupled to AMC (7-amino-4-methylcoumarin) and provide a quenched fluorogenic substrate for MALT1 protease. Cleavage of AMC from arginine residues results in a cleavage at 450nmCoumarin fluorescence measured at this point increased (excitation 360 nm). The final assay buffer consisted of 5.625nM MALT1 protein, 2.5. Mu.M Ac-LRSR-MCA, 20mM HEPES, 10mM KCl, 1.5mM MgCl. 6H2O, 1mM 2Na (EDTA. 2 Na), 0.01% Triton X-100, 1M trisodium citrate dihydrate (Trisodium Citrate Dihydrate), and 10mM DTT. Test compounds dissolved in 100% dmso were added to 384-well plates (Greiner-781086) using Echo in an amount of 200nL per well. The highest concentration of each test compound was 10 μm or 1 μm, 3-fold gradient diluted, and the concentration tested ranged from 10 μm to 0.2nM. Control wells without enzyme detection buffer were used as Low Controls (LC) and vehicle (1% dmso) wells reacted with enzyme but without compound treatment were used as High Controls (HC). The compounds were incubated with MALT1 enzyme and substrate for 15 hours at room temperature. Fluorescence was then measured at excitation 360nm and emission 450nm using Envision. Fitting of inhibition curves using XLfit and calculation of IC ₅₀ Value, IC ₅₀ The values are shown in table 1.

Calculate IC using the following ₅₀ Value (Z prime)>0.5)：

Median lc=low control value

Low control: MALT1 enzyme-free reaction

Median hc=high control value

High control: vehicle control without compound

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

Curve fitting formula: fit= (a+ ((B-ase:Sub>A)/(1+ ((C/x)/(D)))))

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

Experimental results: IC for inhibition of MALT1 biochemical protease by the compounds of the present disclosure ₅₀ Value, a: IC (integrated circuit) ₅₀ A value < 100nm; b: IC with 100nm < ₅₀ Values < 600nm; c:600nm < IC ₅₀ The value is less than 1000nm; d:1000nm < IC ₅₀ Values.

TABLE 1

Numbering of compounds	MALT1 inhibits IC 50 (nM)
1	2689
2	199
3	4416
4	1114
5	624
6	131
7	78
8	22
9	951
10	46
11	34
12	388
13	37
14	608
15	39
16	117
17	69
18	44
19	166
20	127
21	41

22	129
23	76
24	27
25	383
26	236
27	477
28	39
29	170
30	76
31	62
32	184
33	12
34	221
35	205
36	512
37	725
38	75
39	350
40	119
Control compounds	43

The control compound was prepared as follows, with reference to WO2018119036 a:

test example 2 determination of intratumoral drug concentration

0.2mL (5 x 10) ⁶ OCI-Ly3 cells (human diffuse large B cell lymphoma cells, ming Kangde pharmaceutical technology Co., ltd.) added with matrigel at a volume ratio of 1:1 were inoculated subcutaneously on the right back of each female NOG mouse (6-8 weeks old, body weight 18-22g, shanghai Vitolihua laboratory animal technologies Co., ltd.) with an average tumor volume of 230mm ³ The administration of the packets was started at that time.

Table 2 in vivo efficacy experimental animal grouping and dosing regimen

And (3) injection: n: number of mice per group; dosing volume: based on the weight of the mice, 10. Mu.l/g. If the weight is reduced by more than 15 percent, stopping administration, and recovering administration until the weight is reduced to less than 10 percent; BID: the administration was 2 times per day.

Plasma and tumor samples were collected at 0, 2, 4 and 8 hours after the last dose, 28 days after continuous dosing. Plasma and intratumoral concentrations of the compounds were quantitatively analyzed by LC-MS/MS using an AB API4000 mass spectrometer. (chromatographic column: raptor Biphenyl 2.7 μm 50X 2.1mm; mobile phase: A0% acetonitrile aqueous solution (0.1% formic acid), B100% acetonitrile aqueous solution (0.1% formic acid; quantitative method: internal standard method).

Plasma sample preparation:

the analyte stock solution was diluted with 50% acetonitrile in water to give the desired working solution series of concentrations. Working solution 3 mu L (5, 10, 20, 50, 100, 500, 1000, 5000, 10000 ng/mL) is added into 30 mu L of blank NOG mouse plasma to reach the standard of 0.5-1000 ng/mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng/mL), and the total volume is 33 mu L (standard sample). Plasma quality control samples of 1ng/mL, 2ng/mL, 50ng/mL and 800ng/mL were prepared separately from the quality control samples used for the calibration curve. These quality control samples were prepared on the day of analysis in the same manner as the calibration standard.

To 200. Mu.L of the acetonitrile-containing internal standard mixture, 33. Mu.L of the standard sample, 33. Mu.L of the quality control sample, and 33. Mu.L of the plasma sample (30. Mu.L of plasma, 3. Mu.L of blank) collected after the administration were added, respectively, for precipitating proteins. The sample was then vortexed for 30s. After centrifugation at 4000rpm at 4℃for 15 minutes, the supernatant was diluted 3-fold with water, and 20. Mu.L of the diluted supernatant was injected into an LC/MS/MS system for quantitative analysis.

Tumor sample preparation:

the analyte stock solution was diluted with 50% acetonitrile in water to give the desired working solution series of concentrations. mu.L of working fluid (5, 10, 20, 50, 100, 500, 1000, 5000, 10000 ng/mL) was added to 30. Mu.L of blank NOG mouse tumor to reach a calibration standard of 0.5 to 1000ng/mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng/mL) and the total amount was 33. Mu.L (standard sample). 4 quality control samples for tumors were prepared, 1ng/mL, 2ng/mL, 50ng/mL and 800ng/mL, respectively, independent of the samples used for the calibration curve. These quality control samples were prepared on the day of analysis in the same manner as the calibration standard.

To 200. Mu.L of acetonitrile mixture containing an internal standard, 33. Mu.L of a standard sample, 33. Mu.L of a quality control sample, and 33. Mu.L of a tumor sample (30. Mu.L of tumor homogenate, 3. Mu.L of blank) collected after administration were added, respectively, for precipitating proteins. The sample was then vortexed for 30s. After centrifugation at 4000rpm at 4℃for 15min, the supernatant was diluted 3-fold with water, and 20. Mu.L of the diluted supernatant was injected into an LC/MS/MS system for quantitative analysis. The results are summarized in tables 3 and 4.

TABLE 3 comparative compound drug concentration determination results

Table 4 results of determination of drug concentration of compound 11

The results indicate that the intratumoral/plasma concentration ratio of compound 11 is higher.

Claims

A compound of formula III or a pharmaceutically acceptable salt thereof,

wherein:

Y ₁ is CR (CR) ₁₄ ；Y ₂ Is N;

ring C is selected from optionally 1-3R ₁₃ Substituted

R ₁₁ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a nitro group, a cyano group, a halogen, a 3-6 membered heterocyclic group, a 3-6 membered heteroaryl group; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₂ selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, optionally substituted with 1-3R _12a Substituted, the R _12a Selected from oxo, thio, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₃ 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 heterocyclyl, 3-6 membered heteroaryl, -NHCOR _13a 、-COR _13b 、-SO ₂ R _13c 、-SOCH ₃ The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₄ selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, halogen, nitro, cyano, hydroxy;

with the proviso that the compound of formula III does not include the following:
a compound of formula III or a pharmaceutically acceptable salt thereof,

wherein:

Y ₁ is CR (CR) ₁₄ ；Y ₂ Is N;

ring C is selected from optionally 1-3R ₁₃ Substituted

R ₁₁ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a nitro group, a cyano group, a halogen, a 3-6 membered heterocyclic group, a 3-6 membered heteroaryl group; wherein saidC of (2) _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 5-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₂ Selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, optionally substituted with 1-3R _12a Substituted, the R _12a Selected from oxo, thio, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₃ 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 heterocyclyl, 3-6 membered heteroaryl, -NHCOR _13a 、-COR _13b 、-SO ₂ R _13c The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group, a 3-6 membered heterocyclyl group, a 3-6 membered heteroaryl group optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;

R ₁₄ selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, halogen, nitro, cyanoA hydroxyl group;

With the proviso that the compound of formula III does not include the following:
the compound represented by formula III or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by formula III-a, formula III-b, formula III-c, formula III-d, formula III-e, formula III-h or formula III-j or a pharmaceutically acceptable salt thereof,

preferred are compounds of the formula III-h

Wherein:

n is selected from the integers from 0 to 3,

R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ as defined in claim 1.
The compound represented by formula III or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by formula III-i or a pharmaceutically acceptable salt thereof,

wherein:

n is selected from the integers from 0 to 3,

R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ as defined in claim 1.
A compound of formula III or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R ₁₄ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, halogen, nitro, cyano, hydroxy; preferably R ₁₄ Selected from hydrogen, methyl, cyclopropyl, halogen, nitro, cyano, hydroxy; more preferably R ₁₄ Selected from hydrogen.
A compound of formula III or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein each R ₁₃ Independently selected from trifluoromethyl, hydrogen, halogen; preferably R ₁₃ Independently selected from trifluoromethyl.
A compound of formula III or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein each R ₁₃ Independently selected from nitro, cyano, halogen, -NHCOR _13a 、-COR _13b 、-SO ₂ R _13c 、-SOCH ₃ ；

R _13a 、R _13b And R is _13c Independently selected from amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, phenyl, p-methylphenyl.
A compound of formula III or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein each R ₁₃ Independently selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, -SOCH ₃ Halogen, cyano; preferably R ₁₃ Selected from trifluoromethyl.
A compound of formula III or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein n is selected from integers from 0 to 2, preferably n is selected from integers from 1 to 2, more preferably n is 1.
A compound of formula III according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

R ₁₂ selected from 1-oxo-1, 2-dihydroisoquinolin-5-yl, 1-thioxo-1, 2-dihydroisoquinolin-5-yl, preferably 1-oxo-1, 2-dihydroisoquinolin-5-yl;

the 1-oxo-1, 2-dihydroisoquinolin-5-yl group, 1-thio-1, 2-dihydroisoquinolin-5-yl group is optionally substituted with 1 to 3R _12a Substituted, the R _12a Selected from C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy radicals 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 is _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group, the 3-6 membered heterocyclic group containing 1-3 hetero atoms, the 3-6 membered heteroaryl group containing 1-3 hetero atoms are optionally substituted with 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino.
A compound of formula III according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

R ₁₁ selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, nitro, cyano, halogen; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

preferably R ₁₁ Selected from hydrogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 Cycloalkoxy, nitro, cyano, halogen; wherein said C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy group is optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopropyloxy, nitro, cyano, amino, hydroxy;

More preferably R ₁₁ Selected from hydrogen, cyclopropyl, trifluoromethyl.
A compound of formula III according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from:
isotopic substitution of a compound of formula III or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-12, preferably wherein the isotopic substitution is deuterium atom substitution.
A pharmaceutical composition comprising a compound of formula III according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof or an isotopically substituted compound according to claim 13 and a pharmaceutically acceptable excipient.
Use of a compound of formula III according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or an isotopic substitution according to claim 13 or a pharmaceutical composition according to claim 14 in the manufacture of a medicament for the prevention and/or treatment of a MALT 1-related disorder.
Use of a compound of formula III according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof or an isotopic substitution according to claim 13 or a pharmaceutical composition according to claim 14 for the manufacture of a medicament for the prevention and/or treatment of autoimmune diseases, inflammatory diseases, cancers, tumors.