CN110818683B

CN110818683B - 2-pyridine substituted urea structure small molecule compound and synthesis and application thereof

Info

Publication number: CN110818683B
Application number: CN201910716810.XA
Authority: CN
Inventors: 赵玉军; 李佳; 王增涛; 张世言; 臧奕; 王培培; 孙丹丹; 张含烟
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2018-08-10
Filing date: 2019-08-05
Publication date: 2023-04-14
Anticipated expiration: 2039-08-05
Also published as: CN110818683A

Abstract

The invention relates to a 2-pyridine substituted urea structure micromolecule compound and synthesis and application thereof. Specifically, the invention discloses a compound shown in formula (I), an enantiomer, a diastereoisomer, a racemate or a mixture thereof, or a pharmaceutically acceptable salt, a hydrate or a solvate thereof, a preparation method thereof, and an application of the compound in preparing ASK1 small molecule inhibitors or medicines for preventing and/or treating ASK1 related diseases, especially liver diseases, lung diseases, cardiovascular diseases, kidney diseases and metabolic diseases.

Description

2-pyridine substituted urea structure small molecule compound and synthesis and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a small molecule inhibitor of ASK1 kinase, in particular to a small molecule compound with a 2-pyridine substituted urea structure, a preparation method thereof and application thereof in preparing ASK1 small molecule inhibitors or medicines for preventing and/or treating ASK1 related diseases, especially liver diseases, lung diseases, cardiovascular diseases, kidney diseases and metabolic diseases.

Background

ASK1 Kinase, known as Apoptosis Signal-regulating Kinase-1 (Apoptosis Signal-Kinase 1), is an intracellular Kinase and belongs to one of the family members of mitogen-activated protein Kinase kinase Kinase (MAP 3 Ks). ASK1 kinase has the ability to activate JNK kinase and p38 kinase downstream of the cell signaling pathway, and has important roles in regulating cellular oxidative stress, inflammatory gene dysfunction, mitochondrial dysfunction, intracellular reticulum stress, and apoptosis.

ASK1 kinase has potential therapeutic value for the treatment of a range of cardiovascular diseases, such as heart failure. Recent studies have also shown that ASK1 kinase inhibitors have potential therapeutic prospects for the treatment of common liver diseases, such as non-alcoholic steatohepatitis, chronic liver disease, metabolic liver disease, hepatic fibrosis, primary sclerosing cholangitis, hepatic ischemia-reperfusion injury, primary biliary cirrhosis, diabetes-related liver diseases, and the like. Biologically and medically relevant studies have also shown that ASK1 kinase inhibitors have therapeutic efficacy in the treatment of pulmonary diseases (e.g. pulmonary hypertension, pulmonary fibrosis). In addition, inhibition of ASK1 kinase also has feasibility to treat kidney diseases (glomerulonephritis, diabetic nephropathy, hypertensive nephropathy). The inhibition of ASK1 kinase activity has obvious treatment effect in a diabetic mouse model; the ASK1 small molecule inhibitor GS-444217 can reduce the parameter index of diabetes.

At present, some documents report some ASK1 kinase small molecule inhibitors and potential biological research and potential clinical application prospects thereof,

some ASK1 kinase small molecule inhibitors reported in the literature have the potential problems of poor molecular level activity, poor ASK1 target selectivity, unobvious animal drug effect-dose relationship, poor drug-like property of compounds and the like. In addition, some compounds have potential problems with chemical stability and metabolic stability in vivo. Some ASK1 kinase small molecule inhibitors have too strong water solubility, the in vivo exposure amount of the animal orally-taken medicine is low, and the pharmacokinetic property of the corresponding medicine in the animal body is poor, so that the in vivo efficacy of the compound needs to be improved.

Therefore, the development of a more effective small molecule inhibitor of ASK1 kinase is still needed in the art.

Disclosure of Invention

The invention aims to provide a small molecule inhibitor of ASK1 kinase with novel structure.

The invention also aims to provide a preparation method and application of the compound.

The invention provides a compound shown in a formula (I), an enantiomer, a diastereoisomer, a racemate or a mixture thereof, or a pharmaceutically acceptable salt, a hydrate and a solvate thereof,

wherein,

R ₃ represents a substituted or unsubstituted 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, said substitution being such that one or more hydrogen atoms on the group are replaced by a group selected from: halogen, deuterium atom, cyano group, hydroxyl group, amino group, nitro group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted C1-C6 alkoxy group; wherein one or more hydrogen atoms of said substituent group are substituted with a group selected from the group consisting of: hydroxyl, amino, carboxyl;

represents an M-substituted pyridine ring or a 6-membered heterocyclic ring containing two nitrogen atoms;

m represents hydrogen, deuterium, halogen, substituted or unsubstituted C1-C4 alkyl or substituted or unsubstituted C1-C4 alkoxy, said substitution being such that one or more hydrogen atoms on the group are replaced by a group selected from: halogen, deuterium atoms, cyano, hydroxyl, amino, nitro, C3-C6 cycloalkyl, C1-C6 alkoxy;

a represents an oxygen atom, a sulfur atom or NH;

and Y represents a nitrogen atom or an oxygen atom;

wherein,

when Y represents an oxygen atom, the compound (A),

R ₁ is absent;

R ₂ represents hydrogen, C1-C6 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted 5-14 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;

wherein said substitution means that one or more hydrogen atoms on the group are substituted by a group selected from the group consisting of: an oxygen atom, a halogen, a deuterium atom, a cyano group, a hydroxyl group, an amino group, a nitro group, a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, a substituted or unsubstituted 5-13 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C1-C4 alkylcarbonylamino group, a substituted or unsubstituted C1-C4 alkoxycarbonylamino group, a substituted or unsubstituted C1-C4 sulfonyl group, a substituted or unsubstituted C1-C4 alkylthio group, a substituted or unsubstituted C2-C10 alkyl group, a substituted or unsubstituted C1-C4 alkoxycarbonyl group, a substituted or unsubstituted C1-C4 alkylcarbonylamino group, a substituted or unsubstituted alkoxycarbonyl group, or a substituted or a combination thereof; wherein one or more hydrogen atoms of said substituent group are substituted with a group selected from the group consisting of: halogen, cyano, amino, C1-C4 alkoxy, C1-C4 alkyl, haloC 1-C4 alkyl, C1-C4 alkylcarbonylamino, C1-C4 alkylamino, C3-C4 epoxyalkyl, C3-C6 cycloalkyl, aminocarbonyl;

when Y represents a nitrogen atom, the compound represented by the formula,

R ₁ represents hydrogen or C1-C6 alkyl;

wherein said substitution means that one or more hydrogen atoms on the group are substituted by a group selected from the group consisting of: an oxygen atom, a halogen, a deuterium atom, a cyano group, a hydroxyl group, an amino group, a nitro group, a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, a substituted or unsubstituted 5-13 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C1-C4 alkylcarbonylamino group, a substituted or unsubstituted C1-C4 alkoxycarbonylamino group, a substituted or unsubstituted C1-C4 sulfonyl group, a substituted or unsubstituted C1-C4 alkylthio group, a substituted or unsubstituted C2-C10 acyl group, a substituted or unsubstituted C1-C4 alkoxycarbonyl group, a substituted or unsubstituted C1-C4 alkylcarbonylamino group, a substituted or unsubstituted alkylcarbonylamino group, a substituted or unsubstituted carbonyl group, or a substituted or a combination thereof; wherein one or more hydrogen atoms of said substituent group are substituted with a group selected from the group consisting of: halogen, cyano, amino, C1-C4 alkoxy, C1-C4 alkyl, haloC 1-C4 alkyl, C1-C4 alkylcarbonylamino, C1-C4 alkylamino, C3-C4 epoxyalkyl, aminocarbonyl;

or, when Y represents a nitrogen atom, R ₁ 、R ₂ And the attached nitrogen atoms may be organized into the following cyclic structure:

wherein ring D represents an unsubstituted or substituted partially unsaturated or unsaturated 5-to 14-membered heterocyclic ring containing 1 to 4 atoms selected from N, O and S, or an unsubstituted or substituted saturated 5-to 12-membered heteroaromatic ring containing 1 to 4 atoms selected from N, O and S, and these heterocyclic or heteroaromatic rings are linked by an N atom and a carbonyl group within the ring;

wherein said substitution means that one or more hydrogen atoms of said ring D are substituted by a group selected from the group consisting of: an oxygen atom, halogen, a deuterium atom, a cyano group, a hydroxyl group, an amino group, an imino group, a nitro group, a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted 5-to 12-membered heteroaromatic ring containing 1 to 4 atoms selected from the group consisting of N, O and S, a substituted or unsubstituted 5-to 13-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkylcarbonylamino, substituted or unsubstituted C1-C4 alkoxycarbonylamino, substituted or unsubstituted C1-C4 sulfonyl, substituted or unsubstituted C1-C4 alkylthio, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C1-C4 alkoxycarbonyl, substituted or unsubstituted C1-C4 alkylaminocarbonyl, or a combination thereof; wherein one or more hydrogen atoms of said substituent group are substituted with a group selected from the group consisting of: halogen, cyano, amino, C1-C4 alkoxy, C1-C4 alkyl, haloC 1-C4 alkyl, C1-C4 alkylcarbonylamino, C1-C4 alkylamino, C3-C4 epoxyalkyl, C3-C6 cycloalkyl, aminocarbonyl.

In another preferred embodiment, the compound has the structure shown in formula Ia below:

wherein,

R ₃ represents a substituted or unsubstituted 5-6 membered heteroaromatic ring containing 1 to 4 heteroatoms selected from N, O and S (e.g. tetrazolyl, triazolyl, imidazolyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, etc.), said substitution being such that one or more hydrogen atoms on the group are substituted by a group selected from: halogen, deuterium atom, cyano group, hydroxyl group, amino group, nitro group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C3-C6 cycloalkyl group; wherein one or more hydrogen atoms of said substituent group are selected fromGroup substitution of group (b): hydroxy, amino;

m represents hydrogen, deuterium, halogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1-C4 alkoxy;

and Y represents a nitrogen atom or an oxygen atom;

wherein,

when Y represents an oxygen atom, the compound represented by the formula,

R ₁ is absent;

R ₂ represents hydrogen, C1-C6 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S (e.g., pyridine, benzopyridine, pyrazole, benzopyrrole, benzopyrazole, imidazole, benzimidazole, benzopyridazine, pyridopyrrole, etc.), substituted or unsubstituted 5-14 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S (e.g., benzodihydropyrrole, pyridotetrahydropyrrole, benzodioxolyl, etc.);

when Y represents a nitrogen atom, the compound represented by formula (I),

R ₁ represents hydrogen or C1-C6 alkyl;

R ₂ represents hydrogen, C1-C6 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S (e.g., pyridine, benzopyridine, pyrazole, benzopyrrole, benzopyrazole, imidazole, benzimidazole, benzopyridazine, pyridopyrrole, etc.), substituted or unsubstituted 5-14 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S (e.g., benzotriazolyl, pyridotetrahydropyrrole, benzodioxolyl, etc.);

wherein said substitution means that one or more hydrogen atoms on the group are substituted by a group selected from the group consisting of: an oxygen atom, a halogen, a deuterium atom, a cyano group, a hydroxyl group, an amino group, a nitro group, a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, a substituted or unsubstituted 5-13 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C1-C4 alkylcarbonylamino group, a substituted or unsubstituted C1-C4 alkoxycarbonylamino group, a substituted or unsubstituted C1-C4 sulfonyl group, a substituted or unsubstituted C1-C4 alkylthio group, a substituted or unsubstituted C2-C10 alkyl group, a substituted or unsubstituted C1-C4 alkoxycarbonyl group, a substituted or unsubstituted C1-C4 alkylcarbonylamino group, a substituted or unsubstituted alkoxycarbonyl group, or a substituted or a combination thereof; wherein one or more hydrogen atoms of said substituent group are substituted with a group selected from the group consisting of: halogen, cyano, amino, C1-C4 alkoxy, C1-C4 alkyl, haloC 1-C4 alkyl, C1-C4 alkylcarbonylamino, C1-C4 alkylamino, C3-C4 epoxyalkyl, aminocarbonyl;

wherein ring D represents a partially unsaturated or unsaturated 5-14 membered heterocyclic ring containing 1 to 4 atoms selected from N, O and S (e.g., monocyclic heterocyclic ring, bicyclic fused ring heterocyclic ring or tricyclic fused ring heterocyclic ring) or a saturated 5-12 membered heteroaromatic ring containing 1 to 4 atoms selected from N, O and S, and these heterocyclic or heteroaromatic rings are linked by an N atom and a carbonyl group within the ring;

wherein said substitution means that one or more hydrogen atoms of the above ring D are substituted by a group selected from the group consisting of: an oxygen atom, halogen, a deuterium atom, a cyano group, a hydroxyl group, an amino group, a nitro group, a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted 5-to 12-membered heteroaromatic ring containing 1 to 4 atoms selected from the group consisting of N, O and S, a substituted or unsubstituted 5-to 13-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkylcarbonylamino, substituted or unsubstituted C1-C4 alkoxycarbonylamino, substituted or unsubstituted C1-C4 sulfonyl, substituted or unsubstituted C1-C4 alkylthio, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C1-C4 alkoxycarbonyl, substituted or unsubstituted C1-C4 alkylaminocarbonyl, or a combination thereof; wherein one or more hydrogen atoms of said substituent group are substituted with a group selected from the group consisting of: halogen, cyano, amino, C1-C4 alkoxy, C1-C4 alkyl, haloC 1-C4 alkyl, C1-C4 alkylcarbonylamino, C1-C4 alkylamino, C3-C4 epoxyalkyl, aminocarbonyl.

In another preferred embodiment, the compound has a structure represented by the following formula I-1 or I-2:

wherein R is ₁ 、R ₂ 、R ₃ And M is defined as before.

In another preferred embodiment, the compound has a structure represented by the following formula I-3:

wherein, the rings D and R ₃ And M are as defined above;

wherein R is ₄ 、R _4a Each independently is an oxygen atom, a halogen, a deuterium atom, a cyano group, a hydroxyl group, an amino group, an imino group, a nitro group, a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, a substituted or unsubstituted 5-13 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C1-C4 alkylcarbonylamino group, a substituted or unsubstituted C1-C4 alkoxycarbonylamino group, a substituted or unsubstituted C1-C4 sulfonyl group, a substituted or unsubstituted C1-C4 alkylthio group, a substituted or unsubstituted C2-C10 alkylcarbonyl group, a substituted or unsubstituted C1-C4 alkoxy carbonyl group, a substituted or unsubstituted carbonyl group, or a combination thereof; wherein one or more hydrogen atoms of said substituent group are substituted with a group selected from the group consisting of: halogen, cyano, amino, C1-C4 alkoxy, C1-C4 alkyl, haloC 1-C4 alkyl, C1-C4 alkylcarbonylamino, C1-C4 alkylamino, C3-C4 alkylene oxide, C3-C6 cycloalkyl, aminocarbonyl.

In another preferred embodiment, the compound has the structure shown in formula I-4, I-5 or I-6 below:

wherein R is ₄ 、R _4a 、R ₃ And M is as defined above;

x represents-CH ₂ -、-O-、-NR ₅ -or-S-; wherein R is ₅ Represents hydrogen, C1-C6 alkyl, formyl, C1-C5 alkylcarbonyl or C1-C5 alkylsulfonyl.

In another preferred embodiment, the compound has the structure shown in I-7, I-8, I-9 or I-10:

wherein ring A, ring B, ring C, R4, R4a are as previously defined, and ring A and ring B are fused ring systems and ring A and ring B and ring C are fused ring systems.

In another preferred embodiment, the compounds have the structures shown in formulas I-19 and I-20 below:

In another preferred embodiment, the compound is selected from the group consisting of:

in another preferred embodiment, the compound is selected from the group consisting of: compounds Nos. 1 to 336.

In another preferred embodiment, R ₃ The corresponding specific groups in the compounds of Nos. 1 to 336, e.g.

In another preferred embodiment, similarly, R ₁ 、R ₂ The corresponding specific groups in the compounds also numbered 1 to 336 are not specifically exemplified but are not limited to space.

In a second aspect, the present invention provides an ASK1 kinase inhibitor, wherein the inhibitor comprises the compound of the first aspect, an enantiomer, a diastereomer, a racemate or a mixture thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In a third aspect, the present invention provides a pharmaceutical composition comprising: (A) A therapeutically effective amount of a compound according to the first aspect of the invention, one or more of its enantiomers, diastereomers, racemates or mixtures thereof, or its pharmaceutically acceptable salts, hydrates and solvates; and (B) a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutically acceptable carrier is selected from the group consisting of: binders, fillers, diluents, disintegrants, suspensions, suspending agents, slow (controlled) release agents, lyoprotectants, coatings, enteric materials, lubricants, glidants, anti-adherents, sweeteners, flavoring agents, plasticizers, opacifiers, solubilizers, humectants, solvents, tonicity adjusting agents, colorants, pigments, surfactants, emulsifiers, water-soluble bases, fat-soluble bases, oleaginous bases, porogens, gels, preservatives, buffers, chelating agents, antioxidants, or combinations thereof.

The fourth aspect of the present invention provides the use of the compound of the first aspect, its enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, hydrates and solvates thereof, for the manufacture of a medicament for the treatment of a disease associated with the activity or expression level of ASK1 kinase.

In another preferred embodiment, the ASK1 kinase-associated disease is selected from the group consisting of: liver diseases, lung diseases, cardiovascular diseases, kidney diseases and metabolic diseases.

In another preferred embodiment, the liver disease is selected from the group consisting of: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, chronic liver disease, metabolic liver disease, hepatic fibrosis, primary sclerosing cholangitis, hepatic ischemia-reperfusion injury, primary biliary cirrhosis, and liver disease related to diabetes. In another preferred embodiment, the pulmonary disease is selected from the group consisting of: pulmonary hypertension, and pulmonary fibrosis. In another preferred embodiment, the cardiovascular disease is selected from the group consisting of: heart failure. In another preferred embodiment, the kidney disease is selected from the group consisting of: glomerulonephritis, diabetic nephropathy, and hypertensive nephropathy. In another preferred embodiment, the metabolic disease is selected from the group consisting of: type ii diabetes, type one diabetes.

In a fifth aspect, the present invention provides a process for the preparation of a compound of the first aspect of the present invention, enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, hydrates and solvates thereof,

the compound is a compound of formula (I-1-1), the method comprising the steps of:

the method comprises the following steps: reacting compound S1 with compound S2 in an inert solvent, thereby forming intermediate S3;

step two: reacting compound S3 with compound S4 in an inert solvent to form the final product I-1-1;

wherein M, R3, R1 and R2 are as defined above; z represents H or a substituent on the benzene ring, the substituent being selected from the group consisting of: nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl.

The compound is of formula (I-3), the method comprising the steps of:

the method comprises the following steps: reacting compound SS1 with compound S5 in an inert solvent, thereby forming the final product I-3;

wherein M and R3, R4 and R4a are as defined above; z represents H or a substituent on the benzene ring, and the substituent is selected from the following group: nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl;

or the compound is of formula (I-4), said method comprising the steps of:

the method comprises the following steps: reacting compound S10 with compound S11 in an inert solvent, thereby forming compound S14; alternatively, compound S12 and compound S13 are reacted in an inert solvent, thereby forming compound S14;

step three: removing the Boc protecting group from compound S14 in an inert solvent to form intermediate S15;

step four: reacting intermediate S15 and compound S3 in an inert solvent to form the final product I-4;

wherein M and R3, R4 and R4a are as defined above; z represents H or a substituent on the benzene ring, the substituent being selected from the group consisting of: nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl,

or the compound of formula (I) is a compound of formula (I-5), the method comprising the steps of:

the method comprises the following steps: reacting compound S16 with compound S3 in an inert solvent to form the final product I-5;

or the compound of formula (I) is a compound of formula (I-6), the method comprising the steps of:

the method comprises the following steps: reacting compound S17 with compound S3 in an inert solvent to form the final product I-6;

wherein M and R3, R4 and R4a are as defined above; z represents H or a substituent on the benzene ring, and the substituent is selected from the following group: nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl.

The compound is of formula (I-7), the method comprising the steps of:

the method comprises the following steps: reacting compound S18 with compound S2 in an inert solvent, thereby forming intermediate S19;

step two: compound S19 is reacted with compound S20 in an inert solvent to form the final product I-7.

Wherein R3, R4a are as defined in claim 1; z represents H or a substituent on the benzene ring, the substituent being selected from the group consisting of: nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl; using similar synthetic methods, I-8, I-9 and I-10 can be prepared.

The compounds are of formulae (I-19) and (I-20), the method comprising the steps of:

the method comprises the following steps: reacting compound I-4 with a compound lawson's reagent in an inert solvent to give compound I-20;

step two: reacting compound I-20 with aqueous ammonia in an inert solvent to give compound I-19;

wherein R3, R4 and R4a are defined as in claim 1; z represents H or a substituent on the benzene ring, the substituent being selected from the group consisting of: nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl;

the compounds are of formulae (I-21) and (I-22), the method comprising the steps of:

the method comprises the following steps: reacting compound I-5 with compound lawson's reagent in an inert solvent to give compound I-22;

step two: reacting compound I-22 with aqueous ammonia in an inert solvent to give compound I-21;

wherein R3, R4 and R4a are defined as in claim 1; z represents H or a substituent on the benzene ring, the substituent being selected from the group consisting of: nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The inventors of the present invention have conducted extensive and intensive studies and have found a compound having a novel structure which is useful as an ASK1 kinase inhibitor. The compound of the invention has good ASK1 kinase inhibitory activity. On the basis of this, the present invention has been completed.

Term(s) for

Herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on a group are replaced with a substituent selected from the group consisting of: an oxygen atom, a halogen, a deuterium atom, a cyano group, a hydroxyl group, an amino group, a nitro group, a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, a substituted or unsubstituted 5-13 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C1-C4 alkylcarbonylamino group, a substituted or unsubstituted C1-C4 alkoxycarbonylamino group, a substituted or unsubstituted C1-C4 sulfonyl group, a substituted or unsubstituted C1-C4 alkylthio group, a substituted or unsubstituted C2-C10 alkyl group, a substituted or unsubstituted C1-C4 alkoxycarbonyl group, a substituted or unsubstituted C1-C4 alkylcarbonylamino group, a substituted or unsubstituted alkoxycarbonyl group, or a substituted or a combination thereof; wherein one or more hydrogen atoms of said substituent group are substituted with a group selected from the group consisting of: halogen, cyano, amino, C1-C4 alkoxy, C1-C4 alkyl, haloC 1-C4 alkyl, C1-C4 alkylcarbonylamino, C1-C4 alkylamino, C3-C4 epoxyalkyl, aminocarbonyl.

When the number of carbon atoms previously noted for an alkyl group is changed, it is indicated that the alkyl group has the corresponding number of carbon atoms.

The term "C1-C6 alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

The term "C2-C4 alkenyl" refers to straight or branched chain alkenyl groups having 2 to 4 carbon atoms, such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, or the like.

The term "C2-C4 alkynyl" refers to a straight or branched chain alkynyl group having 2 to 4 carbon atoms, such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, or the like.

The term "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or the like.

The term "C1-C4 alkoxy" means a straight or branched chain alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.

The term "halogen" refers to F, cl, br and I.

The term "C1-C4 alkylamino (or alkylamino)" refers to C1-C4 alkyl substituted by an amine group, e.g.with "(C1-C4 alkyl) -NH-" or "(C1-C4 alkyl) ₂ -N- "," - (C1-C4 alkylene) -NH ₂ "," (C1-C4 alkyl) -NH- (C1-C4 alkylene) - ", or" (C1-C4 alkyl) ₂ Radicals of the structure-N- (C1-C4 alkylene) -, e.g. CH ₃ NH-、C ₂ H ₅ NH-、C ₃ H ₇ NH-、(CH ₃ ) ₂ N-、-CH ₂ NH ₂ 、-C ₂ H ₅ NH ₂ 、-C ₃ H ₇ NH ₂ 、-C ₂ H ₄ N(CH ₃ ) ₂ Or the like. Wherein C1-C4 alkyl is as defined above.

The term "C2-C10 acyl" refers to a substituent of the structure straight or branched alkyl/cycloalkyl/heteroaryl-carbonyl having 1-9 carbon atoms, such as acetyl, propionyl, butyryl, isovaleryl, neopentyl acyl, cyclohexylacyl, cyclobenzoyl, 2-naphthoyl, 3-tetrahydrofuranoyl, 4-pyridinoyl, 3-pyrroyl or the like.

The term "C1-C4 sulfonyl" refers to a sulfonyl group having 1-4 carbon atoms (-S (O) ₂ -)；

The term "C3-C4 epoxyalkyl" refers to a cyclic group having 3 or 4 carbon atoms and having one oxygen atom;

the term "C6-C10 aryl" refers to an aryl group having 6-10 carbon atoms, such as phenyl, naphthyl, and the like, which may be substituted or unsubstituted.

The term "5-14 membered heterocyclic ring" refers to a cyclic saturated, partially unsaturated or aromatic group having 5-14 members, wherein the heterocyclic ring has at least 1 (1, 2,3 or 4) ring atoms selected from the group consisting of: o, S and/or N.

The term "5-12 membered heteroaromatic ring" refers to a cyclic aromatic group having 5-12 members, wherein the heterocyclic ring has at least 1 (1, 2,3 or 4) ring atoms selected from the group consisting of: o, S and/or N

In particular, expressions like "C1-Cn" refer to groups having 1-n carbon atoms, e.g., "C1-C12" refers to groups having 1,2,3,4, 5,6,7, 8,9, 10, 11, or 12 carbon atoms; "C6 to C10" means that the group has 6,7, 8,9 or 10 carbon atoms.

In the present invention, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.

In the present invention, the term "effective amount" refers to an amount of a therapeutic agent that treats, ameliorates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect. The precise effective amount for a subject will depend upon the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount, which can be determined by the clinician.

Unless otherwise specified, all occurrences of a compound in the present invention are intended to include all possible optical isomers, such as a single chiral compound, or a mixture of various chiral compounds (i.e., a racemate). In all compounds of the invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.

As used herein, the term "compounds of the invention" refers to compounds of formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has excellent ASK1 inhibitory activity, the compound of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient are useful for the treatment, prevention and alleviation of ASK 1-related diseases. According to the prior art, the compounds of the invention can be used for the prophylaxis and therapy of liver diseases, lung diseases, cardiovascular diseases, kidney diseases and metabolic diseases.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, andmust be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and between the compounds of the present invention without significantly diminishing the pharmaceutical effectiveness of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), and the like

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) Disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary amine compounds; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, and oils, in particular, cottonseed, groundnut, corn germ, olive, castor, and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When using pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment at a dosage that is pharmaceutically considered to be effective, typically 1 to 2000mg, preferably 5 to 500mg per day for a human of 60kg body weight. Of course, the particular dosage will also take into account such factors as the route of administration, the health of the patient, and the like, which are within the skill of the skilled practitioner.

Preparation method

The compound of the present invention can be prepared by a conventional method, and can also be prepared by the preparation examples provided by the present invention.

(a) The compound is a compound of formula (I-1-1), the method comprising the steps of:

the method comprises the following steps: the amine S1 is mixed with the corresponding acid chloride S2 in a suitable solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or N, N-dimethylformamide and the like. A base (triethylamine, diisopropylethylamine, N-methylmorpholine or the like) is added and the reaction is carried out at room temperature under appropriately low temperature conditions (-10 ℃ to 0 ℃) or appropriately elevated temperature conditions (e.g., 40 ℃ to 50 ℃), to give intermediate S3.

Step two: s3 is mixed with the corresponding raw material S4 in a proper solvent and reacts at room temperature or under the condition of proper rising temperature (for example, 50-70 ℃) to obtain a final product I-1-1.

(b) The compound is of formula (I-2-1), the method comprising the steps of:

the amine S1 is mixed with the corresponding acid chloride S5 in a suitable solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or N, N-dimethylformamide and the like. Adding a base (triethylamine, diisopropylethylamine, N-methylmorpholine, or the like), and reacting at room temperature under a suitable low temperature condition (-10 ℃ to 0 ℃) or a suitable elevated temperature condition (e.g., 40 ℃ to 50 ℃), to obtain a final product I-2-1;

(c) The compound is of formula (I-3-1), the method comprising the steps of:

the method comprises the following steps: intermediate S3 is combined with the appropriate starting material S6 in a solvent and reacted at room temperature or at an appropriately elevated temperature (e.g., 40-50 ℃ C.) to provide intermediate S7.

Step two: the intermediate S7 can be reacted with a boronic acid S8 or a boronic ester S9 to prepare the target compound I-3 by Suzuki coupling. If R4-H is an N-H containing amine, S7 can be reacted with R4-H via Buchwald-Hartwig coupling, or Cu (I) -catalyzed C-N coupling to produce the title compound I-3. If R4-H is a terminal alkyne, S7 can be reacted with R4-H by Sonogashira coupling reaction to prepare I-3-1 from the target compound.

(d) The compound is of formula (I-8-1), the method comprising the steps of:

the method comprises the following steps: s14 is prepared by Suzuki coupling reaction of S10 and S11. S14 can also be prepared by the Suzuki coupling reaction of S12 and S13.

Step three: s14 removal of the Boc protecting group under acidic conditions, e.g., trifluoroacetic acid in dichloromethane or HCl-1,4 dioxane affords intermediate S15.

Step four mixing S15 and S3 in a suitable solvent, adding a base (triethylamine, diisopropylethylamine, N-methylmorpholine, or the like), and reacting at room temperature or at a suitably elevated temperature (e.g., 50 to 70 ℃ C.) to obtain the final product I-8-1.

(e) The compound is of formula (I-11-1), the method comprising the steps of:

the method comprises the following steps: the amine S18 is mixed with the corresponding acid chloride S2 in a suitable solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or N, N-dimethylformamide and the like. A base (triethylamine, diisopropylethylamine, N-methylmorpholine or the like) is added, and the reaction is carried out at room temperature under a suitably low temperature condition (-10 ℃ to 0 ℃) or a suitably elevated temperature condition (for example, 40 ℃ to 50 ℃), to obtain an intermediate S19. (ii) a

Step two: s19 and the corresponding raw material S20 are mixed in a proper solvent and react at room temperature or a proper elevated temperature (for example, 50-70 ℃) to obtain a final product I-11-1.

(f) The compound is of formula (I-15), the method comprising the steps of:

/>

Step two: s19 and the corresponding raw material S21 are mixed in a proper solvent and reacted at room temperature or a proper elevated temperature (for example, 50-70 ℃) to obtain a final product I-15.I-16, I-117 and I-18 can be prepared synthetically using the synthetic strategies described above.

(g) The compounds are of formulae (I-19) and (I-20), the method comprising the steps of:

the method comprises the following steps: compound I-4 with Lawson's reagent or P ₂ S ₅ The reaction mixture is mixed in a suitable solvent such as toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, methylene chloride, or N, N-dimethylformamide, and the reaction is carried out at room temperature, under a suitably low temperature condition (-10 ℃ to 0 ℃) or under a suitably elevated temperature condition (e.g., 40 ℃ to 120 ℃). To obtain a compound I-20;

step two: mixing the compound I-20 and ammonia water in a proper solvent such as methanol, ethanol, isopropanol, N-butanol, toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane or N, N-dimethylformamide, and reacting at room temperature, a proper low temperature condition (-10 ℃ to 0 ℃) or a proper elevated temperature condition (for example, 40 ℃ to 120 ℃), thereby obtaining a compound I-19;

(h) The compounds are of formulae (I-21) and (I-22), the method comprising the steps of:

the method comprises the following steps: compound I-5 is reacted with Lawson' S reagent or P2S5 in a suitable solvent, such as toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or N, N-dimethylformamide, at room temperature, suitably low temperature (-10 ℃ to 0 ℃) or suitably elevated temperature (e.g. 40 ℃ to 120 ℃). To obtain a compound I-22;

step two: mixing the compound I-22 and ammonia water in a proper solvent such as methanol, ethanol, isopropanol, N-butanol, toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane or N, N-dimethylformamide, and reacting at room temperature, a proper low temperature condition (-10 ℃ to 0 ℃) or a proper elevated temperature condition (for example, 40 ℃ to 120 ℃), thereby obtaining a compound I-21;

the radicals in the above formulae are as defined above.

Compared with the prior art, the invention has the main advantages that:

(1) The preparation method has the advantages of mild reaction conditions, abundant and easily-obtained raw materials, simple operation and post-treatment, good corresponding selectivity and the like. The compound has good ASK1 kinase inhibitory activity.

(2) Provides an ASK1 kinase inhibitor which shows strong ASK1 kinase inhibitory activity and is a potential drug for treating liver diseases, lung diseases, cardiovascular diseases, kidney diseases, metabolic diseases, autoimmune diseases and inflammations.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.

The test materials and reagents used in the following examples are commercially available without specific reference.

Experimental example 1: synthesis of Compounds

Synthesis of intermediate 01:6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (EB 048)

6-aminopyridine hydrazide (1.5g, 10mmol) was placed in a 100mL eggplant type flask, and 20mL of toluene was added. 1, 1-dimethoxy-N, N-dimethylmethylamine (3.6g, 30mmol) and isopropylamine (4.13g, 70mmol) were added, the temperature of the reaction system was lowered to 0 ℃ in an ice-water bath, and glacial acetic acid (1.8g, 30mmol) was added. The ice water bath was removed, the oil bath was changed, and the reaction temperature was raised to 95 ℃ and stirred for 20h. After the reaction is finished, the reaction solution is concentrated by a rotary evaporator at 80 ℃.50 mL of water was added and evaporated to dryness at 80 ℃ on a rotary evaporator. 150mL of water was added and stirred at 85 ℃ overnight. Filtering, washing with water, extracting the filtrate with diethyl ether (50 mL × 3 times), and extracting the aqueous phase with dichloromethane50mL of the dichloromethane phase was combined 3 times and concentrated on a rotary evaporator to obtain 2.15g of the crude target compound. Used directly in the next step. ¹ H NMR(MeOD-d4,400MHz):8.77(s,1H),7.59(dd,J＝8.45,7.39Hz,1H),7.21(dd,J＝7.39,0.83Hz,1H),6.67(dd,J＝8.45,0.83Hz,1H),5.60-5.50(m,1H),1.54(d,J＝6.84Hz,6H)。

Synthesis of intermediate 02: (R) -2- (3- (6-aminopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) propan-1-ol (EB 110)

The method comprises the following steps: synthesis of (E) -N' - (6- (2- (E) - (dimethylamino) methylene) hydrazine-1-carbonyl) pyridin-2-yl) -N, N-dimethylformamidine (EB 109)

6-Aminopyridine hydrazide (5 g,32.9 mmol) was placed in a 100mL eggplant type flask, and 50mL of toluene was added. 1, 1-dimethoxy-N, N-dimethylmethylamine (15.6 g, 131mmol) was added thereto, and the mixture was stirred at 80 ℃ overnight. Cooling the reaction liquid, adding a proper amount of ether, and filtering to obtain a solid crude product. The product was used directly in the next step without purification.

Step two: synthesis of (R) -2- (3- (6-aminopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) propan-1-ol (EB 110)

The product of step one and (R) -2-aminopropan-1-ol (9.9 g, 132mmol) were placed in a 100mL eggplant type flask, and 30mL of toluene was added. Acetic acid was added and the temperature was raised to 95 ℃ and stirred overnight. After the reaction is finished, the reaction solution is concentrated at 80 ℃ by a rotary evaporator. 50mL of water was added and evaporated to dryness at 95 ℃ on a rotary evaporator. 150mL of water was added and stirred at 95 ℃ overnight. Filtration, washing with water, extraction of the filtrate with diethyl ether (50 mL × 3 times), extraction of the aqueous phase with dichloromethane 3 times each 50mL, combining the dichloromethane phases, further extraction with a dichloromethane/ethanol (V/V = 1/1) system, combining the organic phases, concentration on a rotary evaporator, gave 2.48g of crude target compound in 34% yield. ¹ H NMR(MeOD-d4,400MHz):8.77(s,1H),7.59(dd,J＝8.45,7.43Hz,1H),7.24(dd,J＝7.43,0.76Hz,1H),6.67(dd,J＝8.45,0.76Hz,1H),5.54-5.46(m,1H),3.85-3.81(m,2H),1.56(d,J＝7.09Hz,3H)。

Synthesis of intermediate 03: (R) -3- (3- (6-aminopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) butan-1-ol (EB 125)

The method comprises the following steps: synthesis of (E) -N' - (6- (2- ((E) - (dimethylamino) methylene) hydrazine-1-carbonyl) pyridin-2-yl) -N, N-dimethylformamidine

6-aminopyridine hydrazide (2.12g, 14mmol) was placed in a 100mL eggplant-type flask, and 50mL of toluene was added. 1, 1-dimethoxy-N, N-dimethylmethylamine (5.71g, 48mmol) was added thereto, and the mixture was stirred at 80 ℃ overnight. The residue was evaporated to dryness on a rotary evaporator and used directly in the next step.

Step two: synthesis of (R) -3- (3- (6-aminopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) butan-1-ol (EB 125)

The product of step one and (R) -3-aminobutan-1-ol (3.7g, 42mmol) were put into a 100mL eggplant type flask, and 30mL of toluene was added. Acetic acid was added and the temperature was raised to 95 ℃ and stirred overnight. After the reaction is finished, the reaction solution is concentrated by a rotary evaporator at 80 ℃.50 mL of water was added and evaporated to dryness at 95 ℃ on a rotary evaporator. 150mL of water was added and the mixture was stirred at 95 ℃ overnight. Evaporating to dryness by a rotary evaporator, purifying by a normal phase silica gel column, wherein the mass of the product is 3.226g, and the product contains 10-20% of impurities. ¹ H NMR (MeOD-d 4, 400MHz): 9.13 (s, 1H), 7.78 (dd, J =8.72,7.40Hz, 1H), 7.27 (d, J =7.40Hz, 1H), 6.93 (d, J =8.72Hz, 1H), 5.37-5.27 (m, 1H), 3.67-3.58 (m, 1H), 3.49-3.41 (m, 1H), 2.25-2.01 (m, 2H), 1.61 (d, J = 6.853H). ESI-MS theoretical calculation C ₁₁ H ₁₅ N ₅ O[M+H] ⁺ =234.13; the experiment shows that: 234.22.

synthesis of intermediate 04: (R) -2- (3- (6-aminopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) propanoic acid tert-butanoic acid (EB 145-3)

The method comprises the following steps: synthesis of (E) -N' - (6- (2- ((E) - (dimethylamino) methylene) hydrazine-1-carbonyl) pyridin-2-yl) -N, N-dimethylformamidine (EB 143)

6-aminopyridine hydrazide (1.52g, 10 mmol) was placed in a 100mL eggplant type flask, and 30mL of toluene was added. 1, 1-dimethoxy-N, N-dimethylmethylamine (4.4g, 40mmol) was added thereto, and the mixture was stirred at 80 ℃ overnight. The residue was evaporated to dryness on a rotary evaporator and used directly in the next step.

Step two: synthesis of (R) -2- (3- (6-aminopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) propionic acid tert-butanoic acid (EB 145-3)

The product of step one (2.15g, 8.2mmol) and D-alanine tert-butyl ester (3.0g, 16.5mmol) were charged in a 100mL eggplant type flask, and acetonitrile (50 mL) was added. Acetic acid was added and the temperature was raised to 95 ℃ and stirred overnight. After the reaction is finished, the reaction solution is concentrated by a rotary evaporator. 150mL of water was added and stirred at 95 ℃ overnight. Adding concentrated ammonia water, concentrating by a rotary evaporator, adding dichloromethane and water, filtering, extracting the filtrate by dichloromethane, taking the water phase, evaporating by the rotary evaporator, dissolving by 20mL of methanol, adding 120mL of benzene, precipitating a solid, and purifying by HPLC to obtain 2.48g of a crude target compound. ¹ H NMR (MeOD-d 4, 400MHz) 8.72 (s, 1H), 7.55 (dd, J =8.32,7.43Hz, 1H), 7.30 (dd, J =7.43,0.64Hz, 1H), 6.93 (dd, J =8.32,0.64, 1H), 5.99-5.92 (m, 1H), 1.82 (d, J =7.46Hz, 3H). Theoretical calculation of ESI-MS C ₁₀ H ₁₁ N ₅ O ₂ [M+H] ⁺ =234.09; the experiment shows that: 233.96.

intermediate 05: o-phenyl (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) aminomethylformate (ZTB-6)

6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (304.5 mg,1.5 mmol), phenyl chlorothioformate (258.9 mg,1.5 mmol) and sodium carbonate (238.5 mg, 2.25mmol) were charged to a 25mL reaction flask, and 5mL of dioxane was added to dissolve the reaction. Stir at room temperature overnight. After the reaction, ethyl acetate and water were added, and the organic layer was extracted, dried, and concentrated to give 299.7mg of crude product, which was used directly in the next reaction.

Intermediate 06:5- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-amine (ZTB-44)

5-bromo-1H-indazol-3-amine (636.2mg, 3mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (936.5mg, 4.5mmol) and Na ₂ CO ₃ (636 mg,6 mmol) was charged to a 50mL reaction flask, 10mL DME was added to dissolve the reactants, except for O ₂ Adding catalyst (Pd (dppf) Cl) ₂ -CH ₂ Cl ₂ (2458 mg,0.3 mmol), O was removed again ₂ Stirred overnight at 100 ℃. After the reaction, the reaction mixture was filtered, and 10mL of water was added to the filtrate to purify the mixture by HPLC, whereby 517.5mg of the objective compound was obtained. ¹ H NMR (MeOD-d 4, 400MHz) 8.06 (s, 1H), 7.98 (s, 1H), 7.84-7.86 (m, 2H), 7.45 (d, J =8.92Hz, 1H), 3.96 (s, 3H). Theoretical calculation of ESI-MS C ₁₇ H ₁₈ N ₆ O[M+H] ⁺ =214.10; the experiment shows that: 214.58.

intermediate 07:6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-amine (ZTB-45)

6-bromo-1H-indazol-3-amine (636.2mg, 3mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) pyrazole (936.5mg, 4.5mmol) and Na ₂ CO ₃ (636mg, 6mmol) was charged to a 50mL reaction flask, 10mL DME was added to dissolve the reactants, except for O ₂ Adding catalyst (Pd (dppf) Cl) ₂ -CH ₂ Cl ₂ (2458 mg,0.3 mmol), O was removed again ₂ Stirred overnight at 100 ℃. After the reaction, the reaction mixture was filtered, and 10mL of water was added to the filtrate to purify the mixture by HPLC, whereby 530.1mg of the objective compound was obtained. ¹ H NMR (MeOD-d 4, 400MHz) 8.13 (s, 1H), 7.94 (s, 1H), 7.91 (d, J =8.56Hz, 1H), 7.57 (s, 1H), 7.46 (d, J =8.52Hz, 1H). ESI-MS theoretical calculation C ₁₇ H ₁₈ N ₆ O[M+H] ⁺ =214.10; the experiment shows that: 214.01.

intermediate 08:2- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-4-amine (ZTB-82)

Step one, the starting material, methyl 4-aminopyridine-1-carboxylate (4.32g, 28.4 mmol) was charged to a 100mL reaction flask, 50mL MeOH was added to dissolve the reaction, and hydrazine hydrate (2.84g, 56.8mmol) was added. Refluxing for 3h. After completion of the reaction, the reaction mixture was cooled to room temperature to precipitate a solid, which was then filtered, and the solid was washed with ethyl acetate (200 ml, twice) and dried to obtain 3.74g of ZTB-79 compound. The crude ZTB-79 obtained was used directly in the next reaction. ¹ H NMR(MeOD-d4,400MHz):8.03(d,J＝5.68Hz,1H),7.24(d,J＝2.34Hz,1H),6.65(dd,J＝5.68,2.34Hz,1H)。

Step two, dissolving ZTB-79 (3.74g, 24.6 mmol) in 40mL of toluene, adding 1, 1-dimethoxy-N, N-dimethyl methylamine (8.78g, 73.8 mmol) and isopropylamine (10.2g, 172.2mmol), then adding acetic acid (4.43g, 73.8 mmol) under ice bath, after the addition is finished, heating to 95 ℃ and reacting for 20h. TLC monitoring, after the reaction is finished, cooling to room temperature, then concentrating the reaction solution, adding 100ml of water, and rotary evaporating to dryness. Then 10 times the volume of water was added, 85 ℃ and overnight. The next day, filtration was carried out, the filtrate was first extracted with diethyl ether and the diethyl ether layer was discarded. And extracting with dichloromethane for 3 times again, combining organic layers, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product of ZTB-82, wherein the crude product is 3.92g. ¹ H NMR(MeOD-d4,400MHz):8.80(s,1H),8.15(d,J＝5.78Hz,1H),7.10(d,J＝2.29Hz,1H),6.68(dd,J＝5.78,2.29Hz,1H),5.23-5.33(m,1H),1.51(s,3H),1.50(s,3H)。

Intermediate 09: phenyl (2- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-4-yl) carbamate (ZTB-83)

ZTB-82 (203mg, 1.0 mmol) was dissolved in 5mL dioxane, and phenyl chloroformate (156.6 mg,1.0 mmol) and sodium carbonate (159mg, 1.5 mmol) were added and stirred at room temperature overnight. After the reaction is finished, ethyl acetate and water are extracted for 3 times, organic layers are combined, dried by anhydrous sodium sulfate, filtered and concentrated to obtain 221.7mg of crude ZTB-83. The product was used in the subsequent reaction without further purification.

Intermediate 10:4- (4-isopropyl-4H-1, 4-triazol-3-yl) pyridin-2-amine (ZTB-81)

Step one, raw material methyl 2-aminoisonicotinate (4.32g, 28.4mmol) was charged into a 100mL reaction flask, 50mL MeOH was added to dissolve the reaction, and hydrazine hydrate (2.84g, 56.8mmol) was added. Refluxing for 3h. After completion of the reaction, the reaction mixture was cooled to room temperature to precipitate a solid, which was then filtered, and the solid was washed with ethyl acetate (200 ml, twice) and dried to obtain 3.72g of ZTB-80 compound. The crude ZTB-80 obtained was used directly in the next reaction. ¹ H NMR(MeOD-d4,400MHz):7.99(d,J＝5.47Hz,1H),6.89(s,1H),6.86(dd,J＝5.47,1.49Hz,1H)。

Step two, ZTB-80 (3.72g, 24.5 mmol) is dissolved in 40mL of toluene, 1-dimethoxy-N, N-dimethylmethylamine (8.73g, 73.8mmol) and isopropylamine (10.1g, 171.3mmol) are added, then acetic acid (4.40g, 73.4 mmol) is added under ice bath, and after the addition is completed, the temperature is raised to 95 ℃ for reaction for 20h. TLC monitoring, after the reaction is finished, cooling to room temperature, then concentrating the reaction solution, adding 100ml of water, and rotary evaporating to dryness. Then 10 times the volume of water was added, 85 ℃ and overnight. The next day, filtration was carried out, the filtrate was first extracted with diethyl ether and the diethyl ether layer was discarded. The mixture was extracted with dichloromethane again for 3 times, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give 3.22g of crude ZTB-81. ¹ H NMR(MeOD-d4,400MHz):8.87(s,1H),8.10(d,J＝5.18Hz,1H),6.83(s,1H),6.80(d,J＝5.28Hz,1H),4.57-4.66(m,1H),1.52(s,3H),1.51(s,3H)。

Intermediate 11: phenyl (4- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) carbamate (ZTB-84)

ZTB-81 (203mg, 1.0 mmol) was dissolved in 5mL dioxane, and phenyl chloroformate (156.6 mg,1.0 mmol) and sodium carbonate (159mg, 1.5 mmol) were added and stirred at room temperature overnight. After the reaction is finished, extracting the mixture by ethyl acetate and water for 3 times, combining organic layers, drying the organic layers by anhydrous sodium sulfate, filtering and concentrating to obtain 324.9mg of crude ZTB-83. The product was used in the subsequent reaction without further purification.

End product 01: benzyl (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) carbamate (01, ZTAR 41)

Intermediate 01 (30mg, 0.148mmol) was charged into a 50mL eggplant type flask, and 5mL of 1, 4-dioxane was added and dissolved. Benzyl chloride (25.1mg, 0.148mmol) and sodium carbonate (23.5mg, 0.222mmol) were added to the reaction flask. Stirred at room temperature overnight. After the reaction is finished, HPLC purification is carried out to obtain the target compound. ¹ H NMR(CDCl ₃ 400 MHz) 8.91 (s, 1H), 8.18-8.11 (m, 1H), 7.93-7.85 (m, 2H), 7.51-7.35 (m, 5H), 5.68-5.58 (m, 1H), 5.25 (s, 2H), 1.57 (d, J =6.81Hz, 6H). Theoretical calculation of ESI-MS C ₁₈ H ₁₉ N ₅ O ₂ [M+H] ⁺ =338.16; the experiment shows that: 238.66.

end product 02: (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) carbamic acid ethyl ester (02, ZTAR 42)

Intermediate 01 (30mg, 0.148mmol) was charged into a 50mL eggplant type flask, and 5mL of 1, 4-dioxane was added and dissolved. Ethyl chloroformate (1695g, 0.148mmol) and sodium carbonate (23.5mg, 0.222mmol) were added to the reaction flask. Stirred at room temperature overnight. After the reaction is finished, HPLC purification is carried out to obtain the target compound. ¹ H NMR(CDCl ₃ 400 MHz) 9.32 (s, 1H), 8.24-8.10 (m, 1H), 7.95-7.81 (m, 2H), 5.76-5.65 (m, 1H), 4.30 (q, J =7.13Hz, 2H), 1.63 (d, J =6.73Hz, 6H), 1.36 (t, J =7.13Hz, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₉ N ₅ O ₂ [M+H] ⁺ =276.14; the test shows that: 277.2.

the final product 03: phenyl (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) carbamate (03, ZTAA 45)

Intermediate 01 (30mg, 0.148mmol) was put into a 50mL eggplant type flask, and 3mL of 1, 4-dioxane was added thereto and dissolved. Phenyl chloroformate (23.2mg, 0.148mmol) and sodium carbonate (23.5mg, 0.222mmol) were charged in a reaction flask. Stirred at room temperature overnight. After the reaction is finished, HPLC purification is carried out to obtain the target compound. ¹ H NMR(CDCl ₃ ,400MHz):9.19-9.10(m,1H),8.15-8.20(m,1H),7.97-7.92(m,2H),7.44(t,J＝7.8Hz,2H),7.30(t,J＝7.34Hz,1H),7.22(d,J＝8.26Hz,2H),5.76-5.68(m,1H),1.64(d,J＝6.73Hz,6H)。

The final product was 04:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3-phenylurea (04, ZTAA 46)

Final 03 (57mg, 0.176mmol), aniline (49.2mg, 0.528mmol) and triethylamine (57.9mg, 0.572mmol) were charged to a 50mL reaction flask, and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃. After the reaction, 2.5mL of water was added and HPLC purification was performed to obtain the objective compound. ¹ H NMR(CDCl ₃ 400 MHz) 8.74 (s, 1H), 7.86 (d, J =8.64Hz, 1H), 7.71 (dd, J =8.64,7.29Hz, 1H), 7.51 (d, J =7.29Hz, 1H), 7.44 (d, J =7.64Hz, 2H), 7.27-7.22 (m, 2H), 7.02 (t, J =7.28Hz, 1H), 5.40-5.30 (m, 1H), 1.42 (d, J =6.81Hz, 6H). Theoretical calculation of ESI-MS C ₁₇ H ₁₈ N ₆ O[M+H] ⁺ =323.16; the experiment shows that: 322.9.

the final product is 05: 1-benzyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (05, ZTAR 47)

End product 03 (57mg, 0.176mmol), benzylamine (56)6mg,0.528 mmol) and triethylamine (57.9mg, 0.572mmol) were added to a 50mL reaction flask and 2mL DMF was added to dissolve the reactants. Stirring was carried out overnight at 60 ℃. After the reaction, 2.5mL of water was added and HPLC purification was performed to obtain the objective compound. ¹ H NMR(CDCl ₃ ,400MHz):8.77(s,1H),7.77(dd,J＝8.39,7.27Hz,1H),7.50(d,J＝7.27Hz,1H),7.36(d,J＝8.39Hz,1H),7.30-7.20(m,5H),5.00-4.89(m,1H),4.52(s,1H),1.26(d,J＝6.67Hz,6H)。

End product 06:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (3- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) urea (06, ZTa54)

The method comprises the following steps: synthesis of 1- (3-bromophenyl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (ZTA 050)

M-bromoaniline (645mg, 3.76mmol), the final product 03 (405mg, 1.25mmol) and triethylamine (4114.06mmol) were placed in a 50mL eggplant-type flask, and then 1mL of DMF was added thereto, followed by stirring at 50 ℃ overnight. After the reaction is finished, 20mL of water is added into the reaction bottle, a solid is separated out, the crude product of the target compound is obtained by filtration, and part of the crude product is purified by HPLC. ¹ H NMR(CDCl ₃ ,400MHz):8.52(s,1H),7.87-7.80(m,1H),7.77(s,1H),7.57(d,J＝7.20Hz,1H),7.41-7.30(m,2H),7.26-7.14(m,2H),5.13-5.04(m,1H),1.47(d,J＝6.64Hz,6H)。

Step two: synthesis of 4- (3- (3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) ureido) phenyl) -3, 6-dihydropyridine-4-tert-butyl ester-1 (2H) -carboxylic acid tert-butyl ester (ZTA 053)

The reaction mixture was washed with ZTA050 (182mg, 0.455mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (281.4mg, 0.91mmol), potassium carbonate (125.8mg, 0.91mmol), pdCl ₂ (dppf)-CH ₂ Cl ₂ (37.2 mg,0.0455 mmol) was charged in a 50mL reaction flask and dioxane was added to dissolve the reaction. Oxygen was removed, heated to 100 ℃ and stirred for 5h. After the reaction, ethyl acetate and water were added to the reaction flask, the organic layer was extracted, and the organic phase was spin-dried under reduced pressure to obtain 130mg of crude product, which was used directly in the next stepAnd (5) one step.

Step three: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (3- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) urea (06, ZTa54)

ZTA053 (about 130 mg) was added to a 50mL reaction flask, 1mL trifluoroacetic acid and 4mL dichloromethane were added, and the reaction was stirred at 40 ℃ until the reaction was complete. After the reaction was complete, 93mg of a yellow oil were obtained by HPLC. ¹ H NMR (MeOD-d 4, 400MHz) 9.46 (s, 1H), 8.10 (d, J =8.34Hz, 1H), 7.94 (t, J =8.12Hz, 1H), 7.74 (d, J =7.27Hz, 1H), 7.69 (s, 1H), 7.40 (d, J =8.15Hz, 1H), 7.31 (t, J =7.89Hz, 1H), 7.16 (d, J =7.75Hz, 1H), 6.19-6.14 (m, 1H), 5.78-5.65 (m, 1H), 3.87 (s, 2H), 3.52-3.45 (m, 2H), 2.86-2.76 (m, 2H), 1.22 (d, J =6.85Hz, 6H). Theoretical calculation of ESI-MS C ₂₂ H ₂₅ N ₇ O[M+H] ⁺ =404.22; the test shows that: 404.62.

the final product, 07:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) urea (07, ZTAI)

The method comprises the following steps: synthesis of 1- (4-bromophenyl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (ZTA 49)

Para-bromoaniline (645mg, 3.76mmol), final product 03 (405mg, 1.25mmol) and triethylamine (4114.06mmol) were placed in a 50mL eggplant type flask, and then 1mL of DMF was added thereto, followed by stirring at 50 ℃ overnight. After the reaction is finished, 20mL of water is added into the reaction bottle, a solid is separated out, crude product 181mg of the target compound is obtained by filtration, and part of the crude product is purified by HPLC. ¹ H NMR(CDCl ₃ ,400MHz):8.54(s,1H),7.82(t,J＝7.95Hz,1H),7.66(d,J＝8.34Hz,1H),7.51(d,J＝7.41Hz,1H),7.45-7.35(m,4H),5.18-5.08(m,1H),1.46(d,J＝6.72Hz,6H)。

Step two: synthesis of 4- (4- (3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) ureido) phenyl) -3, 6-dihydropyridine-4-tert-butyl ester-1 (2H) -carboxylic acid tert-butyl ester (ZTA 52)

ZA049 (170mg, 0.425mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolane-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (262.8mg, 0.85mmol), potassium carbonate (117.5mg, 0.85mmol), pdCl ₂ (dppf)-CH ₂ Cl ₂ (34.7mg, 0.0425mmol) was added to a 50mL reaction flask and dioxane was added to dissolve the reactants. Oxygen is removed, the mixture is heated to 100 ℃ and stirred for 5 hours. After the reaction, ethyl acetate and water were added to the reaction flask, the organic layer was extracted, and the organic phase was spin-dried under reduced pressure to obtain 80mg of crude product, which was used directly in the next step.

Step three: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) urea (07, ZTAKE)

ZTA052 (about 80 mg) was charged into a 50mL reaction flask, 1mL trifluoroacetic acid and 4mL dichloromethane were added, and the reaction was stirred at 40 ℃ until the reaction was complete. After the reaction, 82mg of a yellow solid was obtained by HPLC. ¹ H NMR (MeOD-d 4, 400MHz) 9.39 (s, 1H), 8.09 (d, J =8.70Hz, 1H), 7.92 (t, J =8.09Hz, 1H), 7.73 (d, J =7.54Hz, 1H), 7.49 (d, J =8.67Hz, 2H), 7.40 (d, J =8.67Hz, 2H), 6.10 (s, 1H), 5.74-5.64 (m, 1H), 3.85 (s, 2H), 3.51-3.42 (m, 2H), 2.82-2.73 (m, 2H), 1.62 (d, J =6.62Hz, 6H). Theoretical calculation of ESI-MS C ₂₂ H ₂₅ N ₇ O[M+H] ⁺ =404.22; the test shows that: 404.58.

the final product 08:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (piperidin-4-yl) phenyl) urea (08, ZTA-56)

Final product 07 (62mg, 0.072mmol) was added to a round bottom flask and oxygen was removed. 7mL of methanol was added to remove oxygen. Add 10% Pd/C (6.2 mg), remove oxygen, introduce hydrogen, stir at room temperature overnight. And (4) after the reaction is finished, filtering, spin-drying the filtrate, and purifying by HPLC to obtain the target compound. ¹ H NMR (MeOD-d 4, 400MHz): 9.35 (s, 1H), 8.07 (d, J =8.37Hz, 1H), 7.94 (t, J =7.69Hz, 1H), 7.73 (d, J =7.21Hz, 1H), 7.45 (s, J =8.41Hz, 2H), 7.22 (d, J =8.41Hz, 2H), 5.72-5.62 (m, 1H), 3.56-3.43 (m, 2H), 3.22-3.06 (m, 2H), 2.94-2.81 (m, 1H), 2.10-1.83 (m, 4H), 1.61 (d, J =6.72Hz, 6H). Theoretical calculation of ESI-MS C ₂₂ H ₂₇ N ₇ O[M+H] ⁺ =406.23; the experiment shows that: 406.0,405.88.

The final product 09:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (3- (piperidin-4-yl) phenyl) urea (09, ZTA-57)

Final product 06 (73 mg) was added to a round bottom flask and oxygen was removed. 4mL of methanol was added to remove oxygen. Add 10% Pd/C (7.3 mg), remove oxygen, introduce hydrogen, stir at room temperature overnight. And after the reaction is finished, filtering, spin-drying the filtrate, and purifying by HPLC to obtain the target compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.38 (s, 1H), 8.08 (d, J =8.56Hz, 1H), 7.95 (t, J =8.56Hz, 1H), 7.74 (d, J =7.24Hz, 1H), 7.51 (s, 1H), 7.37-7.24 (m, 2H), 7.01-6.96 (m, 1H), 5.74-5.61 (m, 1H), 3.59-3.45 (m, 2H), 3.23-3.10 (m, 2H), 2.96-2.82 (m, 1H), 2.15-1.88 (m, 4H), 1.61 (d, J =6.87Hz, 6H). Theoretical calculation of ESI-MS C ₂₂ H ₂₇ N ₇ O[M+H] ⁺ =406.23; the experiment shows that: 406.67.

the final product 10:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (quinolin-8-yl) urea (10, ZTA-63)

The final product 03 (135mg, 0.63mmol), 8-aminoquinoline (180.7mg, 1.88mmol) and triethylamine (138.1mg, 2.05mmol) were added to a 50mL reaction flask and 5mL of DMF was added to dissolve the reaction. Stirring was carried out overnight at 50 ℃. After the reaction, 6mL of water was added and HPLC purification was performed to obtain 8.2mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz): 9.50 (s, 1H), 8.60-8.53 (m, 2H), 8.32 (dd, J =8.34,1.63Hz, 1H), 8.03-7.93 (m, 2H), 7.72 (dd, J =6.84,1.41Hz, 1H), 7.61-7.49 (m, 3H), 5.72-5.60 (m, 1H), 1.52 (d, J =6.71Hz, 6H). Theoretical calculation of ESI-MS C ₂₀ H ₁₉ N ₇ O[M+H] ⁺ =374.17; the experiment shows that: 373.56.

end product 11:3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-methyl-1-phenylurea (11, ZTA-64)

N-methylaniline (201.3mg, 1.88mmol), final product 03 (135mg, 0.63mmol), and triethylamine (207.2mg, 2.05mmol) were charged to a 50mL reaction flask, and 2mL of DMF was added to dissolve the reaction. Stirred at 60 ℃ overnight. After the reaction, 2mL of water was added, acidified with trifluoroacetic acid, and purified by HPLC to obtain 22.1mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.32 (s, 1H), 8.11 (dd, J =8.48,0.64Hz, 1H), 7.98-7.92 (m, 1H), 7.73 (dd, J =7.55,0.64Hz, 1H), 7.60-7.52 (m, 2H), 7.49-7.51 (m, 3H), 5.42-5.29 (m, 1H), 3.38 (s, 3H), 1.47 (d, J =6.71Hz, 6H). Theoretical calculation of ESI-MS C ₁₈ H ₂₀ N ₆ O ₂ [M+H] ⁺ =337.17; the experiment shows that: 336.32.

the final product 12:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) urea (09, ZTA-67)

The method comprises the following steps: synthesis of 3- (1-methyl-1H-pyrazol-4-yl) aniline

1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (312mg, 1.5 mmol) and m-bromoaniline (172mg, 1mmol) were charged to a round-bottomed flask and DME 5mL was dissolved. Sodium carbonate (212mg, 2mmol,2M in H) was added to the reaction flask ₂ O) and PdCl ₂ (dppf)-CH ₂ Cl ₂ (81.7mg, 0.1mmol). Stir at 100 ℃ overnight. After the reaction is finished, 20mL of water is added, ethyl acetate is used for extraction for 3 times, the organic phase is dried by anhydrous sodium sulfate and then is concentrated under reduced pressure, and the target compound 118mg is obtained after column chromatography, wherein the yield is 70%. ¹ H NMR(MeOD-d4,400MHz):7.84(s,1H),7.74(s,1H),7.09(t,J＝7.82Hz,1H),6.94-6.85(m,2H),6.63-6.58(m,1H),3.91(s,3H)。

Step two: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) urea (12, ZTA-67)

Add step one (97.9 mg, 0.57mmol), final product 03 (135mg, 0.63mmol) and triethylamine (138.1mg, 2.05mmol) to a round bottom flask and dissolve in 2mL DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2.5mL of water was added, and HPLC purification was performed to obtain 27.2mg of the objective compound as a colorless oil. ¹ H NMR (MeOD-d 4, 400MHz): 9.49 (s, 1H), 8.10 (d, J =8.3Hz, 1H), 8.01-7.91 (m, 2H), 7.81 (s, 1H), 7.77-7.70 (m, 2H), 7.34-7.21 (m, 3H), 5.74-5.61 (m, 1H), 3.94 (s, 3H), 1.63 (d, J =6.81Hz, 6H). Theoretical calculation of ESI-MS C ₂₁ H ₂₂ N ₈ O[M+H] ⁺ =403.20; the experiment shows that: 402.5.

the final product 13:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) urea (13, ZTA-68)

The method comprises the following steps: synthesis of 4- (1-methyl-1H-pyrazol-4-yl) aniline (ZTA 59-2)

1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (312mg, 1.5 mmol) and p-bromoaniline (172mg, 1mmol) were charged to a round-bottom flask and DME was dissolved in 5 mL. Sodium carbonate (212mg, 2mmol,2M in H) was added to the reaction flask ₂ O) and PdCl ₂ (dppf)-CH ₂ Cl ₂ (81.7 mg, 0.1mmol). Stir at 100 ℃ overnight. After the reaction, 20mL of water was added, the mixture was extracted with ethyl acetate 3 times, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain 65mg of the objective compound. ¹ H NMR(MeOD-d4,400MHz):7.74(s,1H),7.67(s,1H),7.31-7.26(m,2H),6.77-6.72(m,2H),3.88(s,3H)。

Step two: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) urea (13, ZTA-68)

Step one product (45mg, 0.26mmol), final product 03 (135mg, 0.63mmol) and triethylamine (207.2mg, 2.05mmol) were added to a round bottom flask and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2.5mL of water was added, HPLCPurify to obtain the target compound 2.7mg. ¹ H NMR (MeOD-d 4, 400MHz) 9.27 (s, 1H), 8.05 (d, J =8.15Hz, 1H), 8.01-7.95 (m, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.73 (d, J =7.31Hz, 1H), 7.55-7.46 (m, 4H), 5.66-5.54 (m, 1H), 3.94 (s, 3H), 1.62 (d, J =6.86Hz, 6H). Theoretical calculation of ESI-MS C ₂₁ H ₂₂ N ₈ O[M+H] ⁺ =403.20; the experiment shows that: 402.0.

end product 14:1- (1H-indazol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (14, ZTa69-28.5)

The method comprises the following steps: synthesis of 1H-indazol-5-amine

5-Nitro-1H-indazole (326.3mg, 2mmol) was dissolved in methanol and oxygen was removed. 119.2mg of Pd/C (10%), oxygen removed, hydrogen introduced and stirred overnight. After the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated and purified by HPLC to obtain 190.6mg of the objective compound. ¹ H NMR(MeOD-d4,400MHz):8.15(d,J＝0.95Hz,1H),7.89-7.86(m,1H),7.75-7.70(m,1H),7.45-7.40(m,1H)。

Step two: synthesis of 1- (1H-indazol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (14, ZTAR 69-28.5)

Step one (160.6 mg, 1.21mmol), final product 03 (130mg, 0.4 mmol), triethylamine (131.56mg, 1.3mmol) were added to a round bottom flask and 2mL of DMF was dissolved. Stirred at 50 ℃ overnight. After the reaction, 2mL of water was added, acidified with trifluoroacetic acid, and purified by HPLC to obtain 4.3mg of the objective product. ¹ H NMR (MeOD-d 4, 400MHz) 9.12 (s, 1H), 8.31 (s, 1H), 8.19-8.12 (m, 2H), 8.07-7.94 (m, 2H), 7.73 (d, J =7.26Hz, 1H), 7.60 (dd, J =9.15,1.98Hz, 1H), 5.62-5.51 (m, 1H), 1.61 (d, J =6.63Hz, 6H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.16; the experiment shows that: 363.60.

end product 15: 5-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indazole-1-carboxamide (15, ZTA-69-21.5)

The step one product (160.6mg, 1.21mmol), the final product 03 (130mg, 0.4mmol), and triethylamine (131.56mg, 1.3mmol) were added to a round-bottomed flask and dissolved in 2mL of DMF. Stirred at 50 ℃ overnight. After the reaction, 2mL of water was added, acidified with trifluoroacetic acid, and purified by HPLC to obtain 35.4mg of the objective product. ¹ H NMR (MeOD-d 4, 400MHz) 9.61 (s, 1H), 8.17-7.95 (m, 4H), 7.82-7.71 (m, 1H), 7.55 (d, J =9.09Hz, 1H), 7.43 (dd, J =9.09,2.04Hz, 1H), 5.77-5.64 (m, 1H), 1.65 (d, J =6.72Hz, 6H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.16; the experiment shows that: 364.41.

end product 16:1- (4, 5-dihydro- [1,2,4] triazolo [4,3-a ] quinolin-6-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (16, ZTA-70)

Reacting 4, 5-dihydro- [1,2,4]Triazolo [4,3-a]Quinolin-6-amine (44mg, 0.24mmol), final product 03 (77.5mg, 0.24mmol), and triethylamine (79mg, 0.78mmol) were added to a round bottom flask and dissolved in 2mL of DMF. Stirred at 50 ℃ overnight. After the reaction is finished, 2mL of water is added, trifluoroacetic acid is used for acidification, and HPLC purification is carried out to obtain the target product. ¹ H NMR (MeOD-d 4, 400MHz) 9.51 (s, 1H), 9.25 (s, 1H), 8.08-7.89 (m, 2H), 7.83 (d, J =8.36Hz, 1H), 7.71 (d, J =7.11Hz, 1H), 7.63 (d, J =7.94Hz, 1H), 7.54-7.45 (m, 1H), 5.55-5.43 (m, 1H), 3.30-3.20 (m, 2H), 3.15-3.04 (m, 2H), 1.61 (d, J =6.62Hz, 6H). Theoretical calculation of ESI-MS C ₂₁ H ₂₁ N ₉ O[M+H] ⁺ =416.19; the test shows that: 415.9.

end product 17:1- (5, 6-dihydro- [1,2,4] triazolo [3,4- α ] isoquinolin-7-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (17, ZTA-71)

Reacting 5, 6-dihydro- [1,2,4]Triazolo [3, 4-alpha ] s]Isoquinoline-7-amine (46.7 mg, 0.25mmol), final product 03 (81.1mg, 0.25mmol), and triethylamine (75.9mg, 0.75mmol) were added to the round-bottomed flask, and dissolved in 2mL of DMF. Stirred at 50 ℃ overnight. After the reaction, 2mL of water was added, acidified with trifluoroacetic acid, and purified by HPLC to obtain 1.0mg of the objective product. ¹ H NMR (MeOD-d 4, 400MHz) 9.30 (s, 1H), 9.21 (s, 1H), 8.05-7.86 (m, 4H), 7.72 (d, J =7.24Hz, 1H), 7.56 (t, J =7.24Hz, 1H), 5.59-5.47 (m, 1H), 4.49 (t, J =6.97Hz, 2H), 3.28 (t, J =6.97Hz, 2H), 1.61 (d, J =6.67Hz, 6H). Theoretical calculation of ESI-MS C ₂₁ H ₂₁ N ₉ O[M+H] ⁺ =416.19; the test shows that: 415.8.

end product 18:1- (5, 6-dihydro-4H-benzo [ f ] [1,2,4] triazolo [4,3-a ] azepin-7-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (18, ZTA-72)

Reacting 5, 6-dihydro-4H-benzo [ f)][1,2,4]Triazolo [4,3-a]Aza-7-amine (35mg, 0.175mmol), final product 03 (56.5mg, 0.175mmol), triethylamine (53.1mg, 0.525mmol) were added to the round bottom flask and dissolved in 2mL of DMF. Stirred at 50 ℃ overnight. After the reaction, 2mL of water was added, acidified with trifluoroacetic acid, and purified by HPLC to obtain 3.0mg of the objective product. ¹ H NMR (MeOD-d 4, 400MHz) 9.25 (s, 1H), 9.24 (s, 1H), 8.04-7.88 (m, 2H), 7.93-7.88 (m, 1H), 7.75-7.71 (m, 1H), 7.54 (t, J =8.05Hz, 1H), 7.47-7.43 (m, 1H), 5.58-5.47 (m, 1H), 2.99 (t, J =7.03Hz, 2H), 2.70 (t, J = 6.822H), 2.38-2.28 (m, 2H), 1.61 (d, J =6.86Hz, 6H). Theoretical calculation of ESI-MS C ₂₂ H ₂₃ N ₉ O[M+H] ⁺ =430.21; the experiment shows that: 430.21.

end product 19:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (1H-pyrrolo [2,3-b ] pyridin-6-yl) urea (19, ZTA-77)

Reacting 1H-pyrrolo[2,3-b]Pyridin-6-amine (102.8mg, 0.63mmol), final product 03 (135mg, 0.63mmol) and triethylamine (207.2mg, 2.05mmol) were added to a round-bottomed flask and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2.5mL of water was added, and the mixture was purified by HPLC to obtain 3.3mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.34 (s, 1H), 8.19 (d, J =8.69Hz, 1H), 8.09-7.99 (m, 2H), 7.76 (d, J =7.51Hz, 1H), 7.28 (d, J =3.37Hz, 1H), 7.18-7.07 (m, 1H), 6.51 (d, J =3.37Hz, 1H), 5.62-5.50 (m, 1H), 1.62 (d, J =6.74Hz, 6H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.16; the test shows that: 362.41.

the final product 20:1- (benzo [ d ] [1,3] dioxol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (20, ZTAA 78)

Benzo [ d ] benzene][1,3]Dioxol-5-amine (259.2mg, 1.89mmol), final product 03 (135mg, 0.63mmol) and triethylamine (207.2mg, 2.05mmol) were added to a round bottom flask and dissolved in 2mL of DMF. Heat to 50 ℃ and stir overnight. After the reaction, 2.5mL of water was added, and HPLC purification was performed to obtain 93.7mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.54 (s, 1H), 8.06 (d, J =8.66Hz, 1H), 7.97 (dd, J =8.66,7.55Hz, 1H), 7.74 (d, J =7.55Hz, 1H), 7.17 (s, 1H), 6.78 (s, 2H), 5.94 (s, 2H), 5.74-5.61 (m, 1H), 1.64 (d, J =6.72Hz, 6H). ESI-MS theoretical calculation C ₁₈ H ₁₈ N ₆ O ₃ [M+H] ⁺ =367.14; the test shows that: 367.45.

end product 21: (R) -1- (6- (4- (4-hydroxybut-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -3-phenylurea (21, ZTAA 80)

The method comprises the following steps: synthesis of phenyl (R) - (6- (4- (4- ((phenoxycarbonyl) oxy) but-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) carbamate (ZTA 74)

Intermediate 03 (64.2mg, 0.293mmol) was added to a round bottom flask and 2mL dioxane dissolved solids. Sodium carbonate (46.6 mg, 0.44mmol) was added and stirred. Phenyl chloroformate (49.8mg, 0.293mmol) was added at 0 ℃ and allowed to stand overnight at room temperature. After the reaction, water was added, extraction was performed with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was filtered and concentrated to obtain a crude product, which was used directly in the next step.

Step two: synthesis of (R) -1- (6- (4- (4-hydroxybut-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -3-phenylurea (21, ZTAA 80)

The product of step one (94.7mg, 0.293mmol), aniline (81.9mg, 0.879mmol) and triethylamine (96.4mg, 0.952mmol) were added to a 50mL reaction flask and 2mL of DMF was added to dissolve the reaction. Stirring was carried out overnight at 60 ℃. After the reaction, 2.5mL of water was added and HPLC purification was performed to obtain 1.6mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz): 9.36 (s, 1H), 8.09 (d, J =7.94Hz, 1H), 8.02 (dd, J =7.94,6.94Hz, 1H), 7.88 (d, J =6.94Hz, 1H), 7.49-7.42 (m, 2H), 7.32-7.22 (m, 3H), 6.06-5.94 (m, 1H), 3.71-3.60 (m, 2H), 2.34-2.22 (m, 1H), 2.13-2.01 (m, 1H), 1.65 (d, J =6.86Hz, 3H). ESI-MS theoretical calculation C ₁₈ H ₂₀ N ₆ O ₂ [M+H] ⁺ =353.17; the experiment shows that: 353.2.

end product 22:1- (1H-indol-6-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (22, ZTA84)

1H-indol-6-amine (116.3mg, 0.88mmol), final product 03 (94.5mg, 0.29mmol) and triethylamine (95.4 mg, 0.94mmol) were added to a round-bottom flask and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, acidified with trifluoroacetic acid, and purified by HPLC to obtain 87.4mg of a yellow oil. ¹ H NMR (MeOD-d 4, 400MHz): 9.45 (s, 1H), 8.04 (d, J =8.59Hz, 1H), 7.95-7.86 (m, 1H), 7.75-7.63 (m, 2H), 7.45 (d, J =8.31Hz, 1H), 7.18 (s, 1H), 6.91 (dd, J =8.45,1.88Hz, 1H), 5.71-5.55 (m, 1H), 1.58 (d, J =6.71Hz, 6H). Theoretical calculation of ESI-MS C ₁₉ H ₁₉ N ₇ O[M+H] ⁺ =362.17; the experiment shows that: 362.44.

end product 23:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (quinoxalin-6-yl) urea (23, ZTAA 85)

Quinoxalin-6-amine (127.4mg, 0.88mmol), final product 03 (94.5mg, 0.29mmol) and triethylamine (95.4mg, 0.94mmol) were added to a round bottom flask and 2mL of DMF were dissolved. Heat to 50 ℃ and stir overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 124mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.58 (s, 1H), 8.90-8.68 (m, 2H), 8.47-8.40 (m, 1H), 8.24-8.15 (m, 1H), 8.09-7.94 (m, 2H), 7.92-7.84 (m, 1H), 7.82-7.72 (m, 1H), 5.82-5.67 (m, 1H), 1.67 (d, J =6.71Hz, 6H). ESI-MS theoretical calculation C ₁₉ H ₁₈ N ₈ O[M+H] ⁺ =365.16; the experiment shows that: 374.64.

end product 24:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (quinolin-5-yl) urea (24, ZTAA 86)

Quinolin-5-amine (126.9mg, 0.88mmol), final product 03 (94.5mg, 0.29mmol) and triethylamine (95.4mg, 0.94mmol) were added to the round-bottom flask and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 65.1mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.27-9.22 (m, 1H), 9.21-9.17 (m, 1H), 9.15 (s, 1H), 8.46 (d, J =7.91Hz, 1H), 8.14 (t, J =8.23Hz, 1H), 8.06-7.91 (m, 4H), 7.72 (d, J =7.55Hz, 1H), 5.47-5.35 (m, 1H), 1.59 (d, J =6.75Hz, 6H). ESI-MS theoretical calculation C ₂₀ H ₁₉ N ₇ O[M+H] ⁺ =374.17; the experiment shows that: 374.49.

the final product 25: (R) -1- (6- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -3-phenylurea (25, ZTAA 88)

The method comprises the following steps: phenyl (R) - (6- (4- (1- ((phenoxycarbonyl) oxy) propan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) carbamate

Intermediate 02 (69.7mg, 0.32mmol) was put into a 50mL round bottom flask, and 2mL of 1, 4-dioxane was added and dissolved. Phenyl chloroformate (54.1mg, 0.32mmol) and sodium carbonate (50.9mg, 0.48mmol) were charged into a reaction flask. Stirred at room temperature overnight. After the reaction is finished, filtering, and concentrating the filtrate to obtain the target compound. Directly used for the next reaction.

Step two: synthesis of (R) -1- (6- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -3-phenylurea (25, ZTAA 88)

Aniline (89.4 mg, 0.96mmol), step one (108.5mg, 0.32mmol) and triethylamine (328.9mg, 1.04mmol) were added to the round bottom flask and dissolved in 2mL DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, acidified with trifluoroacetic acid, and purified by HPLC to obtain 1.3mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.39 (s, 1H), 8.11-7.93 (m, 2H), 7.76 (d, J =7.34Hz, 1H), 7.49 (d, J =7.93Hz, 2H), 7.33 (t, J =7.74Hz, 2H), 7.12-7.05 (m, 1H), 5.68-5.58 (m, 1H), 3.94-3.81 (m, 2H), 1.64 (d, J =6.97Hz, 3H). Theoretical calculation of ESI-MS C ₁₇ H ₁₈ N ₆ O ₂ [M+H] ⁺ =339.15; the test shows that: 338.4.

end product 26: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) indoline-1-carboxamide (26, ZTAA89)

Indoline (55.3mg, 0.464mmol), final product 03 (50mg, 0.155mmol) and triethylamine (51mg, 0.50mmol) were added to a round-bottomed flask and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 61.8mg of a white solid. ¹ H NMR(MeOD-d4,400MHz):9.63(s,1H),8.08(d,J＝8.26Hz,1H),7.96(t,J＝8.26Hz,1H),7.89(d,J＝8.01Hz,1H),7.79(d,J＝7.51Hz,1H),724-7.12 (m, 2H), 6.97 (t, J =7.44hz, 1h), 5.96-5.84 (m, 1H), 4.18 (t, J =8.77hz, 2h), 3.21 (t, J =8.64hz, 2h), 1.62 (d, J =6.65hz, 6H). Theoretical calculation of ESI-MS C ₁₉ H ₂₀ N ₆ O[M+H] ⁺ =349.17; the experiment shows that: 349.4.

end product 27: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3, 4-dihydroquinoline-1 (2H) -carboxamide (27, ZTA-90)

1,2,3, 4-tetrahydroquinoline (61mg, 0.464mmol), final product 03 (50mg, 0.155mmol) and triethylamine (51mg, 0.50mmol) were added to a round-bottomed flask and dissolved in 2mL of DMF. Heat to 50 ℃ and stir overnight. After the reaction, 2mL of water was added, acidified with trifluoroacetic acid, and purified by HPLC to obtain 46mg of the objective compound as a colorless oil. ¹ H NMR (MeOD-d 4, 400MHz) 9.36 (s, 1H), 8.10 (d, J =8.70Hz, 1H), 7.97 (dd, J =8.70,7.31Hz, 1H), 7.78 (d, J =7.31Hz, 1H), 7.39 (d, J =7.961Hz, 1H), 7.29-7.19 (m, 2H), 7.17-7.10 (m, 1H), 5.72-5.61 (m, 1H), 3.83 (t, J =6.32Hz, 2H), 2.84 (t, J =6.58Hz, 2H), 2.08-1.97 (m, 2H), 1.54 (d, J =6.62Hz, 6H). Theoretical calculation of ESI-MS C ₂₀ H ₂₂ N ₆ O[M+H] ⁺ =363.19; the experiment shows that: 363.52.

end product 28:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (2-oxoindol-5-yl) urea (28, ZTA-91)

Step 5-Aminoindolin-2-one (79.5mg, 0.54mmol), final product 03 (57.8mg, 0.178mmol) and triethylamine (161.9mg, 1.6mmol) were added to a round bottom flask and dissolved in 2mL DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, acidified with trifluoroacetic acid, and purified by HPLC to obtain 22.4mg of a white solid. ¹ H NMR(MeOD-d4,400MHz):9.36(s,1H),8.07-7.93(m,2H),7.73(d,J＝7.25Hz,1H),7.46(s,1H),7.30-7.25(m,1H),6.88(d,J＝8.42Hz,1H),5.67-5.55(m,1H),3.56(s,2H),1.62(dJ =6.76hz, 6h). Theoretical calculation of ESI-MS C ₁₉ H ₁₉ N ₇ O ₂ [M+H] ⁺ =378.16; the test shows that: 377.11.

end product 29: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxamide (29, ZTa94)

Reacting 2, 3-dihydro-1H-pyrrolo [3,4-c ]]Pyridine hydrochloride (90mg, 0.465mmol) and triethylamine (98mg, 0.97mmol) were added to a round bottom flask and dissolved in 2mL of DMF. After stirring for 10 min, the above solution was added to the reaction flask containing the final product 03 (50mg, 0.155mmol). Heat to 50 ℃ and stir overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 19.9mg of a yellow oily compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.24 (s, 1H), 8.91 (s, 1H), 8.81 (d, J =5.85Hz, 1H), 8.10-7.95 (m, 3H), 7.78 (d, J =7.34Hz, 1H), 5.88-5.73 (m, 1H), 5.26-5.12 (m, 4H), 1.59 (d, J =6.66Hz, 6H). ESI-MS theoretical calculation C ₁₈ H ₁₉ N ₇ O[M+H] ⁺ =350.17; the experiment shows that: 350.57.

30 parts of a final product: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) isoindole-2-carboxylic acid amide (30, ZTAK)

Isoindoline (55.4 mg, 0.465mmol), final product 03 (50mg, 0.155mmol) and triethylamine (51mg, 0.5mmol) were added to a round bottom flask and dissolved in 2mL of DMF. Heat to 50 ℃ and stir overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 49.9mg of a yellow oily compound. ¹ H NMR (MeOD-d 4, 400MHz): 9.44 (s, 1H), 8.10 (d, J =8.45Hz, 1H), 7.96 (dd, J =8.45,7.54Hz, 1H), 7.77 (d, J =7.54Hz, 1H), 7.40-7.29 (m, 4H), 5.95-5.82 (m, 1H), 5.89 (s, 2H), 1.62 (d, J =6.76Hz, 6H). Theoretical calculation of ESI-MS C ₁₉ H ₂₀ N ₆ O[M+H] ⁺ =349.17; experimental surveyObtaining: 350.15.

end product 31: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) piperidine-1-carboxamide (31, ZTAR 97)

Piperidine (39.6 mg, 0.465mmol), final product 03 (50mg, 0.155mmol) and triethylamine (51mg, 0.5mmol) were added to the round bottom flask and dissolved in 2mL DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 58.1mg of a colorless oily compound. ¹ H NMR (MeOD-d 4, 400MHz): 9.53 (s, 1H), 7.99-7.84 (m, 2H), 7.74 (dd, J =7.31,0.92Hz, 1H), 5.96-5.85 (m, 1H), 3.63-3.52 (m, 4H), 1.77-1.62 (m, 6H), 1.59 (d, J =6.71Hz, 6H). Theoretical calculation of ESI-MS C ₁₆ H ₂₂ N ₆ O[M+H] ⁺ =315.19; the experiment shows that: 315.9.

end product 32: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-methylpiperazine-1-carboxamide (32, ZTa98)

1-methylpiperazine (46.6 mg, 0.465mmol), final product 03 (50mg, 0.155mmol) and triethylamine (51mg, 0.5mmol) were added to a round-bottom flask and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 66.4mg of a colorless oily compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.44 (s, 1H), 7.99-7.91 (m, 2H), 7.77 (d, J =5.75Hz, 1H), 5.93-5.80 (m, 1H), 4.54-4.31 (m, 2H), 3.73-3.09 (m, 6H), 2.99 (s, 3H), 1.58 (d, J =6.81Hz, 6H). Theoretical calculation of ESI-MS C ₁₆ H ₂₃ N ₇ O[M+H] ⁺ =330.20; the experiment shows that: 330.97.

end product 33: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) morpholine-4-carboxamide (33, ZTa99)

Morpholine (40.5mg, 0.465mmol), final product 03 (50mg, 0.155mmol) and triethylamine (51mg, 0.5mmol) were added to a round-bottomed flask and dissolved in 2mL of DMF. Heat to 50 ℃ and stir overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 81.2mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.61 (s, 1H), 8.00-7.89 (m, 2H), 7.77 (d, J =6.48Hz, 1H), 6.00-5.85 (m, 1H), 3.78-3.70 (m, 4H), 3.63-3.56 (m, 4H), 1.60 (d, J =6.80Hz, 6H). Theoretical calculation of ESI-MS C ₁₅ H ₂₀ N ₆ O ₂ [M+H] ⁺ =317.16; the test shows that: 317.72.

end product 34: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxamide (34, ZTAA 102)

1,2,3, 6-tetrahydropyridine (55.6 mg, 0.465mmol), final product 03 (50mg, 0.155mmol) and triethylamine (51mg, 0.5mmol) were added to a round-bottom flask and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 49.5mg of a colorless oily compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.47 (s, 1H), 7.96-7.85 (m, 2H), 7.73 (dd, J =6.91,1.2Hz, 1H), 5.99-5.69 (m, 3H), 4.12-4.02 (m, 2H), 3.66 (t, J =5.55Hz, 2H), 2.29-2.20 (m, 2H), 1.57 (d, J =6.73Hz, 6H). ESI-MS theoretical calculation C ₁₆ H ₂₀ N ₆ O[M+H] ⁺ =313.17; the experiment shows that: 313.63.

end product 35: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (35, ZTAA 104)

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1,2,3, 4-tetrahydroisoquinoline (62mg, 0.465mmol), final product 03 (50mg, 0.155mmol) and triethylamine (51mg, 0.5mmol) were added to a round-bottomed flask, and 2mL of DMF was dissolved in waterAnd (4) solving. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 53.9mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.30 (s, 1H), 7.93-7.86 (m, 2H), 7.73-7.70 (m, 1H), 7.21-7.13 (m, 4H), 5.90-5.76 (m, 1H), 4.72 (s, 2H), 3.79 (t, J =5.89Hz, 2H), 2.93 (t, J =5.92Hz, 2H), 1.55 (d, J =6.75Hz, 6H). ESI-MS theoretical calculation C ₂₀ H ₂₂ N ₆ O[M+H] ⁺ =363.19; the test shows that: 363.65.

end product 36: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxamide (36, ZTAA 110)

The method comprises the following steps: synthesis of 5- (1-methyl-1H-pyrazol-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (ZTA 103)

4-bromo-1-methyl-1H-pyrazole (161mg, 1mmol), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (618.4mg, 2mmol) and 2M sodium carbonate (4mL, 2mmol,2M in H ₂ O) was charged to a round bottom flask and dissolved with DME. PdCl is added ₂ (dppf)-CH ₂ Cl ₂ (86.7mg, 0.1mmol) and stirred at 95 ℃ overnight. After the reaction was complete, 568.2mg of crude product were obtained by column chromatography and used directly in the next step.

Step two: synthesis of 5- (1-methyl-1H-pyrazol-4-yl) -1,2,3, 6-tetrahydropyridine (ZTA 106)

The product of step one was added to a round bottom flask, 1mL trifluoroacetic acid, 4mL dichloromethane were added, and refluxed overnight. After the reaction is finished, the reaction mixture is dried by spinning, 3mL of water and trifluoroacetic acid are added to adjust the pH value to be less than or equal to 1, and the HPLC purification is carried out to obtain 399.7mg of product. ¹ H NMR(MeOD-d4,400MHz):7.74(s,1H),7.64(s,1H),6.24-6.19(m,1H),4.00-3.91(m,2H),3.89(s,3H),3.39-3.34(m,2H),2.58-2.50(m,2H)。

Step three: synthesis of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxamide (36, ZTAR 110)

The step two product (129mg, 0.465mmol), the final product 03 (50mg, 0.155mmol) and triethylamine (102mg, 1mmol) were added to a round bottom flask and dissolved in 2mL of DMF. Heat to 50 ℃ and stir overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 44.1mg of a yellow oily compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.52 (s, 1H), 7.98-7.85 (m, 2H), 7.78-7.67 (m, 2H), 7.61 (s, 1H), 6.22-6.13 (m, 1H), 5.93-5.81 (m, 1H), 4.31 (s, 2H), 3.87 (s, 3H), 3.70 (t, J =5.61Hz, 2H), 2.43-2.31 (m, 2H), 1.58 (d, J =6.71Hz, 6H). ESI-MS theoretical calculation C ₂₀ H ₂₄ N ₈ O[M+H] ⁺ =393.21; the experiment shows that: 393.70.

end product 37: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- (1-methyl-1H-pyrazol-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxamide (37, ZTAR 111)

The method comprises the following steps: synthesis of 4- (1-methyl-1H-pyrazol-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (ZTA 105)

4-bromo-1-methyl-1H-pyrazole (161mg, 1mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (618.4mg, 2mmol) and 2M sodium carbonate (4mL, 2mmol,2M in H ₂ O) was charged to a round bottom flask and dissolved with DME. PdCl is added ₂ (dppf)-CH ₂ Cl ₂ (86.7 mg,0.1 mmol) was stirred at 95 ℃ overnight. After the reaction was completed, 542.7mg of crude product was obtained by column chromatography and used in the next step.

Step two: synthesis of 4- (1-methyl-1H-pyrazol-4-yl) -1,2,3, 6-tetrahydropyridine (ZTA 107)

Add the product of step one to a round bottom flask, add 1mL trifluoroacetic acid, 4mL dichloromethane, reflux overnight. After the reaction, the reaction mixture was spin-dried, 3mL of water was added, the pH was adjusted to 1 or less with trifluoroacetic acid, and HPLC purification gave 367.7mg of the product. ¹ H NMR(MeOD-d4,400MHz):7.74(s,1H),7.64(s,1H),6.04-5.97(m,1H),3.87(s,3H),3.81-3.76(m,2H),3.42(t,J＝6.22Hz,2H),2.71-2.64(m,2H)。

Step three: synthesis of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- (1-methyl-1H-pyrazol-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxamide (37, ZTAA 111)

The product of step two (129mg, 0.465mmol), final product 03 (50mg, 0.155mmol) and triethylamine (102mg, 1mmol) were added to a round bottom flask and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, and the mixture was acidified with trifluoroacetic acid and purified by HPLC to obtain 68.3mg of a yellow oily compound. ¹ H NMR (MeOD-d4, 400MHz): 9.69 (s, 1H), 7.99-7.89 (m, 2H), 7.82-7.74 (m, 1H), 7.70 (s, 1H), 7.64 (s, 1H), 6.07-6.00 (m, 1H), 6.00-5.88 (m, 1H), 4.22 (s, 2H), 3.89 (s, 3H), 3.79 (t, J =5.61Hz, 2H), 2.60-2.45 (m, 2H), 1.61 (d, J =6.54Hz, 6H). ESI-MS theoretical calculation C ₂₀ H ₂₄ N ₈ O[M+H] ⁺ 393.21; the experiment shows that: 393.65.

end product 38: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- (1-methyl-1H-pyrazol-4-yl) isoindoline-2-carboxamide (38, ZTAA 118)

The method comprises the following steps: synthesis of 4-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) isoindole-2-carboxamide (ZTA 114)

4-Bromoisoindoline hydrochloride (174mg, 0.74mmol) and triethylamine (158.1mg, 1.56mmol) were added to a round bottom flask, dissolved in DMF and stirred for 10 min. The final product 03 (80mg, 0.25mmol) was added and stirred overnight at 50 ℃. After the reaction is complete, HPLC purification gives 100mg of the compound as a colorless oil. ¹ H NMR(MeOD-d4,400MHz):9.47(s,1H),8.03(d,J＝8.75Hz,1H),7.87(dd,J＝8.75,7.50Hz,1H),7.72(d,J＝7.50Hz,1H),7.39(d,J＝7.81Hz,1H),7.26(d,J＝7.25Hz,1H),7.21-7.15(m,1H),5.96-5.82(m,1H),4.89(s,2H),4.74(s,2H),1.59(d,J＝6.68Hz,6H)。

Step two: synthesis of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- (1-methyl-1H-pyrazol-4-yl) isoindoline-2-carboxamide (38, ZTAA 118)

The step-one product (61mg, 0.143mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-1H-pyrazole (59.6mg, 0.286mmol) and 2M sodium carbonate (1mL, 0.286mmol,2M in H ₂ O) was charged to a round bottom flask and dissolved with DME. PdCl is added ₂ (dppf)-CH ₂ Cl ₂ (11.7mg, 0.0143mmol) was stirred at 95 ℃ overnight. After the reaction is finished, the mixture is filtered, the filtrate is extracted, the organic phase is dried and concentrated, and the target compound 56.1mg is obtained after HPLC purification. ¹ H NMR (MeOD-d 4, 400MHz) 9.61 (s, 1H), 8.14-7.99 (m, 1H), 7.96-7.79 (m, 2H), 7.79-7.67 (m, 2H), 7.43 (d, J =7.51Hz, 1H), 7.27 (t, J =7.66Hz, 1H), 7.13 (d, J =7.21Hz, 1H), 5.98-5.72 (m, 1H), 4.91-4.70 (m, 4H), 3.90 (s, 3H), 1.61 (d, J =6.55Hz, 6H). Theoretical calculation of ESI-MS C ₂₃ H ₂₄ N ₈ O[M+H] ⁺ =429.21; the test shows that: 429.81.

end product 39: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) isoindoline-2-carboxamide (39, ZTa119)

The method comprises the following steps: synthesis of 5-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) isoindole-2-carboxamide (ZTA 115)

5-Bromoisoindoline hydrochloride (174mg, 0.74mmol) and triethylamine (158.1mg, 1.56mmol) were added to a round bottom flask, dissolved in DMF and stirred for 10 min. The final product 03 (80mg, 0.25mmol) was added and stirred overnight at 50 ℃. At the end of the reaction, HPLC purification afforded 83.8mg of a white solid. ¹ H NMR(MeOD-d4,400MHz):9.43(s,1H),8.06(d,J＝8.39Hz,1H),7.95(t,J＝8.39,7.27Hz,1H),7.75(d,J＝7.27Hz,1H),7.52(s,1H),7.49-7.44(m,1H),7.29-7.24(m,1H),5.92-5.81(m,1H),4.87(s,2H),4.83(s,2H),1.59(d,J＝6.78Hz,6H)。

Step two: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) isoindoline-2-carboxamide (39, ZTa119)

The product of step one (61mg, 0.143mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (59.6 mg,0.286 mmol) and 2M sodium carbonate (1mL, 0.286mmol,2M in H ₂ O) is added into a round-bottom flask,solubilisation with DME. Adding PdCl ₂ (dppf)-CH ₂ Cl ₂ (11.7mg, 0.0143mmol) and stirred at 95 ℃ overnight. After the reaction is finished, the mixture is filtered, the filtrate is extracted, the organic phase is dried and concentrated, and the target compound 47.2mg is obtained through HPLC purification. ¹ H NMR (MeOD-d 4, 400MHz) 9.40 (s, 1H), 7.92-7.76 (m, 1H), 7.76-7.58 (m, 2H), 7.58-7.44 (m, 2H), 7.22 (d, J =7.63Hz, 1H), 7.06 (t, J =7.53Hz, 1H), 6.92 (d, J =7.48Hz, 1H), 5.72-5.50 (m, 1H), 4.72-4.42 (m, 4H), 3.69 (s, 3H), 1.40 (d, J =6.66Hz, 6H). ESI-MS theoretical calculation C ₂₃ H ₂₄ N ₈ O[M+H] ⁺ =429.21; the test shows that: 429.73.

the final product 40: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -8- (1-methyl-1H-pyrazol-4-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (40, ZTAA 120)

The method comprises the following steps: synthesis of 8-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (ZTA 116)

8-bromo-1, 2,3, 4-tetrahydroisoquinoline (159mg, 0.75mmol), final product 03 (80mg, 0.25mmol) and triethylamine (82.2mg, 0.813mmol) were added to the round-bottom flask, and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added and HPLC purification was performed to obtain 94.2mg of a white solid. ¹ H NMR(MeOD-d4,400MHz):9.46(s,1H),8.00-7.84(m,2H),7.75(d,J＝7.19Hz,1H),7.47(d,J＝7.59Hz,1H),7.22(d,J＝7.39Hz,1H),7.17-7.10(m,1H),5.94-5.79(m,1H),4.73(s,2H),3.81(t,J＝6.08Hz,2H),2.99(t,J＝5.85Hz,2H),1.59(d,J＝6.70Hz,6H)。

Step two: synthesis of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -8- (1-methyl-1H-pyrazol-4-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (40, ZTAA 120)

Step one product (83mg, 0.189mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (78.5mg, 0.377 mmol) and 2M sodium carbonate (1mL, 0.377mmol,2M in H ₂ O) was charged to a round bottom flask and dissolved with DME. PdCl is added ₂ (dppf)-CH ₂ Cl ₂ (15.4mg, 0.0189mmol) and stirred at 95 ℃ overnight. After the reaction is finished, suction filtration is carried out, filtrate is extracted, organic phase is dried and concentrated, and HPLC purification is carried out to obtain 66.6mg of the target compound. ¹ H NMR (MeOD-d4, 400MHz): 9.53 (s, 1H), 7.93-7.83 (m, 2H), 7.76 (s, 1H), 7.73-7.66 (m, 1H), 7.62 (s, 1H), 7.24-7.17 (m, 2H), 7.16-7.09 (m, 1H), 5.87-5.72 (m, 1H), 4.72 (s, 2H), 3.93 (s, 3H), 3.79 (t, J =6.11Hz, 2H), 3.01 (t, J =6.05Hz, 2H), 1.55 (d, J =6.80Hz, 6H). Theoretical calculation of ESI-MS C ₂₄ H ₂₆ N ₈ O[M+H] ⁺ =443.22; the test shows that: 443.80.

end product 41: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (1-methyl-1H-pyrazol-4-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (41, ZTAA 121)

The method comprises the following steps: synthesis of 7-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (ZTA 117)

7-bromo-1, 2,3, 4-tetrahydroisoquinoline (159mg, 0.75mmol), final product 03 (80mg, 0.25mmol) and triethylamine (82.2mg, 0.813mmol) were added to a round-bottomed flask, and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, and HPLC purification was performed to obtain 115mg of a colorless oily compound. ¹ H NMR(MeOD-d4,400MHz):9.54(s,1H),7.96-7.86(m,2H),7.77-7.69(m,1H),7.35-7.24(m,2H),7.07(d,J＝8.00Hz,1H),5.97-5.82(m,1H),4.70(s,2H),3.78(t,J＝5.96Hz,2H),2.87(t,J＝5.84Hz,2H),1.57(d,J＝6.77Hz,6H)。

Step two: synthesis of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (1-methyl-1H-pyrazol-4-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxamide (41, ZTAA 121)

Step one product (100.4 mg, 0.228mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (95mg, 0.456 mmol) and 2M sodium carbonate (1mL, 0.456mmol,2M in H. Sub. ₂ O) was charged to a round bottom flask and dissolved with DME. Adding PdCl ₂ (dppf)-CH ₂ Cl ₂ (18.6mg,0.0228 mmol), and stirred at 95 deg.c overnight. After the reaction, the reaction solution is filtered, the filtrate is extracted, the organic phase is dried and concentrated, and the target compound 240.1mg is obtained after HPLC purification. ¹ H NMR (MeOD-d4, 400MHz) 9.53 (s, 1H), 7.97-7.87 (m, 3H), 7.78 (s, 1H), 7.76-7.69 (m, 1H), 7.39-7.31 (m, 2H), 7.16 (d, J =8.07Hz, 1H), 5.94-5.82 (m, 1H), 4.74 (s, 2H), 3.91 (s, 3H), 3.80 (t, J =5.62Hz, 2H), 2.92 (t, J =5.56Hz, 2H), 1.57 (d, J =6.81Hz, 6H). Theoretical calculation of ESI-MS C ₂₄ H ₂₆ N ₈ O[M+H] ⁺ =443.22; the experiment shows that: 443.75.

end product 42:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) urea (42, ZTa123)

5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine (65.1mg, 0.372mmol), final product 03 (40mg, 0.124mmol) and triethylamine (40.8mg, 0.403mmol) were added to a round-bottomed flask, and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, and HPLC purification was performed to obtain 48.3mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.40 (s, 1H), 8.42 (d, J =1.86Hz, 1H), 8.24-8.15 (m, 2H), 8.06 (s, 1H), 8.00 (t, J =8.16Hz, 1H), 7.88 (s, 1H), 7.84 (d, J =7.59Hz, 1H), 7.50 (d, J =8.31Hz, 1H), 5.82-5.69 (m, 1H), 3.96 (s, 3H), 1.66 (d, J =6.76Hz, 6H). Theoretical calculation of ESI-MS C ₂₀ H ₂₁ N ₉ O[M+H] ⁺ =404.19; the test shows that: 404.62.

end products 43 and 180:1- (1H-indazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (43, ZTA128-1) and 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indazole-1-carboxamide (180, ZTA128-2)

1H-indazol-3-amine (49.5mg, 0.371mmol), final product 03 (40mg, 0.124mmol) and triethylamine (40.8mg, 0.403mmol) were added to a round-bottomed flaskBottle, 2mL DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, and HPLC purification was carried out to obtain the objective compound ZTA128-1 (11.9 mg), ¹ H NMR(MeOD-d4,400MHz): ¹ h NMR (MeOD-d 4, 400MHz) 9.39 (s, 1H), 8.28-8.18 (m, 1H), 8.06-7.98 (m, 1H), 7.91 (d, J =8.36Hz, 1H), 7.82 (d, J =7.35Hz, 1H), 7.51-7.40 (m, 2H), 7.19-7.12 (m, 1H), 5.66 (septiuple, J =6.75Hz, 1H), 1.70 (d, J =6.76Hz, 6H). The results of the experiments: 363.57.ZTA128-2 (6.2 mg), 9.27 (s, 1H), 8.35 (d, J =8.57hz, 1h), 8.24 (d, J =8.57hz, 1h), 8.03 (dd, J =8.57,7.91hz, 1h), 7.88-7.76 (m, 2H), 7.55 (t, J =8.30hz, 1h), 7.30 (t, J =7.66hz, 1h), 5.75-5.62 (m, 1H), 1.64 (d, J =6.78hz, 6H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.16; theoretical calculation of ESI-MS C ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.16; the experiment shows that: 363.71.

the final product 44:1- (1H-benzo [ d ] imidazol-6-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (44, ZTa129)

By reacting 1H-benzo [ d ]]Imidazol-6-amine (49.4 mg, 0.371mmol), final product 03 (40mg, 0.124mmol) and triethylamine (40.8mg, 0.403mmol) were added to a round-bottomed flask and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added and HPLC purification was performed to obtain 59.2mg of a white solid. ¹ H NMR (MeOD-d 4, 400MHz): 9.41 (s, 1H), 9.31 (s, 1H), 8.41 (d, J =1.64Hz, 1H), 8.14 (d, J =8.44Hz, 1H), 8.02 (t, J =7.78Hz, 1H), 7.82-7.75 (m, 2H), 7.53 (dd, J =8.93,1.86Hz, 1H), 5.73-5.61 (m, 1H), 1.65 (d, J =6.79Hz, 6H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.16; the test shows that: 363.77.

end products 45 and 179:1- (1H-indol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (45, ZTAA-1) and 5-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-1-carboxamide (179, ZTAA-2)

1H-indol-5-amine (49.0 mg, 0.371mmol), final product 03 (40mg, 0.124mmol) and triethylamine (40.8 mg, 0.403mmol) were added to a round-bottom flask, and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added and HPLC purification was performed to obtain 31.5mg of a yellow oily compound. ¹ H NMR (MeOD-d 4,400MHz, mix of two iso meters, 45 179= 2): 9.11 (s, 0.3H), 9.04 (s, 0.6H), 8.00-7.94 (m, 0.3H), 7.88-7.78 (m, 1.7H), 7.70-7.54 (m, 2H), 7.36-7.26 (m, 1H), 7.20-7.12 (m, 1H), 7.09-7.03 (m, 0.6H), 5.56-5.36 (m, 1H), 3.70-3.62 (m, 0.6H), 1.53 (d, J =6.83Hz, 2H), 1.49-1.40 (m, 4H). Theoretical calculation of ESI-MS C ₁₉ H ₁₉ N ₇ O[M+H] ⁺ =362.17; the experiment shows that: 362.89.

end product 46: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) pyrrolidine-1-carboxamide (46, ZTa131)

Pyrrolidine (26.4 mg, 0.371mmol), final product 03 (40mg, 0.124mmol) and triethylamine (40.8 mg, 0.403mmol) were added to the round-bottom flask and dissolved in 2mL of DMF. Heat to 50 ℃ and stir overnight. After the reaction, 2mL of water was added, and HPLC purification was performed to obtain 45mg of a yellowish brown oily compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.62 (s, 1H), 8.03 (d, J =8.36Hz, 1H), 7.98-7.91 (m, 1H), 7.74 (t, J =7.48Hz, 1H), 5.93-5.79 (m, 1H), 3.60-3.43 (m, 4H), 2.05-1.92 (m, 4H), 1.59 (d, J = 6.726H). Theoretical calculation of ESI-MS C ₁₅ H ₂₀ N ₆ O[M+H] ⁺ =301.17; the test shows that: 301.75.

the final product 47: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxamide (47, ZTAA 132)

2, 5-dihydro-1H-pyrrole hydrochloride(39.2mg, 0.371mmol), final product 03 (40mg, 0.124mmol) and triethylamine (78.4 mg, 0.775mmol) were added to the round bottom flask, and 2mL of DMF was dissolved. Heat to 50 ℃ and stir overnight. After the reaction, 2mL of water was added, and HPLC purification was performed to obtain 50.9mg of a colorless oily compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.56 (s, 1H), 8.06 (d, J =8.32Hz, 1H), 7.97 (t, J =8.40Hz, 1H), 7.76 (d, J =7.20Hz, 1H), 5.95 (s, 2H), 5.84-5.90 (m, 1H), 4.35 (s, 4H), 1.61 (d, J =6.40Hz, 6H). ESI-MS theoretical calculation C ₁₅ H ₁₈ N ₆ O[M+H] ⁺ =299.15; the experiment shows that: 299.72.

the final product 48:3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-methyl-1- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) urea (48, ZTAA 133)

The method comprises the following steps: synthesis of 1- (4-bromophenyl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-methylurea (ZTA 124)

The final product 03 (80mg, 0.25mmol) and 4-bromo-N-methylaniline (139.5mg, 0.75mmol) and triethylamine (82.2mg, 0.813mmol) were added to a round-bottomed flask and dissolved in 2mL of DMF. Heat to 50 ℃ and stir overnight. After the reaction, 2mL of water was added, and HPLC purification was performed to obtain 75.5mg of the objective compound. ¹ H NMR(MeOD-d4,400MHz):9.24(s,1H),8.08-7.89(m,2H),7.78-7.59(m,3H),7.36(d,J＝8.33Hz,2H),5.51-5.32(m,1H),3.37(s,3H),1.48(d,J＝6.65Hz,6H)。

Step two: synthesis of 3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-methyl-1- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) urea (48, ZTAA 133)

ZTA124 (45mg, 0.11mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (45mg, 0.22mmol) and sodium carbonate (23.32mg, 0.22mmol,2M in H ₂ O) was charged to a round bottom flask and dissolved with DME. Adding PdCl ₂ (dppf)-CH ₂ Cl ₂ (9mg, 0.011mmol), and stirring at 95 deg.C overnight. After the reaction was completed, HPLC purification gave 28.4mg of the objective compound. ¹ H NMR(MeOD-d4,400MHz):9.17(s,1H),8.06-8.10(m,1H),8.05(s,1H),7.91-7.98 (m, 1H), 7.89 (s, 1H), 7.73-7.75 (m, 3H), 7.43-7.45 (m, 2H), 5.30-5.35 (m, 1H), 3.96 (s, 3H), 1.42 (d, J =6.00hz, 6H). ESI-MS theoretical calculation C ₂₂ H ₂₄ N ₈ O[M+H] ⁺ =417.21; the test shows that: 417.58.

end product 49:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) urea (49, ZTA134)

The method comprises the following steps: synthesis of 1- (6-bromopyridin-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (ZTA 125)

The final product 03 (80mg, 0.25mmol) and 6-bromopyridin-3-amine (129.8mg, 0.75mmol) and triethylamine (82.2mg, 0.813mmol) were added to a round-bottomed flask and dissolved in 2mL of DMF. Heat to 50 ℃ and stir overnight. After the reaction, 2mL of water was added, and HPLC purification was performed to obtain 67.7mg of the objective compound. ¹ H NMR(MeOD-d4,400MHz):9.43(s,1H),8.52(d,J＝2.60Hz,1H),8.12(d,J＝8.48Hz,1H),8.04-7.93(m,2H),7.78(d,J＝7.12Hz,1H),7.56(d,J＝8.48Hz,1H),5.73-5.61(m,1H),1.64(d,J＝6.73Hz,6H)。

Step two: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) urea (49, ZTA 134)

A mixture of ZTA125 (30mg, 0.075mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (31.1mg, 0.15mmol) and sodium carbonate (15.9mg, 0.15mmol,2M in H ₂ O) was charged to a round bottom flask and dissolved with DME. PdCl is added ₂ (dppf)-CH ₂ Cl ₂ (6.2mg, 0.0075mmol), and stirred at 95 ℃ overnight. After the reaction was completed, HPLC purification gave 25.1mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz): 9.19 (s, 1H), 9.13 (d, J =2.0Hz, 1H), 8.38 (s, 1H), 8.34 (dd, J =8.80,2.00Hz, 1H), 8.15 (s, 1H), 8.09-8.11 (m, 2H), 8.00 (t, J =8.36Hz, 1H), 7.79 (d, J =7.20Hz, 1H), 5.63-5.69 (m, 1H), 4.03 (s, 3H), 1.63 (d, J =6.60Hz, 6H). ESI-MS theoretical calculation C ₂₀ H ₂₁ N ₉ O[M+H] ⁺ =404.19; experiment ofAnd (3) measuring: 404.68.

the final product 51: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) indoline-1-carboxamide (51, ZTAA 136)

Step one 5-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) indoline-1-carboxamide (ZTA 127)

The final product 03 (80mg, 0.25mmol), 5-bromoindoline (148.5mg, 0.75mmol) and triethylamine (82.2mg, 0.813mmol) were added to a round bottom flask and dissolved in 2mL of DMF. Heat to 50 ℃ and stir overnight. After the reaction, 2mL of water was added, and HPLC purification was performed to obtain the objective compound ZTA127 (93.3 mg). ¹ H NMR(MeOD-d4,400MHz):9.28(s,1H),8.07(d,J＝8.25Hz,1H),8.00(t,J＝8.49Hz,1H),7.84(d,J＝8.74Hz,1H)7.79(d,J＝7.28Hz,1H),7.38(s,1H),7.34-7.29(m,1H),5.81(sept,J＝6.70Hz,1H),4.25(d,J＝8.52Hz,2H),3.27(d,J＝8.52Hz,2H),1.59(d,J＝6.70Hz,6H).

Step two: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) indoline-1-carboxamide (51, ZTAA 136)

ZTA127 (48mg, 0.113mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (46.9 mg, 0.225mmol) and sodium carbonate (23.9 mg,0.225mmol,2M in H ₂ O) was charged to a round bottom flask and dissolved with DME. PdCl is added ₂ (dppf)-CH ₂ Cl ₂ (9.22mg, 0.0113mmol), and stirred at 95 ℃ overnight. After the reaction, HPLC purification gave the desired compound ZTA136 (37.8 mg). ¹ H NMR(MeOD-d4,400MHz):9.50(s,1H),8.12-8.06(m,1H),8.05-7.97(m,1H),7.94-7.86(m,2H),7.84-7.75(m,2H),7.44(s,1H),7.41-7.35(m,1H),5.87(septet,J＝6.68Hz,1H),4.24(t,J＝8.27Hz,2H),3.28(t,J＝8.27Hz.,2H),1.62(d,J＝6.55Hz,6H).

End product 55:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (1-methyl-1H-indazol-3-yl) urea (55, YB138)

The final product 03 (30mg, 0.0927mmol), 1-methyl-1H-indazol-3-amine (41mg, 0.278mmol) and Et ₃ N (38mg, 0.376 mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reactants. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to afford the target compound YB138 (38 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.27 (s, 1H), 8.23 (d, J =8.4Hz, 1H), 8.02 (dd, J =7.6,8.5Hz, 1H), 7.90 (dt, J =1.0,8.3Hz, 1H), 7.81 (d, J =7.5Hz, 1H), 7.55-7.38 (m, 2H), 7.16 (ddd, J =2.0,5.8,8.1Hz, 1H), 5.64 (p, J =6.7Hz, 1H), 4.02 (s, 3H), 1.68 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C ₁₉ H ₂₀ N ₈ O[M+H] ⁺ =377.18, determined experimentally: 377.77.

end product 59 1- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (59, yb115)

The final product 03 (30mg, 0.0973mmol), 3-cyclopropyl-1-methyl-1H-pyrazol-5-amine (38mg, 0.278mmol) and Et ₃ N (38 mg) was weighed into a bottle, and DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to afford the target compound YB115 (23 mg). ¹ H NMR (MeOD-d 4, 400MHz) 9.35 (s, 1H), 8.07 (d, J =8.15Hz, 1H), 8.03-7.97 (s, 1H), 7.78 (d, J =7.77Hz, 1H), 6.23 (s, 1H), 5.63 (septit, J =6.80Hz, 1H), 3.76 (s, 3H), 1.97-1.89 (m, 1H), 1.62 (d, J =6.80Hz, 6H), 1.07-0.99 (m, 2H), 0.83-0.76 (m, 2H), ESI-MS theoretical calculation C ₁₈ H ₂₃ N ₈ O[M+H]+ 367.20, experimentally determined: 367.58.

end product 60

Step one, synthesizing 1- (4-nitrophenyl) -1H-imidazole (YB 112)

Imidazole (68mg, 1mmol) was dissolved in DMF (5 mL) in a glass reaction flask, and 4-fluoronitrobenzene (1699 mg,1.2 mmol) and potassium carbonate (300mg, 2.2 mmol) were added. The reaction was heated to 110 ℃ and reacted for 2 hours. After cooling the reaction, 20mL of ethyl acetate was added and washed three times with water. Dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to obtain YB112 (162 mg). ¹ H NMR(MeOD-d4,400MHz):8.45-8.40(m,2H),8.38(s,1H),7.92-7.86(m,2H),7.79-7.76(m,1H),7.24(s,1H).

Step two, synthesizing 4- (1H-imidazole-1-yl) aniline (YB 126)

YB112 (162 mg) was dissolved in THF solvent, and after the reaction system was deaerated, 10% of Pd/C was added to 20mg. Hydrogen balloon was added to the reaction system and the reaction was allowed to proceed overnight. The reaction was filtered, washed with ethyl acetate, concentrated, and purified by silica gel column to obtain YB126 (154 mg) as a target product. ¹ H NMR(CDCl ₃ ,400MHz):7.74(s,1H),7.21-7.14(m,4H),6.79-6.72(m,2H),4.05-3.55(br,2H).

Step three, synthesizing 1- (4- (1H-imidazole-1-yl) phenyl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-yl) urea (60, YB130)

The final product 03 (30mg, 0.0973mmol), YB126 (45mg, 0.278mmol) and Et3N (38 mg) were weighed into a bottle, and DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The reaction crude product is directly purified by reversed phase HPLC to obtain a target compound YB130. ¹ H NMR (MeOD-d 4, 400MHz): 9.43 (s, 1H), 9.34 (s, 1H), 8.13 (d, J =8.58Hz, 1H), 8.05 (s, 1H), 8.02-7.96 (m, 1H), 7.85-7.74 (m, 4H), 7.72-7.65 (m, 2H), 5.68 (septet, J =6.73Hz, 1H), 1.64 (d, J =6.73Hz, 6H), ESI-MS theoretical calculation C ₂₀ H ₂₁ N ₈ O[M+H]+ =389.18, experimentally determined: 389.62.

final product 142N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5, 6-dihydro- [3,3' -bipyridine ] -1 (2H) -carboxamide (142, YB127)

Step one, synthesizing 5, 6-dihydro- [3,3' -bipyridine ] -1 (2H) -carboxylic acid tert-butyl ester (YB 119)

5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (200mg, 0.65mmol) and 3-bromopyridine (51.1mg, 0.323mmol) were weighed into a bottle, 1, 2-dimethoxyethane (4 mL) and 2M Na were added ₂ CO ₃ Aqueous solution (1.5 mL). After the reaction system is deoxygenated, pd (dppf) Cl is added ₂ -CH ₂ Cl ₂ (26.4 mg, 0.032mmol). The reaction is heated at 95 ℃ overnight, diluted by water and extracted by ethyl acetate, dried, concentrated and purified by a column to obtain the target compound YB119. ¹ H NMR(MeOD-d4,400MHz):8.58(s,1H),8.45(d,J＝4.10Hz,1H),7.61(dt,J＝7.91,1.80Hz,1H),7.26-7.18(m,1H),6.24-6.16(m,1H),4.21(s,2H),3.51(t,J＝5.70Hz,2H),2.29(s,2H),1.45(s,9H).

Step two, synthesizing 1,2,5, 6-tetrahydro-3, 3' -bipyridine (YB 123)

All crude YB119 were dissolved in 4mL CH ₂ Cl ₂ Then 1mL of trifluoroacetic acid was added. The reaction was stirred at room temperature overnight. The reaction solution was spin dried, water was added and the pH was adjusted to 7-8. Extracting with ethyl acetate, drying, evaporating to remove solvent to obtain crude product 103mg, and directly using in next reaction without purification. ¹ H NMR(MeOD-d4,400MHz):8.55(d,J＝2.00Hz,1H),8.42(dd,J＝4.86,1.38Hz,1H),7.82(dt,J＝8.10,2.00Hz,1H),6.36-6.29(m,1H),3.68-3.64(m,2H),2.97(t,J＝5.87Hz,2H),2.36-2.28(m,2H).

Step three, synthesis of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5, 6-dihydro- [3,3' -bipyridine ] -1 (2H) -carboxamide (142, YB127)

The final product 03 (30mg, 0.0973mmol), YB123 (45mg, 0.278mmol) and Et ₃ N (38 mg) was weighed into a bottle, and DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. And purifying the reaction crude product directly by using reverse phase HPLC to obtain a target compound YB127. ¹ H NMR(MeOD-d4,400MHz):9.66(s,1H),8.98(d,J＝2.0Hz,1H),8.78(d,J＝5.66Hz,1H),8.74(dt,J＝8.43,1.65Hz,1H),8.14-8.08(m,1H),8.02-7.96(m,1H),7.92(d,J＝7.86Hz,1H),7.78(d,J＝7.17Hz,1H),6.83-6.77(m,1H),5.91(septet,J＝6.66Hz,1H),4.63-4.53(m,2H),3.82(t,J＝5.88hz, 2h), 2.62-2.52 (m, 2H), 1.61 (d, J =6.66hz, 6H) ESI-MS theoretically calculated value C ₂₁ H ₂₄ N ₇ O[M+H]+ 390.20, experimentally determined: 390.78.

end product 146: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (pyrazin-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxamide (146, YB147)

Step one, synthesizing 5- (pyrazine-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (YB 131)

Tert-butyl 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (100mg, 0.32mmol) and 2-bromopyrazine (103.3mg, 0.65mmol) were weighed into a bottle, 1, 2-dimethoxyethane (4 mL) and 2M Na were added ₂ CO ₃ Aqueous solution (1.5 mL). After the reaction system is deoxygenated, pd (dppf) Cl is added ₂ -CH ₂ Cl ₂ (26.4mg, 0.032mmol). The reaction was heated at 95 ℃ overnight, diluted with water and extracted with ethyl acetate, dried and concentrated to give 100mg of crude product which was used directly in the next reaction without purification.

Step two, synthesizing 2- (1, 2,5, 6-tetrahydropyridine-3-yl) pyrazine (YB 136)

The crude YB131 (100mg, 0.38mmol) was dissolved in 4mL CH ₂ Cl ₂ Then 1mL of trifluoroacetic acid was added. The reaction was stirred at room temperature overnight. The reaction solution was spin-dried, water was added and the pH was adjusted to 7-8. Extracting with ethyl acetate, drying, evaporating to remove solvent to obtain crude product, and purifying to obtain target compound YB136 (35.5 mg). ¹ H NMR(MeOD-d4,400MHz):δ8.80(d,J＝1.5Hz,1H),8.53(dd,J＝1.6,2.6Hz,1H),8.42(d,J＝2.6Hz,1H),6.90(tt,J＝1.7,3.9Hz,1H),3.85(q,J＝2.3Hz,2H),3.04(t,J＝5.8Hz,2H),2.43(dd,J＝3.6,6.7Hz,2H).

Step three, synthesizing N- (6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-yl) -5- (pyrazine-2-yl) -3, 6-dihydropyridine-1 (2H) -formamide (146, YB147)

The final product 03 (30mg, 0.0973mmol), YB136 (25.5mg, 0.22mmol) and Et ₃ Weighing N (38mg, 0.376mmol)Put into a bottle, and DMF is added to dissolve the reaction reagent. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YB147 (30.9 mg). ¹ H NMR (MeOD-d 4, 400MHz): δ 9.48 (s, 1H), 8.90 (d, J =1.5Hz, 1H), 8.58 (dd, J =1.6,2.6Hz, 1H), 8.45 (d, J =2.6Hz, 1H), 8.01-7.85 (m, 2H), 7.76 (dd, J =1.2,7.2Hz, 1H), 6.99 (tt, J =1.9,4.2Hz, 1H), 5.89 (H, J =6.6Hz, 1H), 4.64 (q, J =2.4Hz, 2H), 3.78 (t, J =5.7Hz, 2H), 2.54 (dh, J =2.6,8.5Hz, 2H), 1.60 (d, J =6.6Hz, ESI), theoretical calculation of C-7H, C ₂₀ H ₂₂ N ₈ O[M+H] ⁺ =391.2, determined experimentally: 391.2.

the final product 150: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5, 6-dihydro- [3,4' -bipyridine ] -1 (2H) -carboxamide (150, YB133)

Step one, synthesizing 5, 6-dihydro- [3,4' -bipyridine ] -1 (2H) -carboxylic acid tert-butyl ester (YB 121)

5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (100mg, 0.32mmol) and 4-bromopyridine (126mg, 0.65mmol) were weighed into a bottle, 1, 2-dimethoxyethane (4 mL) and 2M Na were added ₂ CO ₃ Aqueous solution (1.5 mL). After the reaction system is deoxygenated, pd (dppf) Cl is added ₂ -CH ₂ Cl ₂ (26.4mg, 0.032mmol). The reaction was heated at 95 ℃ overnight, diluted with water and extracted with ethyl acetate, dried, concentrated and purified by column chromatography to give YB121 (81 mg) product. ¹ H NMR(CDCl ₃ ,400MHz):8.68-8.42(m,2H),7.43-7.26(m,2H),6.60-6.46(m,1H),4.34-4.16(m,2H),3.62-3.45(m,2H),2.42-2.23(m,2H),1.46(s,9H).

Step two, synthesizing 1,2,5, 6-tetrahydro-3, 4' -bipyridine (YB 128)

Dissolving the YB121 crude product in 4mL of CH ₂ Cl ₂ Then 1mL of trifluoroacetic acid was added. The reaction was stirred at room temperature overnight. The reaction solution was spin dried, water was added and the pH was adjusted to 7-8. Extracting with ethyl acetate, drying, evaporating to remove solvent to obtain crude product, and directly using in next reaction without purification.

Step three, synthesizing N- (6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-yl) -5, 6-dihydro- [3,4' -bipyridine ] -1 (2H) -formamide (150, YB133)

The final product 03 (30mg, 0.0973mmol), YB128 (50mg, 0.278mmol) and Et ₃ N (38 mg) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. And purifying the reaction crude product directly by using reverse phase HPLC to obtain a target compound YB133. ¹ H NMR(MeOD-d4,400MHz):9.58(s,1H),8.79(d,J＝6.80Hz,2H),8.16(d,J＝6.93Hz,2H),8.00-7.94(m,1H),7.91(d,J＝8.22Hz,1H),7.77(d,J＝7.41Hz,1H),7.25-7.20(m,1H),5.90(septet,J＝6.71Hz,1H),4.66-4.58(m,2H),3.82(t,J＝5.72Hz,2H),2.71-2.59(m,2H),1.60(d,J＝6.71Hz,6H).

End product 187: 6-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3, 4-dihydroquinoline-1 (2H) -carboxamide (187, ZTAA 126)

The final product 03 (80mg, 0.25mmol) and 6-bromo-1, 2,3, 4-tetrahydroquinoline (159.1mg, 0.75mmol) and triethylamine (82.2mg, 0.813mmol) were added to a round-bottomed flask and dissolved in 2mL of DMF. Heated to 50 ℃ and stirred overnight. After the reaction, 2mL of water was added, and HPLC purification was performed to obtain the objective compound ZTA126 (61.6 mg). ¹ H NMR (MeOD-d 4, 400MHz) 9.63 (s, 1H), 8.10-7.98 (m, 2H), 7.84-7.79 (m, 1H), 7.42 (s, 1H), 7.35 (s, 2H), 5.80 (septet, J =6.73Hz, 1H), 3.84 (t, J =6.23Hz, 2H), 2.85 (t, J =6.56Hz, 2H), 2.09-2.00 (m, 2H), 1.59 (d, J =6.73Hz, 6H), ESI-MS calculated theoretical C.Cc. ₂₀ H ₂₂ ⁷⁹ BrN ₆ O[M+H] ⁺ =441.10, experimentally determined: 440.48.

end product 189: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5',6' -dihydro- [2,3' -bipyridine ] -1' (2 ' H) -carboxamide (189, YB129)

Step one, synthesizing 5',6' -dihydro- [2,3' -bipyridyl ] -1' (2 ' H) -carboxylic acid tert-butyl ester (YB 120)

5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (100mg, 0.32mmol) and 2-bromopyridine (102mg, 0.65mmol) were weighed into a bottle, 1, 2-dimethoxyethane (4 mL) and 2M Na were added ₂ CO ₃ Aqueous solution (1.5 mL). After the reaction system is deoxygenated, pd (dppf) Cl is added ₂ -CH ₂ Cl ₂ (26.4mg, 0.032mmol). The reaction was heated at 95 ℃ overnight, diluted with water and extracted with ethyl acetate, dried and concentrated, and used in the next reaction without purification. ¹ H NMR(CDCl ₃ ,400MHz):8.57-8.48(m,1H),7.62(t,J＝7.69Hz,1H),7.45-7.29(m,1H),7.19-7.06(m,1),6.84-6.63(m,1H),4.49-4.34(m,2H),3.64-3.48(m,1H),2.41-2.23(m,2H),1.48(s,9H).

Step two, synthesizing 1',2',5',6' -tetrahydro-2, 3' -bipyridine (YB 125)

The crude YB120 (84mg, 0.32mmol) was dissolved in 4mL CH ₂ Cl ₂ Then 1mL of trifluoroacetic acid was added. The reaction was stirred at room temperature overnight. The reaction solution was spin-dried, water was added and the pH was adjusted to 7-8. Extracting with ethyl acetate, drying, evaporating to remove solvent to obtain crude product, and purifying to obtain target compound YB125 (28.3 mg). ¹ H NMR(MeOD-d4,400MHz):8.47(d,J＝8.46Hz,1H),7.77(td,J＝7.80,1.49Hz,1H),7.55(d,J＝8.10Hz,1H),7.29-7.21(m,1H),6.77-6.68(m,1H)，3.91-3.83(m,2H),3.05(t,J＝5.72Hz,2H),2.44-2.36(m,2H).

Step three Synthesis of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5',6' -dihydro- [2,3' -bipyridine ] -1' (2 ' H) -carboxamide (189, YB129)

End product 03 (30mg, 0.0973mmol), YB125 (28.3mg, 0.177mmol) and Et ₃ N (38 mg) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The reaction crude product is directly purified by reversed phase HPLC to obtain a target compound YB129. ¹ H NMR(MeOD-d4,400MHz):9.51(s,1H),8.74(dd,J＝5.71,0.98Hz,1H),8.49(td,J＝8.00,1.44Hz,1H),8.09(d,J＝8.25Hz,1H),7.99-7.92(m,2H),7.92-7.85(m,1H),7.77(dd,J＝7.17,0.92Hz,1H),7.05-7.00(m,1H),5.88(septet,J＝6.74Hz,1H),4.66-4.61(m,2H),3.83(t,J＝5.72hz, 2h), 2.67-2.58 (M, 2H), 1.60 (d, J =6.69hz, 6H) ESI-MS theoretical calculation C21H24N7O [ M + H ],]+ 390.2, experimentally determined: 390.9.

the final product 190: n- (6- (4-isopropyl-4H-1, 4-triazol-3-yl) pyridin-2-yl) -1H-indazole-1-carboxamide (190, ZTB-8)

The final product 03 (40mg, 0.124mmol), 1H-indazole (43.8mg, 0.371mmol), and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask, and 2mL DMF was added to dissolve the reaction. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 14.2mg of the objective compound. ¹ H NMR (MeOD-d4, 400MHz): 9.44 (s, 1H), 8.32-8.40 (m, 2H), 8.08 (t, J =4.06Hz, 1H), 7.86-7.92 (m, 2H), 7.61 (t, J =7.64Hz, 1H), 7.39 (t, J =7.48Hz, 1H), 5.72-5.82 (m, 1H), 1.67 (s, 3H), 1.65 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ N ₇ O[M+H] ⁺ =348.2, experimentally determined: 347.7.

end product 191:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (1H-pyrazolo [3,4-b ] pyridin-3-yl) urea (191, ZTB-10)

The final product 03 (40mg, 0.124mmol), 1H-pyrazolo [3,4-b ] is added]Pyridin-3-amine (43.8mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask, and 2mL of DMF was added to dissolve the reaction. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 7.1mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 13.22 (s, 1H), 10.19 (s, 1H), 8.90 (s, 1H), 8.53-8.54 (m, 2H), 8.07 (d, J =8.31Hz, 1H), 7.98 (t, J =8.12Hz, 1H), 7.76 (d, J =7.44Hz, 1H), 7.16-7.19 (m, 1H), 5.39-5.45 (m, 1H), 1.54 (s, 3H), 1.53 (s, 3H). ESI-MS theoretical calculation C ₁₇ H ₁₈ N ₉ O[M+H] ⁺ =364.2, experimentally determined: 364.2.

end product 192:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3-phenylthiourea (192, ZTB-11)

The final product ZTB-6 (100mg, 0.295mmol), aniline (82.4mg, 0.885mmol) and triethylamine (97mg, 0.959mmol) were added to a 50mL reaction flask and 2mL DMF was added to dissolve the reaction. Stirred at 60 ℃ overnight. After the reaction, 2.5mL of water was added and HPLC purification was performed to obtain 60mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.07 (s, 1H), 8.04 (t, J =8.08Hz, 1H), 7.66 (d, J =7.52Hz, 1H), 7.58 (d, J =7.52Hz, 1H), 7.38-7.43 (m, 3H), 7.26 (t, J =7.46Hz, 1H), 5.06-5.13 (m, 1H), 1.40 (s, 3H), 1.39 (s, 3H). ESI-MS theoretical calculation C ₁₇ H ₁₉ N ₆ S[M+H] ⁺ =339.1, experimentally determined: 339.2.

end product 193:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) thiourea (193, ZTB-12)

Intermediate ZTB-6 (50mg, 0.147mmol), 4- (1-methyl-1H-pyrazol-4-yl) aniline (76.6 mg, 0.442mmol) and triethylamine (40.3 mg, 0.478mmol) were added to a 50mL reaction flask, and 2mL of DMF was added to dissolve the reaction. Stirring was carried out overnight at 60 ℃. After the reaction, 2.5mL of water was added and HPLC purification was performed to obtain 35mg of the objective compound. ¹ H NMR(DMSO-d ₆ 400 MHz) 12.54 (s, br, 1H), 11.00 (s, br, 1H), 8.87 (s, 1H), 8.14 (s, 1H), 8.03 (t, J =8.04Hz, 1H), 7.87 (s, 1H), 7.64 (d, J =7.46Hz, 1H), 7.56 (s, 3H), 7.48 (d, J =8.46Hz, 1H), 4.95-5.02 (m, 1H), 3.87 (s, 3H), 1.29 (s, 3H), 1.27 (s, 3H). Theoretical calculation of ESI-MS C ₂₁ H ₂₃ N ₈ S[M+H] ⁺ =419.2, determined experimentally: 419.0.

end products 194 and 195:1- (6-fluoro-1H-indazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (194, ZTB-13-14 g) and 3-amino-6-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indazole-1-carboxamide (195, ZTB-13-18 g)

The final product 03 (40mg, 0.124mmol), 6-fluoro-1H-indazol-3-amine (56mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask and the reaction was dissolved by the addition of 2mL DMF. Stirred at 60 ℃ overnight. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain the objective compounds ZTB-13-14g (9.2 mg) and ZTB-13-18g (16 mg). ZTB-13-14g: ¹ H NMR(DMSO-d ₆ 400 MHz) 12.72 (s, 1H), 10.53 (s, 1H), 10.14 (s, 1H), 8.95 (s, 1H), 8.08-8.12 (m, 2H), 7.98 (d, J =8.14Hz, 1H), 7.76 (d, J =7.48Hz, 1H), 7.24 (dd, J =9.60,1.96Hz, 1H), 6.85 (td, J =9.10,2.09Hz, 1H), 5.37-5.44 (m, 1H), 1.56 (s, 3H), 1.54 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ FN ₈ O[M+H] ⁺ And =381.2, 380.3 ztb-13-18g: ¹ h NMR (MeOD-d 4, 400MHz) 9.40 (s, 1H), 8.31 (d, J =7.68Hz, 1H), 8.02 (t, J =8.08Hz, 1H), 7.76-7.89 (m, 3H), 7.05 (td, J =8.02,1.78Hz, 1H), 5.68-5.74 (m, 1H), 1.67 (s, 3H), 1.65 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ FN ₈ O[M+H] ⁺ =380.2, determined experimentally: 380.3.

end product 196:1- (6-bromo-1H-indazol-3-yl) -3 (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (196, ZTB-14)

The final product 03 (40mg, 0.124mmol), 6-bromo-1H-indazol-3-amine (78.7 mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask and the reaction was dissolved by the addition of 2mL DMF. Stirred at 60 ℃ overnight. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 7.0mg of the objective compound. ¹ H NMR(DMSO-d ₆ ,400MHz):12.78(s,1H),10.39(s,1H),10.14(s,1H),8.93(s,1H),8.09(d,J＝8.41Hz,1H),7.96-8.02(m,2H),7.76(d,J＝5.74Hz,1H),7.69(d,J＝1.19Hz,1H),7.23(dd,J＝8.73,147hz, 1h), 5.37-5.44 (m, 1H), 1.55 (s, 3H), 1.54 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ ⁷⁹ BrN ₈ O[M+H] ⁺ And (4) the experimental result is 441.9.

End products 197 and 198:1- (5-bromo-1H-indazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (197, ZTB-15-11 g) and 3-amino-5-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indazole-1-carboxamide (198, ZTB-15-16 g)

The final product 03 (40mg, 0.124mmol), 5-bromo-1H-indazol-3-amine (78.7mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 15-11g (8.7 mg) of the objective compound ZTB-15 and 16g (10.7 mg) of ZTB-15. ZTB-15-11g: ¹ H NMR(DMSO-d ₆ 400 MHz) 12.85 (s, 1H), 10.31 (s, 1H), 10.08 (s, 1H), 8.95 (s, 1H), 8.29 (s, 1H), 8.09 (d, J =8.48Hz, 1H), 7.98 (t, J =8.20Hz, 1H), 7.76 (d, J =7.48Hz, 1H), 7.44-7.51 (m, 2H), 5.38-5.45 (m, 1H), 1.55 (s, 3H), 1.53 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ ⁷⁹ BrN ₈ O[M+H] ⁺ 441.1 ZTB-15-16g: ¹ h NMR (MeOD-d 4, 400MHz) 9.21 (s, 1H), 8.32 (d, J =8.44Hz, 1H), 8.16 (d, J =8.83Hz, 1H), 8.00-8.05 (m, 2H), 7.84 (d, J =7.60Hz, 1H), 7.65 (d, J =8.83,1.82Hz, 1H), 5.64-5.71 (m, 1H), 1.65 (s, 3H), 1.64 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ ⁷⁹ BrN ₈ O[M+H] ⁺ 441.3, measured experimentally.

End product 199:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) guanidine (199, ZTB-17)

The final product ZTB-12 (2)0mg, 0.048mmol), ammonia (1.24mg, 0.072mmol) and NaIO ₄ (11.3mg, 0.053mmol) was charged to a 50mL reaction flask, 2mL DMF and 2mL H were added ₂ O dissolves the reactants. Stirred at 85 ℃ overnight. After the reaction, HPLC purification was performed to obtain 20mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.06 (s, 1H), 8.14 (t, J =8.16Hz, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.84 (d, J =3.83Hz, 1H), 7.73 (d, J =8.55Hz, 1H), 7.41 (t, J =7.66Hz, 1H), 5.14-5.25 (m, 1H), 3.96 (s, 3H), 1.51 (s, 3H), 1.50 (s, 3H). Theoretical calculation of ESI-MS C ₂₁ H ₂₄ N ₉ [M+H] ⁺ =402.2, experimentally determined: 402.3.

the final product is 200: 3-amino-4-chloro-N-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indazole-1-carboxamide (200, ZTB-28)

The final product 03 (40mg, 0.124mmol), 4-chloro-1H-indazol-3-amine (62mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask, and the reaction was dissolved by the addition of 2mL DMF. Stirred at 60 ℃ overnight. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 7.6mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.33 (s, 1H), 8.36 (d, J =8.36Hz, 1H), 8.25 (d, J =9.04Hz, 1H), 8.07 (d, J =8.22Hz, 1H), 7.86-7.88 (m, 2H), 7.56 (dd, J =8.80,1.72Hz, 1H), 5.68-5.75 (m, 1H), 1.67 (s, 3H), 1.65 (s, 3H). ESI-MS theoretical calculation C ₁₈ H ₁₈ ³⁵ ClN ₈ O[M+H] ⁺ And (7) 397.2 as measured by experiment, wherein the value is= 397.1.

The final product 201:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (1H-pyrazolo [3,4-c ] pyridin-3-yl) urea (201, ZTB-29)

The final product 03 (40mg, 0.124mmol), 1H-pyrazolo [3,4-c]Pyridin-3-amine (49.7 mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were added to a 50mL reaction flask, and 2mL of DMF was added to dissolve the reactants. Stirred at 60 ℃ overnight. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 7.6mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz): 9.40 (s, 1H), 9.08 (s, 1H), 8.75 (d, J =6.08Hz, 1H), 8.34 (d, J =6.16Hz, 1H), 8.00-8.08 (m, 2H), 7.79 (d, J =6.98Hz, 1H), 5.53-5.60 (m, 1H), 1.64 (s, 3H), 1.63 (s, 3H). ESI-MS theoretical calculation C ₁₇ H ₁₈ N ₉ O[M+H] ⁺ =364.2, experimentally determined: 364.2.

end product 202:1- (6- (4-isopropyl-4H-1, 4-triazol-3-yl) pyridin-2-yl) -3- (7-methyl-1H-indazol-3-yl) urea (202, ZTB-35)

The final product 03 (40mg, 0.124mmol), 7-methyl-1H-indazol-3-amine (79mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask, and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 30.3mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.47 (s, 1H), 8.25 (d, J =8.16Hz, 1H), 8.03 (t, J =8.04Hz, 1H), 7.83 (d, J =7.52Hz, 1H), 7.72 (d, J =8.24Hz, 1H), 7.22 (d, J =6.84Hz, 1H), 7.07 (t, J =7.63Hz, 1H), 5.64-5.71 (m, 1H), 2.56 (s, 3H), 1.72 (s, 3H), 1.70 (s, 3H). Theoretical calculation of ESI-MS C ₁₉ H ₂₁ N ₈ O[M+H] ⁺ =377.2, determined experimentally: 377.2.

end products 203 and 204:1- (6- (4-isopropyl-4H-1, 4-triazol-3-yl) pyridin-2-yl) -3- (6-methyl-1H-indazol-3-yl) urea (203, ZTB-36-30 g) and 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methyl-1H-indazole-1-carboxamide (204, ZTB-36-32 g)

The final product 03 (40mg, 0.124mmol), 6-methyl-1H-indazol-3-amine (79mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask, and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃. After the reaction is finished, the reaction solution is added,2.0mL of water was added and HPLC purification was performed to obtain 36-30g (10.7 mg) of the objective compound ZTB-36-32g (8.4 mg) of ZTB-l. ZTB-36-30g: ¹ h NMR (MeOD-d 4, 400MHz) 9.15 (s, 1H), 8.18 (s, 1H), 8.00 (t, J =8.00Hz, 1H), 7.76-7.81 (m, 2H), 7.25 (s, 1H), 7.00 (d, J =8.42Hz, 1H), 5.57-5.63 (m, 1H), 2.49 (s, 3H), 1.68 (s, 3H), 1.66 (s, 3H). ESI-MS theoretical calculation C ₁₉ H ₂₁ N ₈ O[M+H] ⁺ =377.2, determined experimentally: 376.4.ZTB-36-32g: ¹ h NMR (MeOD-d 4, 400MHz): 9.35 (s, 1H), 8.39 (d, J =7.96Hz, 1H), 8.06-8.10 (m, 2H), 7.87 (d, J =7.12Hz, 1H), 7.69 (d, J =8.16Hz, 1H), 7.17 (d, J =8.36Hz, 1H), 5.68-5.75 (m, 1H), 2.54 (s, 3H), 1.68 (s, 3H), 1.66 (s, 3H). Theoretical calculation of ESI-MS C ₁₉ H ₂₁ N ₈ O[M+H] ⁺ =377.2, determined experimentally: 376.7.

end products 205 and 206:1- (6- (4-isopropyl-4H-1, 4-triazol-3-yl) pyridin-2-yl) -5- (5-methyl-1H-indazol-3-yl) urea (205, ZTB-37-46 g) and 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methyl-1H-indazole-1-carboxamide (206, ZTB-37-49 g)

The final product 03 (40mg, 0.124mmol), 5-methyl-1H-indazol-3-amine (79mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask, and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain the objective compound ZTB-37-46g (12.2 mg) and ZTB-37-49g (13.9 mg). ZTB-37-46g: ¹ h NMR (MeOD-d 4, 400MHz) 9.66 (s, 1H), 8.27 (d, J =7.64Hz, 1H), 8.06 (t, J =8.56Hz, 1H), 7.85 (d, J =7.04Hz, 1H), 7.67 (s, 1H), 7.38 (d, J =8.52Hz, 1H), 7.31 (d, J =8.64Hz, 1H), 5.66-5.75 (m, 1H), 2.48 (s, 3H), 1.73 (s, 3H), 1.71 (s, 3H). Theoretical calculation of ESI-MS C ₁₉ H ₂₁ N ₈ O[M+H] ⁺ =377.2, determined experimentally: 376.5.ZTB-37-49g: ¹ H NMR(MeOD-d4,400MHz):9.18(s,1H),8.34(d,J＝8.32Hz,1H),8.12(d,J＝8.36Hz,1H),8.04(t,J＝8.12Hz,1H),7.83(d,J＝7.52Hz,1H),7.59(s,1H),7.40(d,J＝8.44Hz,1H),5.64-5.71(m,1H),2.48(s,3h) 1.66 (s, 3H), 1.64 (s, 3H). ESI-MS theoretical calculation C ₁₉ H ₂₁ N ₈ O[M+H] ⁺ =377.2, experimentally determined: 376.3.

final products 207 and 208:1- (6-chloro-1H-indazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (207, ZTB-38-9 g) and 3-amino-6-chloro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indazole-1-carboxamide (208, ZTB-38-15 g)

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The final product 03 (40mg, 0.124mmol), 6-chloro-1H-indazol-3-amine (62mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask, and the reaction was dissolved by the addition of 2mL DMF. Stirred at 60 ℃ overnight. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain the objective compounds ZTB-38-9g (24 mg) and ZTB-38-15g (18.1 mg). ZTB-38-9g: ¹ h NMR (MeOD-d 4, 400MHz): 9.54 (s, 1H), 8.24 (d, J =7.84Hz, 1H), 8.04 (d, J =8.08Hz, 1H), 7.92 (d, J =8.80Hz, 1H), 7.83 (d, J =7.44Hz, 1H), 7.49 (s, 1H), 7.13 (d, J =8.64Hz, 1H), 5.65-5.71 (m, 1H), 1.72 (s, 3H), 1.70 (s, 3H). ESI-MS theoretical calculation C ₁₈ H ₁₈ ³⁵ ClN ₈ O[M+H] ⁺ =397.1, found experimentally: 397.2.Ztb-38-15g: ¹ h NMR (MeOD-d 4, 400MHz): 9.29 (s, 1H), 8.35 (d, J =8.28Hz, 1H), 8.29 (s, 1H), 8.09 (t, J =7.84Hz, 1H), 7.88 (d, J =7.92Hz, 1H), 7.80 (d, J =8.51Hz, 1H), 7.32 (d, J =8.88Hz, 1H), 5.66-5.73 (m, 1H), 1.67 (s, 3H), 1.65 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ ³⁵ ClN ₈ O[M+H] ⁺ =397.1, experimentally determined: 397.2.

end products 209 and 210:1- (6- (4-isopropyl-4H-1, 4-triazol-3-yl) pyridin-2-yl) -3- (4-methyl-1H-indazol-3-yl) urea (209, ZTB-39-19 g) and 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-methyl-1H-indazole-1-carboxamide (210, ZTB-39-24 g)

The final product 03 (40mg, 0.124mmol), 4-methyl-1H-indazol-3-amine (79mg, 0.371mmol), and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask, and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 39-19g (14.7 mg) of the objective compound ZTB-39-24g (14.4 mg) of ZTB-A. ZTB-39-19g: ¹ h NMR (MeOD-d 4, 400MHz) 9.12 (s, 1H), 7.94-8.00 (m, 2H), 7.76 (d, J =7.68Hz, 1H), 7.27-7.34 (m, 2H), 6.91 (s, J =6.52Hz, 1H), 5.51-5.58 (m, 1H), 2.65 (s, 3H), 1.58 (s, 3H), 1.56 (s, 3H). Theoretical calculation of ESI-MS C ₁₉ H ₂₁ N ₈ O[M+H] ⁺ =377.2, determined experimentally: 376.0.ZTB-39-24g: ¹ h NMR (MeOD-d 4, 400MHz) 9.18 (s, 1H), 8.33 (d, J =8.32Hz, 1H), 8.10 (d, J =8.37Hz, 1H), 8.03 (t, J =8.20Hz, 1H), 7.83 (d, J =7.52Hz, 1H), 7.40 (t, J =7.90Hz, 1H), 7.03 (d, J =7.24Hz, 1H), 5.64-5.70 (m, 1H), 2.70 (s, 3H), 1.66 (s, 3H), 1.64 (s, 3H). Theoretical calculation of ESI-MS C ₁₉ H ₂₁ N ₈ O[M+H] ⁺ =377.2, experimentally determined: 376.1.

end products 211 and 212:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (1H-pyrazolo [4,3-b ] pyridin-3-yl) urea (211, ZTB-49-9 g) and 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-pyrazolo [4, 3-b) ] pyridine-1-carboxamide (212, ZTB-49-18 g)

The final product 03 (40mg, 0.124mmol), 1H-pyrazolo [4,3-b ] is added]Pyridin-3-amine (49.7 mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were added to a 50mL reaction flask, and 2mL of DMF was added to dissolve the reaction. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 49-9g (6.9 mg) of the objective compound ZTB-49 and 18g (9.9 mg) of ZTB-49. ZTB-49-9g: ¹ h NMR (MeOD-d 4, 400MHz) 9.10 (s, 1H), 8.68 (d, J =4.66Hz, 1H), 8.36 (d, J =8.36Hz, 1H), 8.13 (t, J =8.36Hz, 1H), 8.03 (t, J =8.34Hz, 1H), 7.80 (d, J =7.48Hz, 1H), 7.71-7.74 (m, 1H), 5.54-5.60 (m, 1H), 1.65 (s, 3H), 1.64 (s, 3H). Theoretical calculation of ESI-MS C ₁₇ H ₁₈ N ₉ O[M+H] ⁺ =364.2, experimentally determined: 364.6 ZTB-49-18g: ¹ h NMR (MeOD-d 4, 400MHz) 9.35 (s, 1H), 8.62 (dd, J =8.43,1.17Hz, 1H), 8.59 (dd, J =4.53,1.17Hz, 1H), 8.36 (d, J =9.28Hz, 1H), 8.08 (t, J =8.24Hz, 1H), 7.89 (d, J =7.52Hz, 1H), 7.59 (q, J =4.64Hz, 1H), 5.70-5.77 (m, 1H), 1.67 (s, 3H), 1.66 (s, 3H). ESI-MS theoretical calculation C ₁₇ H ₁₈ N ₉ O[M+H] ⁺ =364.2, experimentally determined: 363.9.

end products 213 and 214:1- (6- (4-isopropyl-4H-1, 4-triazol-3-yl) pyridin-2-yl) -3- (5- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl) urea (213, ZTB-51-14 g) and 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-indazole-1-carboxamide (214, ZTB-51-17 g)

The final product 03 (40mg, 0.124mmol), 5- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-amine (79mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask, and 2mL of DMF was added to dissolve the reaction. Stirring was carried out overnight at 60 ℃. After the reaction, 2.5mL of water was added and HPLC purification was performed to obtain the objective compound ZTB-51-14g (6.8 mg) and ZTB-51-17g (19.3 mg). ZTB-51-14g: ¹ H NMR(DMSO-d ₆ 400 MHz) 12.62 (s, br, 1H), 10.59 (s, br, 1H), 10.02 (s, br, 1H), 8.90 (s, 1H), 8.19 (s, 1H), 8.12 (d, J =8.35Hz, 1H), 8.05 (s, 1H), 7.98 (t, J =8.10Hz, 1H), 7.79 (s, 1H), 7.76 (d, J =7.49Hz, 1H), 7.61 (d, J =7.15H, 1H), 7.46 (d, J =8.68Hz, 1H), 5.39-5.46 (m, 1H), 3.89 (s, 3H), 1.56 (s, 3H), 1.55 (s, 3H). ESI-MS theoretical calculation C ₂₂ H ₂₃ N ₁₀ O[M+H] ⁺ =443.2, experimentally determined: 443.4.ZTB-51-17g: ¹ h NMR (MeOD-d 4, 400MHz) 9.27 (s, 1H), 8.37 (d, J =8.34Hz, 1H), 8.19 (d, J =8.42Hz, 1H), 8.03 (t, J =8.04Hz, 1H), 7.96 (d, J =8.20Hz, 1H), 7.86 (s, 1H), 7.84 (d, J =7.44Hz, 1H), 7.73 (d, J =7.15Hz, 1H), 5.66-5.72 (m, 1H), 3.95 (s, 3H), 1.67 (s, 3H), 1.65 (s, 3H). ESI-MS theoretical calculation C ₂₂ H ₂₃ N ₁₀ O[M+H] ⁺ =443.2, experimentally determined: 443.5。

End products 215 and 216:1- (6- (4-isopropyl-4H-1, 4-triazol-3-yl) pyridin-2-yl) -3- (6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl) urea (215, ZTB-52-20 g) and 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-indazole-1-carboxamide (216, ZTB-52-22 g)

The final product 03 (40mg, 0.124mmol), 6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-amine (79mg, 0.371mmol), and triethylamine (40.8mg, 0.403mmol) were added to a 50mL reaction flask, and 2mL of DMF was added to dissolve the reaction. Stirring was carried out overnight at 60 ℃. After the reaction, 2.5mL of water was added and HPLC purification was performed to obtain 52-20g (5.6 mg) of the objective compound ZTB-52-22g (7.5 mg). ZTB-52-20g: ¹ h NMR (MeOD-d4, 400MHz): 9.64 (s, 1H), 8.27 (s, 1H), 8.01-8.11 (m, 2H), 7.81-7.97 (m, 3H), 7.60 (s, 1H), 7.39 (d, J =7.60Hz, 1H), 5.65-5.77 (m, 1H), 3.97 (s, 3H), 1.73 (s, 3H), 1.71 (s, 3H). Theoretical calculation of ESI-MS C ₂₂ H ₂₃ N ₁₀ O[M+H] ⁺ =443.2, experimentally determined: 443.9.ZTB-52-22g: ¹ h NMR (MeOD-d 4, 400MHz): 9.24 (s, 1H), 8.41 (s, 1H), 8.38 (d, J =8.48Hz, 1H), 8.09 (s, 1H), 8.06 (t, J =8.24Hz, 1H), 7.93 (s, 1H), 7.85 (d, J =7.60Hz, 1H), 7.52 (dd, J =8.20,1.3Hz, 1H), 5.65-5.72 (m, 1H), 3.98 (s, 3H), 1.67 (s, 3H), 1.65 (s, 3H). Theoretical calculation of ESI-MS C ₂₂ H ₂₃ N ₁₀ O[M+H] ⁺ =443.2, experimentally determined: 443.6.

end product 217:1- (7-fluoro-1H-indazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (217, ZTB-53)

The final product 03 (40mg, 0.124mmol), 7-fluoro-1H-indazol-3-amine (56mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃.After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 16.6mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.56 (s, 1H), 9.25 (d, J =8.68Hz, 1H), 8.05 (t, J =8.20Hz, 1H), 7.85 (d, J =7.52Hz, 1H), 7.73 (d, J =8.16Hz, 1H), 7.08-7.20 (m, 2H), 5.66-5.72 (m, 1H), 1.72 (s, 3H), 1.71 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ FN ₈ O[M+H] ⁺ =381.2, experimentally determined: 380.6.

end products 218 and 219:1- (5-fluoro-1H-indazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (218, ZTB-54-27 g) and 3-amino-5-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indazole-1-carboxamide (219, ZTB-54-32 g)

The final product 03 (40mg, 0.124mmol), 5-fluoro-1H-indazol-3-amine (56mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain the objective compounds ZTB-54-27g (12.7 mg) and ZTB-54-32g (12.4 mg). ZTB-54-27g: ¹ h NMR (MeOD-d 4, 400MHz): 9.38 (s, 1H), 8.19 (d, J =7.96Hz, 1H), 8.02 (t, J =8.21Hz, 1H), 7.81 (t, J =7.58Hz, 1H), 7.61 (t, J =8.72Hz, 1H), 7.46-7.49 (m, 1H), 7.26 (d, J =9.04Hz, 1H), 5.61-5.68 (m, 1H), 1.70 (s, 3H), 1.68 (s, 3H). ESI-MS theoretical calculation C ₁₈ H ₁₈ FN ₈ O[M+H] ⁺ =381.2, 390.6 ztb-54-32g measured experimentally: ¹ h NMR (MeOD-d 4, 400MHz) 9.20 (s, 1H), 9.33 (d, J =8.41Hz, 1H), 8.22-8.26 (m, 1H), 8.03 (d, J =8.04Hz, 1H), 7.84 (d, J =7.64Hz, 1H), 7.53 (dd, J =8.17,2.31Hz, 1H), 7.35 (td, J =9.00,2.23Hz, 1H), 5.64-5.71 (m, 1H), 1.66 (s, 3H), 1.64 (s, 3H). ESI-MS theoretical calculation C ₁₈ H ₁₈ FN ₈ O[M+H] ⁺ =381.2, experimentally determined: 380.5.

the final product 220: 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-methoxy-1H-indazole-1-carboxamide (220, ZTB-57)

The final product 03 (40mg, 0.124mmol), 4-methoxy-1H-indazol-3-amine (49.7mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask and the reaction was dissolved by the addition of 2mL DMF. Stirred at 60 ℃ overnight. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 8.9mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 9.69 (s, 1H), 8.27 (d, J =8.20Hz, 1H), 8.05 (t, J =8.16Hz, 1H), 7.84 (d, J =7.64Hz, 1H), 7.44 (d, J =8.20Hz, 1H), 7.08 (d, J =7.85Hz, 1H), 6.89 (d, J =7.49Hz, 1H), 5.69-5.76 (m, 1H), 1.73 (s, 3H), 1.71 (s, 3H). ESI-MS theoretical calculation C ₁₉ H ₂₁ N ₈ O ₂ [M+H] ⁺ =393.2; the test shows that: 393.0.

the final product 221:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (7-methoxy-1H-indazol-3-yl) urea (221, ZTB-58)

The final product 03 (40mg, 0.124mmol), 7-methoxy-1H-indazol-3-amine (49.7mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask and the reaction was dissolved by the addition of 2mL DMF. Stirred at 60 ℃ overnight. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 24.1mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz): 9.73 (s, 1H), 8.28 (d, J =8.12Hz, 1H), 8.05 (t, J =8.14Hz, 1H), 7.85 (d, J =7.28Hz, 1H), 7.44 (d, J =8.36Hz, 1H), 7.08 (t, J =8.00Hz, 1H), 6.90 (d, J =7.52Hz, 1H), 5.70-5.77 (m, 1H), 4.03 (s, 3H), 1.73 (s, 3H), 1.72 (s, 3H). Theoretical calculation of ESI-MS C ₁₉ H ₂₁ N ₈ O ₂ [M+H] ⁺ =393.2, determined experimentally: 393.2.

end products 222 and 223:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (5-methoxy-1H-indazol-3-yl) urea (222, ZTB-61-18 g) and 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methoxy-1H-indazole-1-carboxamide (223, ZTB-61-24 g)

The final product 03 (40mg, 0.124mmol), 5-methoxy-1H-indazol-3-amine (49.7mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 61-18g (9.8 mg) of the objective compound ZTB-61-24g (13.4 mg) of ZTB-A. ZTB-61-18g: ¹ h NMR (MeOD-d 4, 400MHz) 9.44 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.81 (d, J =7.12Hz, 1H), 7.38 (d, J =9.16Hz, 1H), 7.32 (s, 1H), 7.11 (d, J =8.96Hz, 1H), 5.64-5.70 (m, 1H), 3.86 (s, 3H), 1.70 (s, 3H), 1.68 (s, 3H). Theoretical calculation of ESI-MS C ₁₉ H ₂₁ N ₈ O ₂ [M+H] ⁺ =393.2, experimentally determined: 393.3 ZTB-61-24g: ¹ h NMR (MeOD-d 4, 400MHz): 8.33 (d, J =8.04Hz, 1H), 8.10 (d, J =8.84Hz, 1H), 8.02 (t, J =8.16Hz, 1H), 7.82 (d, J =7.76Hz, 1H), 7.29 (d, J =2.37Hz, 1H), 7.15 (d, J =8.64Hz, 1H), 5.63-5.73 (m, 1H), 3.87 (s, 3H), 1.66 (s, 3H), 1.65 (s, 3H). Theoretical calculation of ESI-MS C ₁₉ H ₂₁ N ₈ O ₂ [M+H] ⁺ =393.2, experimentally determined: 393.2.

the final product 224: 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methoxy-1H-indazole-1-carboxamide (224, ZTB-62)

The final product 03 (40mg, 0.124mmol), 6-methoxy-1H-indazol-3-amine (49.7 mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 6.2mg of the objective compound. ¹ H NMR(MeOD,400MHz):9.09(s,1H),8.36(d,J＝8.32Hz,1H),8.06(t,J＝8.32Hz,1H),7.85(d,J＝7.66Hz,1H),7.80(d,J＝1.95Hz,1H),7.67(d,J＝8.70Hz,1H),6.92(dd,J＝8.68,2.11Hz,1H),5.62-5.69(m,1H),3.93(s3H), 1.65 (s, 3H), 1.64 (s, 3H). Theoretical calculation of ESI-MS C ₁₉ H ₂₁ N ₈ O ₂ [M+H] ⁺ =393.2, determined experimentally: 393.4.

the final product 225:1- (7-chloro-1H-indazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (225, ZTB-64)

The final product 03 (40mg, 0.124mmol), 7-chloro-1H-indazol-3-amine (62mg, 0.371mmol), and triethylamine (40.8mg, 0.403mmol) were added to a 50mL reaction flask and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃. After the reaction was completed, 2.0mL of water was added and HPLC purification was carried out to obtain the objective compound ZTB-64: its isomer (2.3: ¹ h NMR (MeOD-d 4, 400mhz): 9.18 (s, 1H), 8.98 (d, J =7.80hz, 1h), 8.01 (t, J =8.24hz, 1h), 7.89 (d, J =8.13hz, 1h), 7.81 (d, J =7.60hz, 1h), 7.46 (d, J =7.45hz, 1h), 7.13 (t, J =7.80hz, 1h), 5.57-5.64 (m, 1H), 1.68 (s, 3H), 1.66 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ ³⁵ ClN ₈ O[M+H] ⁺ And (7) 397.6 as measured by experiment.

The final product 226:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (1H-pyrazolo [4] pyridin-3-yl) urea (226, ZTB-66)

The final product 03 (40mg, 0.124mmol), 1H-pyrazolo [4,3-c]Pyridin-3-amine (49.7mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were added to a 50mL reaction flask and 2mL of DMF was added to dissolve the reaction. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 16.2mg of the objective compound. ¹ H NMR (MeOD-d 4, 400MHz) 10.00 (s, 1H), 9.21 (s, 1H), 8.43 (d, J =6.72Hz, 1H), 8.14 (d, J =6.76Hz, 1H), 8.04 (t, J =8.04Hz, 1H), 7.96 (d, J =6.84Hz, 1H), 7.82 (d, J =7.08Hz, 1H), 5.56-5.67 (m, 1H), 1.65 (s, 3H), 1.64 (s, 3H). Theoretical calculation of ESI-MS C ₁₇ H ₁₈ N ₉ O[M+H] ⁺ =364.2, experimentally determined: 363.5.

end products 227 and 228:1- (5-chloro-1H-indazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (227, ZTB-69-21 g) and 3-amino-5-chloro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indazole-1-carboxamide (228, ZTB-69-25 g)

The final product 03 (40mg, 0.124mmol), 5-chloro-1H-indazol-3-amine (62mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask, and the reaction was dissolved by the addition of 2mL DMF. Stirred at 60 ℃ overnight. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain the objective compound ZTB-69-21g (7.9 mg) and ZTB-64-25g (9.1 mg). ZTB-69-21g: ¹ H NMR(DMSO-d ₆ 400 MHz) 12.85 (s, 1H), 10.33 (s, 1H), 10.08 (s, 1H), 8.98 (s, 1H), 8.13 (d, J =1.80Hz, 1H), 8.10 (d, J =8.30Hz, 1H), 7.98 (t, J =8.12Hz, 1H), 7.76 (d, J =7.44Hz, 1H), 7.51 (d, J =8.92Hz, 1H), 7.39 (d, J =8.88,2.01Hz, 1H), 5.39-5.46 (m, 1H), 1.55 (s, 3H), 1.54 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ ³⁵ ClN ₈ O[M+H] ⁺ And (3) 397.1.ZTB-64-25g: ¹ h NMR (MeOD-d 4, 400MHz) 9.36 (s, 1H), 8.33 (d, J =8.00Hz, 1H), 8.21 (d, J =8.60Hz, 1H), 8.04 (t, J =8.00Hz, 1H), 7.85 (d, J =7.88Hz, 1H), 7.84 (s, 1H), 7.53 (d, J =8.40Hz, 1H), 5.67-5.74 (m, 1H), 1.67 (s, 3H), 1.65 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ ³⁵ ClN ₈ O[M+H] ⁺ =397.1, experimental determination: 397.1.

end products 229 and 230: 3-amino-4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indazole-1-carboxamide (229, ZTB-71-12 g) and 1- (4-fluoro-1H-indazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (230, ZTB-71-15 g)

The final product 03 (40mg, 0.124mmol), 4-fluoro-1H-indazol-3-amine (56mg, 0.371mmol) and triethylamine (40.8mg, 0.403mmol) were charged to a 50mL reaction flask, and the reaction was dissolved by the addition of 2mL DMF. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain the objective compounds ZTB-71-12g (23.6 mg) and ZTB-71-15g (5 mg). ZTB-71-12g: ¹ h NMR (MeOD-d 4, 400MHz) 9.71 (s, 1H), 9.37 (s, 1H), 8.37 (d, J =8.38Hz, 1H), 8.03-8.10 (m, 2H), 7.88 (d, J =7.53Hz, 1H), 7.50-7.55 (m, 1H), 6.95-7.00 (m, 1H), 5.77-5.83 (m, 1H), 1.70 (s, 3H), 1.68 (s, 3H). ESI-MS theoretical calculation C ₁₈ H ₁₈ FN ₈ O[M+H] ⁺ =381.2; the experiment shows that: 380.2.ZTB-71-15g: ¹ h NMR (MeOD-d 4, 400MHz): 9.51 (s, 1H), 8.12 (d, J =8.44Hz, 1H), 7.98 (t, J =8.26Hz, 1H), 7.78 (d, J =7.52Hz, 1H), 7.33-7.39 (m, 1H), 7.27 (d, J =8.49Hz, 1H), 6.75-6.80 (m, 1H), 5.61-5.68 (m, 1H), 1.66 (s, 3H), 1.64 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₈ FN ₈ O[M+H] ⁺ =381.2, experimentally determined: 380.2.

end product 231:1- (1, 3-dimethyl-1H-pyrazol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (231, YB141)

The final product 03 (30mg, 0.0927mmol), 1, 3-dimethyl-1H-pyrazol-5-amine (37mg, 0.33mmol) and Et ₃ N (38mg, 0.376 mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reactants. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to afford the target compound YB141 (27 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.26 (s, 1H), 8.10 (d, J =4.3Hz, 2H), 7.86 (t, J =4.2Hz, 1H), 6.38 (s, 1H), 5.62 (p, J =6.8Hz, 1H), 3.83 (s, 3H), 2.37 (s, 3H), 1.72 (d, J =6.8Hz, 6H), ESI-MS theoretical calculation C ₁₆ H ₂₀ N ₈ O[M+H] ⁺ =341.2, experimentally determined: 341.5.

end product 232:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (1-methyl-1H-pyrazol-4-yl) urea (232, YB144)

The final product 03 (30mg, 0.0927mmol), 1-methyl-1H-pyrazol-4-amine (27mg, 0.278mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to afford the desired compound YB144 (39.6 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.52 (s, 1H), 8.12-7.87 (m, 2H), 7.87-7.65 (m, 2H), 7.51 (s, 1H), 5.75-5.56 (m, 1H), 3.89 (s, 3H), 1.63 (d, J =6.7Hz, 6H). ESI-MS theoretical calculation C ₁₅ H ₁₈ N ₈ O[M+H] ⁺ =327.2, determined experimentally: 327.3.

the final product 233:1- (3-cyclopropyl-1H-pyrazol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (233, YB145)

Step one, synthesizing 3-cyclopropyl-1H-pyrazole-5-amine (YB 140)

Dissolving 3-cyclopropyl-3-oxopropanenitrile (109mg, 1mmol) in 10mL ethanol, adding hydrazine hydrate (200mg, 40mmol), refluxing and stirring overnight, spin-drying the reaction solution, dissolving in ethyl acetate, washing with brine for 3 times, drying the organic phase, spin-drying, and purifying with silica gel column to obtain 90.2mg crude product. ¹ H NMR(400MHz,Methanol-d ₄ )δ5.25(s,1H),1.76(tt,J＝5.0,8.4Hz,1H),0.95–0.81(m,2H),0.68–0.58(m,2H).

Step two: synthesis of 1- (3-cyclopropyl-1H-pyrazol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (YB 145)

The final product 03 (30mg, 0.0927mmol), 3-cyclopropyl-1H-pyrazol-5-amine (45mg, 0.366mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to afford the target compound YB145 (46.9 mg). ¹ H NMR(MeOD-d4,400MHz):δ9.45(s,1H) 8.14 (d, J =8.4hz, 1h), 7.96 (t, J =8.0hz, 1h), 7.80 (d, J =7.5hz, 1h), 6.01 (s, 1H), 5.78 (hept, J =6.8hz, 1h), 1.98 (tt, J =4.9,8.6hz, 1h), 1.62 (d, J =6.7hz, 6h), 1.12 (dt, J =3.4,8.5hz, 2h), 0.87 (calculated value of J =4.7,7.1hz, 2h), ESI-MS theoretical C ₁₇ H ₂₀ N ₈ O[M+H] ⁺ =353.2, experimentally determined: 352.9.

end product 234:1- (3-Ethyl-1H-pyrazol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (234, YB146)

The final product 03 (30mg, 0.0927mmol), 3-ethyl-1H-pyrazol-5-amine (31mg, 0.278mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YB146 (33.7 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.49 (s, 1H), 8.15 (d, J =8.4Hz, 1H), 7.98 (t, J =8.0Hz, 1H), 7.80 (d, J =7.5Hz, 1H), 6.20 (s, 1H), 5.77 (hept, J =6.8Hz, 1H), 2.72 (q, J =7.6Hz, 2H), 1.62 (d, J =6.7Hz, 6H), 1.31 (t, J =7.6Hz, 3H), ESI-MS theoretical calculation C, 6H, 1.31 (t, J =7.6Hz, 3H) ₁₆ H ₂₀ N ₈ O[M+H] ⁺ =341.2, experimentally determined: 341.7.

end product 235: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (pyrimidin-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxamide (235, YB148)

Step one, synthesizing 5- (pyrimidine-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (YB 132)

5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (100mg, 0.32mmol) and 5-bromopyrimidine (103mg, 0.65mmol) were weighed into a bottle, 1, 2-dimethoxyethane (4 mL) and 2M Na were added ₂ CO ₃ Aqueous solution (1.5 mL). After the reaction system is deoxygenatedThen Pd (dppf) Cl is added ₂ -CH ₂ Cl ₂ (26.4mg, 0.032mmol). The reaction was heated at 95 ℃ overnight, diluted with water and extracted with ethyl acetate, dried, concentrated and purified on silica gel column to give 88mg of crude product which was used directly in the next reaction. ¹ H NMR(400MHz,Chloroform-d)δ9.06(s,1H),8.70(s,2H),6.30(tt,J＝2.0,4.3Hz,1H),4.23(s,2H),3.53(t,J＝5.7Hz,2H),2.42–2.24(m,2H),1.45(s,9H).

Step two, synthesizing 5- (1, 2,5, 6-tetrahydropyridine-3-yl) pyrimidine (YB 137)

The crude YB132 (88mg, 0.34mmol) was dissolved in 4mL CH ₂ Cl ₂ Then 1mL of trifluoroacetic acid was added. The reaction was stirred at room temperature overnight. The reaction solution was spin dried, water was added and the pH was adjusted to 7-8. Extracting with ethyl acetate, drying, evaporating to remove solvent to obtain crude product, and purifying to obtain crude product (54 mg) of YB 137. ¹ H NMR(MeOD-d4,400MHz):δ9.03(d,J＝3.9Hz,1H),8.84(d,J＝21.0Hz,2H),6.48(t,J＝4.4Hz,1H),3.64(s,2H),2.98(t,J＝5.8Hz,2H),2.35(tt,J＝2.8,5.8Hz,2H).

Step three, synthesizing N- (6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-yl) -5- (pyrimidine-5-yl) -3, 6-dihydropyridine-1 (2H) -formamide (235, YB148)

End product 03 (27mg, 0.0927mmol), YB137 (54mg, 0.34mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YB148 (34.4 mg). ¹ H NMR (MeOD-d4, 400MHz): delta 9.63 (s, 1H), 9.09 (s, 1H), 8.93 (s, 2H), 8.06-7.84 (m, 2H), 7.77 (dd, J =1.3,7.1Hz, 1H), 6.58 (tt, J =1.9,4.1Hz, 1H), 5.91 (hept, J =6.7,7.1Hz, 1H), 4.53 (q, J =2.4Hz, 2H), 3.86-3.71 (m, 2H), 2.52 (dq, J =3.2,6.0Hz, 2H), 1.61 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation value C ₂₀ H ₂₂ N ₈ O[M+H] ⁺ =391.2, determined experimentally: 391.3.

end product 236:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (3-methyl-1H-pyrazol-5-yl) urea (236, YB150)

The final product 03 (74mg, 0.229 mmol), 3-methyl-1H-pyrazol-5-amine (19mg, 0.195mmol) and Et ₃ N (56mg, 0.554mmol) was weighed into a flask, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to afford the target compound YB150 (76 mg). ¹ H NMR (MeOD-d4, 400MHz): delta 9.64 (s, 1H), 8.20 (d, J =8.4Hz, 1H), 7.98 (t, J =8.0Hz, 1H), 7.83 (d, J =7.5Hz, 1H), 6.18 (s, 1H), 5.87 (p, J =6.7Hz, 1H), 2.36 (d, J =0.0Hz, 3H), 1.62 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C ₁₅ H ₁₈ N ₈ O[M+H] ⁺ =327.2, experimentally determined: 326.3.

end product 237:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (1H-pyrazol-5-yl) urea (237, YB151)

The final product 03 (30mg, 0.0927mmol), 1H-pyrazol-3-amine (30mg, 0.361mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YB151 (35.6 mg). ¹ H NMR (MeOD-d 4, 400MHz): δ 9.62 (s, 1H), 8.12 (d, J =8.4Hz, 1H), 7.98 (t, J =8.0Hz, 1H), 7.78 (d, J =7.5Hz, 1H), 7.70 (d, J =2.6Hz, 1H), 6.36 (s, 1H), 5.79-5.61 (m, 1H), 1.64 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C-MS ₁₄ H ₁₆ N ₈ O[M+H] ⁺ =313.2, determined experimentally: 312.1.

end product 238:1- (1, 5-dimethyl-1H-pyrazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (238, YB152)

The final product 03 (30mg, 0.0927mmol), 1, 5-dimethyl-1H-pyrazol-3-amine (31mg, 0.278mmol) and Et ₃ N(38mg,0.376mmol) into a bottle, and 2mL of DMF is added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to afford the target compound YB152 (54.7 mg). ¹ H NMR (MeOD-d4, 400MHz): delta 9.36 (s, 1H), 8.21-7.89 (m, 2H), 7.73 (d, J =7.5Hz, 1H), 6.08 (s, 1H), 5.57 (p, J =6.7Hz, 1H), 3.69 (s, 3H), 2.28 (s, 3H), 1.63 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C ₁₆ H ₂₀ N ₈ O[M+H] ⁺ =341.2, determined experimentally: 340.3.

the final product 239:1- (3-isopropyl-1H-pyrazol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (239, YB154)

The final product 03 (30mg, 0.0927mmol), 3-isopropyl-1H-pyrazol-5-amine (38mg, 0.376mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YB154 (46.8 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.36 (d, J =4.4Hz, 1H), 8.07 (d, J =8.6Hz, 1H), 7.99 (dd, J =7.5,8.5Hz, 1H), 7.76 (d, J =7.4Hz, 1H), 6.17 (s, 1H), 5.64-5.48 (m, 1H), 3.02 (dt, J =6.9,13.8Hz, 1H), 1.63 (d, J =6.8Hz, 6H), 1.31 (d, J =7.0Hz, 6H), ESI-MS theoretical calculation value C ₁₇ H ₂₂ N ₈ O[M+H] ⁺ =355.2, experimentally determined: 354.2.

final product 240: 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methyl-1H-pyrazole-1-carboxamide (240, YB158)

Step one, synthesizing (3-methyl-1H-pyrazol-5-yl) carbamic acid tert-butyl ester (YB 153)

3-methyl-1H-pyrazol-5-amine (153mg, 1.57mmol) was dissolved in dry THF, di-tert-butyl dicarbonate (0.4 mL) and DMAP (61.4 mg,0.5 mmol) were added, and the mixture was stirred at room temperature overnight,spin-drying, adding water, extracting with ethyl acetate, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, and concentrating through normal phase silica gel column to obtain 163mg. ¹ H NMR(400MHz,Chloroform-d)δ5.18(s,1H),2.12(s,3H),1.60(s,9H)。

Step two, synthesizing 5-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-yl) -3-methyl-1H-pyrazole-1-formamide (YB 158)

The final product 03 (31mg, 0.0927mmol), tert-butyl (3-methyl-1H-pyrazol-5-yl) carbamate (56mg, 0.28mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YB158 (3.7 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.28 (s, 1H), 8.06 (d, J =8.5Hz, 1H), 7.98 (dd, J =7.5,8.5Hz, 1H), 7.76 (d, J =7.4Hz, 1H), 6.13 (s, 1H), 5.58 (H, J =6.8Hz, 1H), 2.32 (s, 3H), 1.62 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C ₁₅ H ₁₈ N ₈ O[M+H] ⁺ =327.2, determined experimentally: 326.9.

end products 241 and 242:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4, 5,6, 7-tetrahydro-1H-indazol-3-yl) urea (241, YB160-1) and 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4,5,6, 7-tetrahydro-1H-indazole-1-carboxamide (242, YB160-2)

The final product 03 (50mg, 0.15mmol), 3-amino-4, 5,6, 7-tetrahydro-1H-indazole hydrochloride (50mg, 0.29mmol) and Et ₃ N (61mg, 0.6 mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reactants. The reaction was heated at 50 ℃ overnight. The crude reaction product is directly purified by reverse phase HPLC to obtain target compounds YB160-1 (28 mg) and YB160-2 (30.8 mg). YB160-1: ¹ h NMR (MeOD-d 4, 400MHz): delta 9.40 (s, 1H), 8.40-7.61 (m, 3H), 6.03-5.47 (m, 1H), 2.83-2.60 (m, 2H), 2.57-2.34 (m, 2H), 2.06-1.73 (m, 4H), 1.62 (d, J =7.4Hz, 6H), ESI-MS theoretical calculation C ₁₈ H ₂₂ N ₈ O[M+H] ⁺ =367.2, experimental determination：366.6。YB160-2: ¹ H NMR (MeOD-d4, 400MHz): delta 9.23 (s, 1H), 8.25 (dd, J =0.8,8.4Hz, 1H), 8.02 (dd, J =7.6,8.5Hz, 1H), 7.83 (dd, J =0.9,7.6Hz, 1H), 5.66 (p, J =6.7Hz, 1H), 2.97 (t, J =6.1Hz, 2H), 2.34 (t, J =5.9Hz, 2H), 1.80 (ddd, J =5.1,8.5,17.6Hz, 4H), 1.62 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C ₁₈ H ₂₂ N ₈ O[M+H] ⁺ =367.2, experimentally determined: 366.6.

the final product 243:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (3-phenyl-1H-pyrazol-5-yl) urea (243, YC005)

Step one, synthesizing 3-phenyl-1H-pyrazole-5-amine (YC 001)

Dissolving 3-oxo-3-phenylpropanenitrile (145mg, 1mmol) in 10mL ethanol, adding hydrazine hydrate (200mg, 4mmol), refluxing and stirring overnight, spin-drying, adding water, extracting with ethyl acetate, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, and concentrating through normal phase silica gel column to obtain 63.5mg. ¹ H NMR(400MHz,CDCl ₃ ):δ7.62–7.46(m,2H),7.38–7.22(m,3H),5.86(s,1H)。

Step two, synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (3-phenyl-1H-pyrazol-5-yl) urea (YC 005)

The final product 03 (30mg, 0.0929mmol), 3-phenyl-1H-pyrazol-5-amine (63.5mg, 0.4mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the objective compound YC005 (34.1 mg). ¹ H NMR (MeOD-d4, 400MHz): delta 9.60 (s, 1H), 8.10 (d, J =8.4Hz, 1H), 7.99 (t, J =8.0Hz, 1H), 7.77 (d, J =7.5Hz, 1H), 7.70 (d, J =7.5Hz, 2H), 7.46 (t, J =7.5Hz, 2H), 7.39 (t, J =7.3Hz, 1H), 6.69 (s, 1H), 5.68 (p, J = 6.71H), 1.65 (d, J =6.7Hz, 6H), ESI-MS theoretical calculated value C, H ₂₀ H ₂₀ N ₈ O[M+H] ⁺ =389.2, experimentally determined: 388.5.

final product 244:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4-phenyl-1H-pyrazol-5-yl) urea (244, YC008)

Step one, synthesizing 4-phenyl-1H-pyrazole-5-amine (YC 006)

3-oxo-2-phenyl propionitrile (660mg, 4.6 mmol) is dissolved in 20mL ethanol, hydrazine hydrate (910mg, 18mmol) is added, the mixture is refluxed and stirred overnight, spin-dried, water is added, then ethyl acetate is used for extraction, an organic phase is washed by saturated salt solution, dried by anhydrous sodium sulfate, and concentrated by a normal phase silica gel column to obtain a product 36mg. ¹ H NMR(400MHz,Chloroform-d):δ7.58(s,1H),7.51–7.43(m,2H),7.36(t,J＝7.7Hz,2H),7.24–7.15(m,1H)。

Step two, synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4-phenyl-1H-pyrazol-5-yl) urea (YC 008)

End product 03 (24.4 mg, 0.075mmol), 4-phenyl-1H-pyrazol-5-amine (36mg, 0.226mmol) and Et ₃ N (30mg, 0.3 mmol) was weighed into a bottle and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YC008 (22 mg). ¹ H NMR (MeOD-d4, 400MHz): delta 9.33 (s, 1H), 8.02-7.87 (m, 3H), 7.73 (dd, J =1.7,6.6Hz, 1H), 7.52-7.44 (m, 2H), 7.34 (dd, J =6.8,8.3Hz, 2H), 7.29-7.21 (m, 1H), 5.56-5.26 (m, 1H), 1.49 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C ₂₀ H ₂₀ N ₈ O[M+H] ⁺ =389.2, experimentally determined: 390.4.

end products 245 and 246:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (2, 4,5, 6-tetrahydrocyclopenta [ c ] pyrazol-3-yl) urea (245, YC033-1) and 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5, 6-dihydrocyclopenta [ c ] pyrazole-1- (4H) -carboxamide (246, YC 0332)

Step one Synthesis of 2,4,5, 6-Tetrahydrocyclopenta [ c ] pyrazol-3-ylamine (YC 027)

Dissolving 2-oxocyclopentane-1-carbonitrile (124mg, 1.13mmol) in an ethanol ring, adding hydrazine hydrate (65mg, 1.3mmol) and glacial acetic acid (0.1mL, 1.76mmol), refluxing and stirring for 16h, concentrating the reaction solution, diluting with saturated sodium bicarbonate, extracting with dichloromethane for 3 times, combining organic phases, washing with brine, drying with anhydrous sodium sulfate, and spin-drying to obtain a crude product (52 mg). ¹ H NMR(400MHz,Methanol-d ₄ )δ2.63–2.53(m,2H),2.52–2.37(m,4H)。

Synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (2, 4,5, 6-tetrahydrocyclopenta [ c ] pyrazol-3 yl) urea (YC 033-1) and 3-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5, 6-dihydrocyclopenta [ c ] pyrazole-2 (4H) -carboxamide (YC 033-2)

Mixing the final product 03 (30mg, 0.0927mmol), 2,4,5, 6-tetrahydrocyclopenta [ c ]]Pyrazol-3-ylamine (52mg, 0.42mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the objective compounds YC033-1 (10.4 mg), YC033-2 (8 mg). YC033-1: ¹ h NMR (MeOD-d 4, 400MHz): delta 9.09 (s, 1H), 8.06 (d, J =8.4Hz, 1H), 7.98 (t, J =8.0Hz, 1H), 7.80-7.72 (m, 1H), 5.51 (p, J =6.8Hz, 1H), 2.85 (t, J =7.3Hz, 2H), 2.73 (t, J =7.0Hz, 2H), 2.59 (p, J =7.5Hz, 2H), 1.60 (d, J =6.7Hz, 6H), ESI-MS theoretical C.C.C.calculated ₁₇ H ₂₀ N ₈ O[M+H] ⁺ =353.2, determined experimentally: 352.5.YC033-2: ¹ h NMR (MeOD-d 4, 400MHz). Delta.9.34 (s, 1H), 8.21 (d, J =8.4Hz, 1H), 8.00 (t, J =8.0Hz, 1H), 7.84 (d, J =7.6Hz, 1H), 5.69 (hept, J =6.7Hz, 1H), 3.01-2.93 (m, 2H), 2.63-2.47 (m, 4H), 1.62 (d, J =6.7Hz, 6H) ESI-MS theoretical calculation C ₁₇ H ₂₀ N ₈ O[M+H] ⁺ =353.2, determined experimentally: 352.6.

end product 247:1- (5- (1, 3-dimethyl-1H-pyrazol-5-yl) pyridin-2-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (247, YC036)

Step one, synthesis of 5- (1, 3-dimethyl-1H-pyrazol-5-yl) -2-nitropyridine (YC 022)

(1, 3-dimethyl-1H-pyrazol-5-yl) boronic acid (100mg, 0.71mmol) and 5-bromo, 2-nitropyridine (290mg, 1.436 mmol) were dissolved in DME, 2.8mL of a 2M aqueous solution of sodium carbonate was added, vacuum evacuation was performed, nitrogen gas was introduced, and a catalyst Pd (dppf) was added ₂ Cl ₂ ﹒CH ₂ Cl ₂ (21 mg), the reaction mixture was again evacuated, then nitrogen gas was introduced, the mixture was refluxed at 95 ℃ overnight, diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and then subjected to spin-drying and purification with a normal-phase silica gel column to obtain YC022 (121 mg). ¹ H NMR(400MHz,Chloroform-d):δ8.72(d,J＝2.2Hz,1H),8.36(dd,J＝0.7,8.4Hz,1H),8.06(dd,J＝2.3,8.4Hz,1H),7.26(s,1H),3.90(s,3H),2.32(s,3H)。

Step two Synthesis of 5- (1, 3-dimethyl-1H-pyrazol-5-yl) -2-aminopyridine (YC 030)

YC022 (121 mg) was dissolved in dry THF, evacuated, then purged with nitrogen, 10% pd/C (15 mg) was added, evacuated again, purged with hydrogen, stirred overnight at room temperature, filtered and rotary dried to give crude YC030 (116 mg). ¹ H NMR(400MHz,Methanol-d ₄ ):δ7.95(d,J＝2.3Hz,1H),7.48(dd,J＝2.4,8.6Hz,1H),6.64(d,J＝8.6Hz,1H),6.06(d,J＝19.7Hz,1H),3.71(s,3H),2.20(s,3H)。

Step three, synthesis of 1- (5- (1, 3-dimethyl-1H-pyrazol-5-yl) pyridin-2-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) Urea (YC 036)

Mixing final product 03 (30mg, 0.0928mmol), YC030 (116mg, 0.617mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the title compound YC036 (4.6 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.37 (s, 1H), 8.37 (d, J =2.3Hz, 1H), 8.20 (d, J =8.4Hz, 1H), 8.01 (t, J =7.5Hz, 1H), 7.94 (dd, J =2.4,8.7Hz, 1H), 7.80 (d, J =7.5Hz, 1H), 7.60 (d, J =8.7Hz, 1H), 6.27 (s, 1H), 5.61 (p, J =6.7Hz, 1H), 3.83 (s, 3H), 2.28 (s, 3H), 1.67 (d, J =6.7Hz, 6H): ESI-MS theoretical calculation C, 1H ₂₁ H ₂₃ N ₉ O[M+H] ⁺ =418.2, determined experimentally: 418.1.

end product 248:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl) urea (248, YC045)

Step one, synthesizing 5- (4-methyl-1H-imidazole-1-yl) -2-nitropyridine (YC 028)

4-methylimidazole (82mg, 1mmol), 5-fluoro, 2-nitropyridine (170mg, 1.2mmol) and potassium carbonate (300mg, 2.2mmol) were mixed with 5mL of DMF, stirred at 110 ℃ for 2 hours, diluted with 20mL of ethyl acetate, washed with saturated sodium chloride three times, the organic phase was dried over anhydrous sodium sulfate, and purified by a normal phase silica gel column to obtain YC028 (99 mg). ¹ H NMR(400MHz,Chloroform-d):δ8.72(d,J＝2.7Hz,1H),8.42(d,J＝8.7Hz,1H),8.00(dd,J＝2.7,8.7Hz,1H),7.92(d,J＝1.5Hz,1H),7.19–7.02(m,1H),2.33(d,J＝1.1Hz,3H)。

Step two, synthesis of 5- (4-methyl-1H-imidazol-1-yl) -2-aminopyridine (YC 032)

Dissolving YC028 (99 mg) in dry THF, vacuumizing, introducing nitrogen, adding 10% Pd/C (20 mg), vacuumizing again, introducing hydrogen, stirring overnight at room temperature, filtering, and spin-drying to obtain crude YC032 (75.4 mg). ¹ H NMR(400MHz,Chloroform-d):δ8.11(d,J＝2.7Hz,1H),7.58(d,J＝1.4Hz,1H),7.42(dd,J＝2.7,8.7Hz,1H),6.86(t,J＝1.3Hz,1H),6.56(d,J＝8.7Hz,1H),2.29(d,J＝1.0Hz,3H)。

Step three Synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl) Urea (YC 045)

Mixing final product 03 (30mg, 0.0928mmol), YC032 (24mg, 0.138mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product is directly purified by reversed phase HPLC to obtain the target productCompound YC045 (6.8 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.39 (s, 1H), 9.33 (d, J =1.6Hz, 1H), 8.60 (d, J =2.7Hz, 1H), 8.18 (d, J =8.4Hz, 1H), 8.10 (dd, J =2.8,9.0Hz, 1H), 8.05-7.92 (m, 2H), 7.85-7.75 (m, 2H), 5.90-5.49 (m, 1H), 2.46 (s, 3H), 1.66 (d, J =6.7Hz, 6H). ESI-MS theoretical calculation C ₂₀ H ₂₁ N ₉ O[M+H] ⁺ =404.2, experimentally determined: 405.0.

final product 249:1- (5- (1-isopropyl-1H-pyrazol-4-yl) pyridin-2-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (249, YC048)

Step one Synthesis of 2-nitro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (YC 042)

Bis (pinacolato) diboron (1.56g, 6.2mmol), 5-bromo, 2-nitropyridine (1g, 4.9mmol) and potassium acetate (1.44g, 14.7mmol) were dissolved in 1, 4-dioxane, evacuated and purged with nitrogen, the catalyst Pd (dppf) was added ₂ Cl ₂ ﹒CH ₂ Cl ₂ (200 mg), again vacuum pumping, nitrogen gas introduction, 90 ℃ reflux overnight, water dilution, ethyl acetate extraction, organic phase drying with anhydrous sodium sulfate, spin drying, purification with normal phase silica gel column to obtain YC042 (1 g). ¹ H NMR(400MHz,CDCl ₃ ):δ8.95(dd,J＝0.8,1.7Hz,1H),8.40(dd,J＝1.8,8.0Hz,1H),8.21(dd,J＝0.8,8.1Hz,1H),1.38(s,12H)。

Step two, synthesizing 5- (1-isopropyl-1H-pyrazol-4-yl) -2-nitropyridine (YC 041)

YC042 (100mg, 0.4mmol), 1-isopropyl-4-bromo-1H-pyrazole 151mg, 0.8mmol) were dissolved in DME, 1.6mL of 2M aqueous sodium carbonate solution was added, vacuum was applied, nitrogen was introduced, and Pd (dppf) as a catalyst was added ₂ Cl ₂ -CH ₂ Cl ₂ (16 mg), the reaction mixture was again evacuated, then nitrogen gas was introduced thereinto, the mixture was refluxed at 95 ℃ overnight, diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and then subjected to spin-drying and purification with a normal-phase silica gel column to obtain YC041 (47 mg).

Step three, synthesizing 5- (1-isopropyl-1H-pyrazol-4-yl) -2-aminopyridine (YC 046)

Dissolving YC041 (47 mg) in dry THF, vacuumizing, introducing nitrogen, adding 10% Pd/C (10 mg), vacuumizing again, introducing hydrogen, stirring overnight at room temperature, filtering, and spin-drying to obtain crude YC046 (32.6 mg). ¹ H NMR(400MHz,Chloroform-d)：δ8.17(d,J＝2.4Hz,1H),7.65(s,1H),7.55(s,1H),7.51(dd,J＝2.4,8.5Hz,1H),6.50(d,J＝8.4Hz,1H),4.49(hept,J＝6.7Hz,1H),1.51(d,J＝6.7Hz,6H)。

Step four Synthesis of 1- (5- (1-isopropyl-1H-pyrazol-4-yl) pyridin-2-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) Urea (YC 048)

The final product 03 (30mg, 0.0928mmol), YC046 (32mg, 0.158mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YC048 (12 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.38 (s, 1H), 8.45 (d, J =2.3Hz, 1H), 8.30-8.11 (m, 3H), 8.00 (t, J =8.0Hz, 1H), 7.94-7.86 (m, 1H), 7.83 (d, J =7.5Hz, 1H), 7.52 (d, J =8.8Hz, 1H), 5.74 (p, J =6.7Hz, 1H), 4.58 (p, J =6.7Hz, 1H), 1.65 (d, J =6.7Hz, 6H), 1.54 (d, J =6.7Hz, 6H). Theoretical calculation C ESI-MS ₂₂ H ₂₅ N ₉ O[M+H] ⁺ =432.2, experimentally determined: 433.9.

end products 250 and 251:1- (5- (1H-imidazol-1-yl) pyridin-2-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (250, YC053-7) and 3- (1H-imidazol-1-yl) -2-imino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) pyridine-1- (2H) -carboxamide (251, YC053-8)

Step one, synthesizing 5- (1H-imidazole-1-yl) -2-nitropyridine (YC 038)

Imidazole (54mg, 0.79mmol), 5-fluoro, 2-nitropyridine (145mg, 1.03mmol) and potassium carbonate (240mg, 1.65mmol) were dissolved in 5mL of DMF, stirred at 110 ℃ for 2 hours, diluted with 20mL of ethyl acetate, washed with saturated sodium chloride three times, the organic phase was dried over anhydrous sodium sulfate, and purified with a normal phase silica gel column to obtain YC038 (138.8 mg).

Step two, synthesizing 5- (1H-imidazole-1-yl) -2-aminopyridine (YC 047)

YC038 (138.8 mg) was dissolved in dry THF, evacuated, then purged with nitrogen, 10% Pd/C (15 mg) was added, evacuated again, purged with hydrogen, stirred overnight at room temperature, filtered and rotary dried to give crude YC047 (27.2 mg). ¹ H NMR(400MHz,Methanol-d ₄ )：δ8.07(d,J＝2.7Hz,1H),7.95(s,1H),7.61(dd,J＝2.7,8.9Hz,1H),7.40(s,1H),7.13(s,1H),6.68(d,J＝8.9Hz,1H)。

Step three Synthesis of 1- (5- (1H-imidazol-1-yl) pyridin-2-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) Urea (YC 053-7) and 3- (1H-imidazol-1-yl) -2-imino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) pyridine-1 (2H) -carboxamide (YC 053-8)

End product 03 (30mg, 0.0929mmol), YC047 (27.2mg, 0.17mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the objective compounds YC053-7 (6.4 mg) and YC053-8 (3.8 mg). YC053-7: ¹ h NMR (MeOD-d 4, 400MHz): delta 9.46 (t, J =1.5Hz, 1H), 9.24 (s, 1H), 8.63 (d, J =2.7Hz, 1H), 8.19-8.10 (m, 2H), 8.07 (t, J =1.8Hz, 1H), 8.04-7.96 (m, 2H), 7.84-7.75 (m, 2H), 5.58 (p, J =6.7Hz, 1H), 1.64 (d, J =6.7Hz, ESI-MS theoretical calculation C.C. ₁₉ H ₁₉ N ₉ O[M+H] ⁺ =390.2, determined experimentally: 390.7; YC053-8: ¹ h NMR (MeOD-d4, 400MHz): delta 9.70 (t, J =1.5Hz, 1H), 9.12 (s, 1H), 8.74 (d, J =2.6Hz, 1H), 8.42-8.28 (m, 2H), 8.11-8.03 (m, 1H), 7.99 (dd, J =7.5,8.5Hz, 1H), 7.90 (d, J =8.9Hz, 1H), 7.81-7.64 (m, 2H), 5.56 (p, J =6.7Hz, 1H), 1.61 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C calculation, MS ₁₉ H ₁₉ N ₉ O[M+H] ⁺ =390.2, experimentally determined: 390.8.

the final product 252:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (5- (1-methyl-1H-pyrazol-3-yl) pyridin-2-yl) urea (252, YC056)

Step one, synthesizing 5- (1-methyl-1H-pyrazol-3-yl) -2-nitropyridine (YC 043)

YC042 (100mg, 0.4mmol) and 1-methyl-3-bromo-1H-pyrazole (129mg, 0.8mmol) were dissolved in DME, 1.6mL of 2M aqueous sodium carbonate solution was added, vacuum was applied, nitrogen was introduced, and Pd (dppf) as a catalyst was added ₂ Cl ₂ -CH ₂ Cl ₂ (16 mg), again after vacuum, nitrogen was introduced, reflux overnight at 95 ℃ C, dilution with water, extraction with ethyl acetate, drying of the organic phase over anhydrous sodium sulfate, spin-drying and purification on normal phase silica gel to give YC043 (24 mg). ¹ H NMR(400MHz,Chloroform-d)：δ8.99(d,J＝2.2Hz,1H),8.38(dd,J＝2.2,8.5Hz,1H),8.27(dd,J＝0.6,8.4Hz,1H),7.47(d,J＝2.3Hz,1H),6.69(d,J＝2.3Hz,1H),4.00(s,3H)。

Step two, synthesizing 5- (1-methyl-1H-pyrazol-3-yl) -2-aminopyridine (YC 051)

Dissolving YC041 (24 mg) in dry THF, vacuumizing, introducing nitrogen, adding 10% Pd/C (10 mg), vacuumizing again, introducing hydrogen, stirring at room temperature overnight, filtering, and spin-drying to obtain crude YC051 (19 mg)

Step three, synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (5- (1-methyl-1H-pyrazol-3-yl) pyridin-2-yl) Urea (YC 056)

The final product 03 (30mg, 0.0928mmol), YC046 (19mg, 0.109mmol) and Et ₃ N (38mg, 0.376 mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reactants. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the objective compound YC056 (8.2 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.44 (s, 1H), 8.80-8.59 (m, 1H), 8.32 (dd, J =2.2,8.8Hz, 1H), 8.22 (d, J =8.4Hz, 1H), 8.03 (t, J =8.0Hz, 1H), 7.83 (d, J =7.5Hz, 1H), 7.67 (d, J =2.3Hz, 1H), 7.48 (d, J =8.9Hz, 1H), 6.69 (d, J =2.3Hz, 1H), 5.68 (p, J =6.7Hz, 1H), 3.96 (s, 3H), 1.69 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation of C ₂₀ H ₂₁ N ₉ O[M+H] ⁺ =404.2, experimentally determined: 404.6.

end product 253:1- (4-isopropyl-1H-pyrazol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (253, YC058)

Step one, synthesizing 2-formyl-3-methylbutyronitrile (YC 049)

LiHMDS (9.5mL, 1N in THF) is added into a single-neck bottle containing THF, the mixture is cooled to-78 ℃, isopentyl nitrile (800mg, 9.6 mmol) is added into a reaction bottle, ethyl formate (741mg, 10.12mmol) is added after stirring for 10 minutes, the mixture is stirred at 78 ℃ for 30 minutes, the mixture is naturally heated to room temperature and stirred for 16 hours, the pH value is adjusted to about 3 by 1N hydrochloric acid, an organic phase is collected, an aqueous phase is extracted by ethyl acetate for 3 times, the organic phases are combined, dried by anhydrous sodium sulfate, and a crude product (277 mg) is obtained by positive phase column purification after spin drying. ¹ H NMR(400MHz,Chloroform-d):δ9.58(d,J＝1.2Hz,1H),3.40(dd,J＝1.1,4.9Hz,1H),2.53–2.40(m,1H),1.12(d,J＝6.8Hz,6H)。

Step two, synthesizing 4-isopropyl-1H-pyrazole-5-amine (YC 052)

Dissolving 2-formyl-3-methylbutyronitrile (270mg, 2.43mmol) in 10mL ethanol, adding 85% hydrazine hydrate (286mg, 4.86mmol) and glacial acetic acid (437.4mg, 7.29mmol), refluxing, stirring overnight, spin-drying, adding water, extracting with ethyl acetate, washing the organic phase with saturated common salt, drying with anhydrous sodium sulfate, and concentrating through a normal phase silica gel column to obtain 192mg of a product. ¹ H NMR(400MHz,Chloroform-d):δ7.16(s,1H),2.72(hept,J＝6.8Hz,1H),1.18(d,J＝6.9Hz,6H)。

Step three, synthesizing 1- (4-isopropyl-1H-pyrazol-5-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (YC 058)

The final product 03 (30mg, 0.0929mmol), 4-isopropyl-1H-pyrazol-5-amine (23mg, 0.186mmol) and Et ₃ N (38mg, 0.376 mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reactants. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YC058 (12.7 mg). ¹ H NMR(MeOD-d4,400MHz):δ9.33(s,1H),8.10(d,J＝8.5Hz,1H),7.99(t,J＝8.0Hz,1H),7.84–7.61(m,2H),5.55(p,J＝6.7Hz,1H),2.88(p,J＝6.8Hz,1H),1.61(d,J＝6.7Hz,6H),1.24 Theoretical calculation of (d, J =6.8Hz, 6H). ESI-MS value C ₁₇ H ₂₂ N ₈ O[M+H] ⁺ =355.2, experimentally determined: 355.6.

end product 254:1- ([ 2,3 '-bipyridyl ] -6' -yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (254, YC061)

Step one, synthesizing 6 '-nitro-2, 3' -bipyridine (YC 050)

YC042 (100mg, 0.4mmol) and 2-bromopyridine (126.4mg, 0.8mmol) were dissolved in DME, 1.6mL of a 2M aqueous solution of sodium carbonate was added, vacuum was applied, nitrogen was introduced, and catalyst Pd (dppf) was added ₂ Cl ₂ ﹒CH ₂ Cl ₂ (17 mg), again after vacuum pumping, nitrogen was passed through, reflux overnight at 95 ℃, water was added for dilution, ethyl acetate was extracted, the organic phase was dried over anhydrous sodium sulfate, spin dried and purified with a normal phase silica gel column to give YC050 (75 mg). ¹ H NMR(400MHz,Chloroform-d)：δ9.26–9.19(m,1H),8.79(dt,J＝1.4,4.8Hz,1H),8.69(dd,J＝2.3,8.5Hz,1H),8.37(dd,J＝0.7,8.4Hz,1H),7.94–7.79(m,2H),7.41(ddd,J＝2.3,4.8,6.3Hz,1H)。

Step two, synthesizing 6 '-amino-2, 3' -bipyridine (YC 057)

Dissolving YC050 (75 mg) in dry THF, vacuumizing, introducing nitrogen, adding 10% Pd/C (10 mg), vacuumizing again, introducing hydrogen, stirring at room temperature overnight, filtering, and spin drying to obtain YC057 crude product (52 mg)

Step three, synthesizing 1- ([ 2,3 '-bipyridine ] -6' -yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (YC 061)

The final product 03 (30mg, 0.0928mmol), YC057 (52mg, 0.279mmol) and Et ₃ N (38mg, 0.376 mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reactants. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the desired compound YC061 (8.9 mg). ¹ H NMR(MeOD-d4,400MHz):δ9.41(d,J＝2.1Hz,1H),8.87(dd,J＝0.8,2.5Hz,1H),8.76(ddd,J＝0.8,1.7,5.4Hz,1H),8.43(dd,J＝2.5,8.8Hz,1H),8.29(td,J＝1.7,7.9Hz, 1H), 8.25-8.18 (m, 1H), 8.15 (dt, J =1.0,8.1hz, 1h), 8.01 (dd, J =7.6,8.5hz, 1h), 7.81 (dd, J =0.8,7.6hz, 1h), 7.79-7.59 (m, 2H), 5.67 (hept, J =6.6hz, 1h), 1.68 (d, J =6.7hz, 6h), ESI-MS theoretical calculation C-MS ₂₁ H ₂₀ N ₈ O[M+H] ⁺ =401.2, determined experimentally: 400.4.

end product 255:1- ([ 3,3' -bipyridin ] -6-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (255, YC066)

Step one, synthesizing 6 '-nitro-3, 3' -bipyridine (YC 054)

YC042 (100mg, 0.4mmol) and 3-bromopyridine (126.4mg, 0.8mmol) were dissolved in DME, 1.6mL of 2M aqueous sodium carbonate solution was added, vacuum was applied, nitrogen was introduced, and Pd (dppf) as a catalyst was added ₂ Cl ₂ -CH ₂ Cl ₂ (17 mg), again after vacuum, nitrogen was introduced, reflux overnight at 95 ℃ C, dilution with water, extraction with ethyl acetate, drying of the organic phase over anhydrous sodium sulfate, spin-drying and purification with normal phase silica gel column to give YC054 (68 mg). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.97(dd,J＝2.3,11.7Hz,2H),8.74–8.63(m,1H),8.52(dd,J＝2.2,8.5Hz,1H),8.44(d,J＝8.5Hz,1H),8.28(dt,J＝2.0,8.0Hz,1H),7.63(dd,J＝5.0,8.0Hz,1H)。

Step two, synthesizing 6 '-amino-3, 3' -bipyridine (YC 059)

Dissolving YC054 (68 mg) in dry THF, vacuumizing, introducing nitrogen, adding 10% Pd/C (10 mg), vacuumizing again, introducing hydrogen, stirring at room temperature overnight, filtering, and spin-drying to obtain crude YC059 (59.6 mg)

Step three Synthesis of 1- ([ 3,3' -bipyridin ] -6-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) Urea (YC 066)

The final product 03 (30mg, 0.0928mmol), YC059 (59.6mg, 0.279mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the desired compound YC066 (12.1 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.58 (s, 1H), 9.22 (d, J =2.1Hz, 1H), 8.95-8.80 (m, 2H), 8.71 (dd, J =0.7,2.6Hz, 1H), 8.32-8.18 (m, 2H), 8.15 (dd, J =5.7,8.2Hz, 1H), 8.02 (td, J =7.5,8.8Hz, 1H), 7.86-7.76 (m, 2H), 5.69 (hept, J =6.7Hz, 1H), 1.69 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C-MS ₂₁ H ₂₀ N ₈ O[M+H] ⁺ =401.2, experimentally determined: 400.4.

the final product 256:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (5- (pyrimidin-5-yl) pyridin-2-yl) urea (256, YC068)

Step one, synthesizing 5- (6-nitro-pyridine-3-yl) pyrimidine (YC 062)

YC042 (100mg, 0.4mmol) and 5-bromopyrimidine (127mg, 0.8mmol) were dissolved in DME, 1.6mL of a 2M aqueous solution of sodium carbonate was added, vacuum was applied, nitrogen was introduced, and Pd as a catalyst (dppf) was added ₂ Cl ₂ -CH ₂ Cl ₂ (17 mg), again after vacuum pumping, nitrogen was passed through, reflux overnight at 95 ℃, water was added for dilution, ethyl acetate was extracted, the organic phase was dried over anhydrous sodium sulfate, spin dried and purified with a normal phase silica gel column to give YC062 (67.6 mg). ¹ H NMR(400MHz,Methanol-d ₄ )δ9.28(s,1H),9.24(s,2H),9.01(d,J＝2.3Hz,1H),8.57(dd,J＝2.3,8.4Hz,1H),8.47(d,J＝8.4Hz,1H)。

Step two Synthesis of 5- (6-amino-pyridin-3-yl) pyrimidine (YC 064)

Dissolving YC062 (67.6 mg) in dry THF, vacuumizing, introducing nitrogen, adding 10% Pd/C (10 mg), vacuumizing again, introducing hydrogen, stirring at room temperature overnight, filtering, and spin-drying to obtain crude YC064 (54 mg)

Step three Synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (5- (pyrimidin-5-yl) pyridin-2-yl) Urea (YC 068)

The final product 03 (30mg, 0.0928mmol), YC064 (54mg, 0.314mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product is directly purified by reversed phase HPLC to obtainTo the target compound YC068 (2.9 mg). ¹ H NMR (MeOD-d4, 400MHz): δ 9.37 (s, 1H), 9.14 (d, J =25.1Hz, 3H), 8.62 (d, J =2.4Hz, 1H), 8.19 (dd, J =2.5,8.7Hz, 2H), 8.02 (t, J =8.0Hz, 1H), 7.80 (d, J =7.6Hz, 1H), 7.66 (d, J =8.7Hz, 1H), 5.62 (p, J =6.7Hz, 1H), 1.68 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C ₂₀ H ₁₉ N ₉ O[M+H] ⁺ =402.2, experimentally determined: 401.3.

end product 257:1- (imidazo [1,2-a ] pyridin-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (257, YC072)

The final product 03 (20mg, 0.062mmol), imidazo [1,2-a ] was added]Pyridin-3-amine (25mg, 0.186mmol) and Et ₃ N (25mg, 0.248mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the desired compound YC072 (27.8 mg). ¹ H NMR (MeOD-d 4, 400MHz). Delta.9.39 (s, 1H), 8.71 (d, J =6.8Hz, 1H), 8.12-7.89 (m, 5H), 7.81 (dd, J =1.4,7.0Hz, 1H), 7.56 (td, J =1.2,6.9Hz, 1H), 5.72 (hept, J =6.7Hz, 1H), 1.62 (d, J =6.7Hz, 6H) ESI-MS theoretical calculation C ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.2, experimentally measured: 362.9.

end product 258:1- (1, 3-dimethyl-1H-pyrazol-4-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (258, YC074)

The final product 03 (20mg, 0.062mmol), 1, 3-dimethyl-1H-pyrazol-4-amine (21mg, 0.186mmol) and Et ₃ N (25mg, 0.248mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YC074 (27.4 mg). ¹ H NMR(MeOD-d4,400MHz):δ9.33(s,1H),8.10–7.86(m,2H),7.77(s,1H),7.70(dd,J＝1.27.3hz, 1h), 5.54 (hept, J =6.8hz, 1h), 3.81 (s, 3H), 2.17 (s, 3H), 1.60 (d, J =6.7hz, 6H) ESI-MS theoretically calculated values C ₁₆ H ₂₀ N ₈ O[M+H] ⁺ =341.2, experimentally determined: 340.7.

the final product 259:1- ([ 3,4' -bipyridin ] -6-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (259, YC081)

Step one, synthesizing 6 '-nitro-4, 3' -bipyridine (YC 070)

YC042 (100mg, 0.4mmol) and 4-bromopyridine hydrochloride (155mg, 0.8mmol) were dissolved in DME, 1.6mL of 2M aqueous sodium carbonate solution was added, vacuum was applied, nitrogen was introduced, and Pd as a catalyst (dppf) was added ₂ Cl ₂ -CH ₂ Cl ₂ (17 mg), again after vacuum pumping, nitrogen was introduced, reflux overnight at 95 ℃, water was added for dilution, ethyl acetate was extracted, the organic phase was dried over anhydrous sodium sulfate, spin dried and purified with a normal phase silica gel column to give YC070 (42 mg).

Step two, synthesis of 6 '-amino-4, 3' -bipyridine (YC 077)

Dissolving YC070 (42 mg) in dry THF, vacuumizing, introducing nitrogen, adding 10% Pd/C (10 mg), vacuumizing again, introducing hydrogen, stirring at room temperature overnight, filtering, and spin-drying to obtain crude YC077 (25 mg)

Step three Synthesis of 1- ([ 3,4' -bipyridin ] -6-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) Urea (YC 081)

The final product 03 (30mg, 0.0928mmol), YC077 (25mg, 0.146mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give YC081 (7.8 mg). ¹ H NMR (MeOD-d4, 400MHz): delta 9.34 (s, 1H), 9.03-8.81 (m, 3H), 8.53-8.33 (m, 3H), 8.21 (d, J =8.4Hz, 1H), 8.03 (dd, J =7.6,8.5Hz, 1H), 7.89 (d, J =8.9Hz, 1H), 7.81 (dd, J =0.8,7.5Hz, 1H), 5.92-5.41 (m, 1H), 1.69 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C ₂₁ H ₂₀ N ₈ O[M+H] ⁺ =401.2, determined experimentally: 401.2.

end product 260:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (5- (pyrazin-2-yl) pyridin-2-yl) urea (260, YC083)

Step one, synthesizing 2- (6-nitro-pyridine-3-yl) pyrazine (YC 075)

YC042 (100mg, 0.4mmol) and 2-bromopyrazine (127mg, 0.8mmol) were dissolved in DME, 1.6mL of 2M aqueous sodium carbonate solution was added, vacuum was applied, nitrogen gas was introduced, and catalyst Pd (dppf) was added ₂ Cl ₂ -CH ₂ Cl ₂ (17 mg), vacuumizing again, introducing nitrogen, refluxing at 95 deg.C overnight, diluting with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, spin-drying, and purifying with normal phase silica gel column to obtain YC075 (75.8 mg)

Step two, synthesizing 2- (6-amino-pyridine-3-yl) pyrazine (YC 080)

Dissolving YC075 (75.8 mg) in dry THF, vacuumizing, introducing nitrogen, adding 10% Pd/C (10 mg), vacuumizing again, introducing hydrogen, stirring at room temperature overnight, filtering, and spin-drying to obtain YC080 crude product (67.1 mg)

Step three, synthesizing 1- (6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-yl) -3- (5- (pyrazine-2-yl) pyridine-2-yl) urea (YC 083)

The final product 03 (30mg, 0.0928mmol), YC080 (48mg, 0.279mmol) and Et ₃ N (38mg, 0.376mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the objective compound YC083 (10.2 mg). ¹ H NMR(MeOD-d4,400MHz):δ9.43(s,1H),9.12(d,J＝1.5Hz,1H),8.96(d,J＝2.3Hz,1H),8.77–8.61(m,1H),8.58–8.44(m,2H),8.20(d,J＝8.4Hz,1H),7.99(t,J＝8.0Hz,1H),7.80(d,J＝7.5Hz,1H),7.56(d,J＝8.8Hz,1H),5.66(p,J＝6.7Hz,1H) Theoretical calculation of 1.69 (d, J =6.7Hz, 6H). ESI-MS C ₂₀ H ₁₉ N ₉ O[M+H] ⁺ =402.2, experimentally determined: 402.8.

end product 261:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) urea (261, YC094)

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Step one Synthesis of pyrazolo [1,5-a ] pyridine-3-carboxylic acid Ethyl ester (YC 079)

1-aminopyridine-1-iodide (1.11g, 5mmol), ethyl propiolate (624mg, 6mmol) and potassium carbonate (828mg, 6mmol) were dissolved in DMF, stirred at room temperature for 3 days, diluted with water, extracted with ethyl acetate and petroleum ether (v/v = 1/1), the organic phase was dried over anhydrous sodium sulfate, and purified by normal phase silica gel column to give YC079 (610.9 mg, 64% yield). ¹ H NMR(400MHz,Chloroform-d):δ8.52(dt,J＝1.1,7.0Hz,1H),8.40(s,1H),8.16(dt,J＝1.2,8.9Hz,1H),7.40(ddd,J＝1.1,6.8,8.9Hz,1H),6.95(td,J＝1.4,6.9Hz,1H),4.38(q,J＝7.1Hz,2H),1.41(t,J＝7.1Hz,3H).

Step two Synthesis of pyrazolo [1,5-a ] pyridine-3-carboxylic acid (YC 087)

YC079 (610.9mg, 3.22mmol) was dissolved in absolute ethanol (10 mL) and water (5 mL), sodium hydroxide (514mg, 12.86mmol) was added, the mixture was stirred under reflux for 2 hours, the ethanol was dried, acidified with 6N hydrochloric acid, and the crude YC087 product was filtered and used directly in the next step.

Step three Synthesis of Benzylpyrazolo [1,5-a ] pyridin-3-ylcarboxamide (YC 090)

YC087 (194.4mg, 1.2mmol) was dissolved in dry THF, DIPEA (0.4mL, 2.42mmol) and DPPA (0.268mL, 1.32mmol) were added, and the mixture was stirred at room temperature overnight. 0.2mL of benzyl alcohol was added, and the mixture was stirred under reflux for 12 hours. The reaction was spin dried, dissolved in ethyl acetate, washed 2 times with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and purified on normal phase silica gel column to give 79mg of crude product. ¹ H NMR(400MHz,Chloroform-d):δ8.32(d,J＝7.1Hz,1H),8.00(s,1H),7.51–7.20(m,5H),7.08–6.97(m,1H),6.87(s,1H),6.68(t,J＝6.9Hz,1H),5.21(s,2H).

Step four Synthesis of 4,5,6,7-tetrahydropyrazolo [1,5-a ] pyridin-3-amine (YC 092)

YC090 (79 mg) was dissolved in dry THF, evacuated and charged with nitrogen, 10% Pd/C (10 mg) was added, evacuated again and charged with hydrogen, stirred at room temperature overnight, filtered and spin-dried to obtain crude YC092 (30.7 mg, yield 76%). ¹ H NMR(400MHz,Chloroform-d):δ7.05(s,1H),3.98(t,J＝6.1Hz,2H),2.57(t,J＝6.4Hz,2H),1.95–1.87(m,2H),1.82–1.74(m,2H).

Step five Synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4, 5,6, 7-tetrahydropyrazolo [1,5-a ] ] pyridin-3-yl) urea (YC 094)

End product 03 (20mg, 0.062mmol), YC092 (31mg, 0.226mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YC094 (29.8 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.51 (s, 1H), 8.03 (d, J =8.5Hz, 1H), 7.96 (dd, J =7.4,8.5Hz, 1H), 7.78-7.66 (m, 2H), 5.64 (hept, J =6.8Hz, 1H), 4.12 (t, J =6.1Hz, 2H), 2.74 (t, J = 6.Hz, 2H), 2.07 (td, J =4.4,7.0,8.2Hz, 2H), 1.97-1.81 (m, 2H), 1.61 (d, J =6.7Hz, 6H), theoretical calculation C ESI-MS value C ₁₈ H ₂₂ N ₈ O[M+H] ⁺ =367.2, experimentally determined: 367.4.

end product 262:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (pyrazin-2-yl) urea (262, YC096)

The final product 03 (20mg, 0.062mmol), pyrazin-2-amine (18mg, 0.186mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the objective compound YC096 (4.5 mg). ¹ H NMR(MeOD-d4,400MHz):δ9.18(s,1H),8.98(s,1H),8.30(dd,J＝1.5,2.7Hz,1H),8.26(d,J＝2.7Hz,1H),8.14(d,J＝8.4Hz,1H),8.00(t,J＝8.0Hz,1H),7.79(d,J＝7.5Hz,1H),5.66–5.41 Theoretical calculation of (m, 1H), 1.64 (d, J =6.7hz, 6H) ESI-MS C ₁₅ H ₁₆ N ₈ O[M+H] ⁺ =325.2, measured experimentally: 324.5.

end product 263:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (quinolin-2-yl) urea (263, YC097)

The final product 03 (20mg, 0.062mmol), 2-aminoquinoline (27mg, 0.186mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YC097 (14.5 mg). ¹ H NMR (MeOD-d 4, 400MHz): δ 9.37 (s, 1H), 8.45 (d, J =9.0Hz, 1H), 8.30 (d, J =8.4Hz, 1H), 8.02 (t, J =8.0Hz, 1H), 7.94 (d, J =8.4Hz, 2H), 7.88 (d, J =7.6Hz, 1H), 7.82 (t, J =7.8Hz, 1H), 7.59 (t, J =7.5Hz, 1H), 7.39 (d, J =9.0Hz, 1H), 5.90 (p, J =6.7Hz, 1H), 1.65 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation value C-MS ₂₀ H ₁₉ N ₇ O[M+H] ⁺ =374.2, experimentally determined: 373.3.

the final product 264:1- (1H-benzo [ d ] imidazol-2-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (264, YC098)

The final product 03 (20mg, 0.062mmol), 1H-benzo [ d ]]Imidazol-2-amine (25mg, 0.186mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YC098 (28.5 mg). ¹ H NMR (MeOD-d4, 400MHz): δ 9.37 (s, 1H), 8.29 (d, J =8.5Hz, 1H), 8.07 (t, J =8.0Hz, 1H), 7.92 (d, J =7.6Hz, 1H), 7.64 (dd, J =3.2,6.0Hz, 2H), 7.47 (dd, J =3.2,6.1Hz, 2H), 5.84 (dd, J =6.9,13.3Hz, 1H), 1.62 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C-MS ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.2, experimentally determined: 363.6.

end product 265:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (pyrazolo [1,5-a ] pyridin-3-yl) urea (265, YC102)

Step one Synthesis of pyrazolo [1,5-a ] pyridin-3-amine (YC 099)

YC090 (73mg, 0.273mmol) was dissolved in 10mL ethanol and 5mL water, KOH (540mg, 8.2mmol) was added, and the mixture was stirred at reflux overnight. Evaporating ethanol, adding water, extracting with ethyl acetate, drying organic phase with anhydrous sodium sulfate, and spinning to obtain 10mg crude product. ¹ H NMR(400MHz,Methanol-d ₄ )：δ8.26(d,J＝7.1Hz,1H),7.63(s,1H),7.38(d,J＝9.0Hz,1H),6.92(dd,J＝6.6,8.9Hz,1H),6.71–6.36(m,1H).

Step two Synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (pyrazolo [1,5-a ] pyridin-3-yl) Urea (YC 102)

The final product 03 (20mg, 0.062mmol), YC099 (8.2mg, 0.06mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YC102 (22 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.44 (s, 1H), 8.45 (dt, J =1.1,7.1Hz, 1H), 8.12 (s, 1H), 8.07-7.89 (m, 2H), 7.78-7.65 (m, 1H), 7.58 (dt, J =1.2,8.9Hz, 1H), 7.21 (ddd, J =1.0,6.7,9.0Hz, 1H), 6.88 (td, J =1.4,6.9, 1H), 5.62 (hept, J =6.8Hz, 1H), 1.60 (d, J =6.7Hz, 6H). ESI-MS theoretical calculation C-MS ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.2, experimentally determined: 363.2.

final product 266:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (1H-tetrazol-5-yl) urea (266, YC106)

The final product is03 (20mg, 0.062mmol), 1H-tetrazol-5-amine (15.8mg, 0.186mmol), and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the desired compound YC106 (20.2 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.23 (s, 1H), 8.14 (d, J =8.4Hz, 1H), 8.02 (t, J =8.0Hz, 1H), 7.82 (d, J =7.5Hz, 1H), 5.57 (H, J =6.7Hz, 1H), 1.62 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C, C-MS ₁₂ H ₁₄ N ₁₀ O[M+H] ⁺ =315.2, determined experimentally: 314.9.

final product 267:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (pyrazolo [1,5-a ] pyridin-2-yl) urea (267, YC107)

The final product 03 (20mg, 0.062mmol), pyrazolo [1,5-a ] was added]Pyridin-2-amine (25mg, 0.186mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YC107 (32.6 mg). ¹ H NMR(400MHz,DMSO-d ₆ ) δ 9.01 (s, 1H), 8.46 (d, J =6.9hz, 1h), 8.02 (d, J =8.3hz, 1h), 7.96 (t, J =7.9hz, 1h), 7.71 (d, J =7.3hz, 1h), 7.57 (d, J =8.8hz, 1h), 7.19 (t, J =7.8hz, 1h), 6.85-6.74 (m, 1H), 6.70 (s, 1H), 5.40 (p, J =6.7hz, 1h), 1.51 (d, J =6.7hz, 6h), ESI-MS theoretical calculation C ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.2, experimentally determined: 362.6.

end product 268:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (quinazolin-2-yl) urea (268, YC116)

The final product 03 (20mg, 0.062mmol), 2-aminoquinazoline (26mg, 0.186mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reaction reagents. Reaction systemHeat at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the desired compound YC116 (0.6 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.51-9.30 (m, 2H), 8.40 (d, J =8.5hz, 1h), 8.06 (t, J =7.3hz, 2h), 7.98 (t, J =8.0hz, 1h), 7.85 (dd, J =8.0,13.5hz, 2h), 7.62 (t, J =7.6hz, 1h), 5.79 (q, J =6.6hz, 1h), 1.72 (d, J =6.7hz, 6h), ESI-MS theoretical calculation value C ₁₉ H ₁₈ N ₈ O[M+H] ⁺ =375.2, experimentally determined: 375.3.

final product 269:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (quinoxalin-2-yl) urea (269, YC117)

End product 03 (20mg, 0.062mmol), 2-aminoquinoxaline (26mg, 0.186mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YC117 (2.7 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.20 (s, 1H), 8.91 (s, 1H), 8.30 (d, J =8.4hz, 1h), 8.08-8.00 (m, 2H), 7.86 (t, J =6.4hz, 2h), 7.83-7.76 (m, 1H), 7.69 (ddd, J =1.5,6.8,8.3hz, 1h), 5.75 (p, J =6.8hz, 1h), 1.68 (d, J =6.7hz, 6H), ESI-MS theoretical calculation C ₁₉ H ₁₈ N ₈ O[M+H] ⁺ =375.2, experimentally determined: 375.2.

end product 270:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (isoquinolin-3-yl) urea (270, YC119)

End product 03 (20mg, 0.062mmol), 3-aminoisoquinoline (26mg, 0.182mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the desired compound YC119 (10.5 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.47 (s, 1H), 9.07 (s, 1H), 8.14 (d, J =8.4hz, 1h), 8.08-7.94 (m, 3H), 7.84 (d, J =8.4hz, 1h), 7.81-7.69 (m, 2H), 7.54 (ddd, J =1.1,6.8,8.1hz, 1h), 5.70 (p, J =6.7hz, 1h), 1.66 (d, J =6.7hz, 6H), ESI-MS theoretical calculation C ₂₀ H ₁₉ N ₇ O[M+H] ⁺ =374.2, experimentally determined: 374.7.

the final product 271:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (quinazolin-4-yl) urea (271, YC120)

End product 03 (20mg, 0.062mmol), 4-aminoquinazoline (26mg, 0.182mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the title compound YC120 (4.1 mg). ¹ H NMR(400MHz,DMSO-d ₆ ) δ 8.99 (s, 1H), 8.90-8.68 (m, 2H), 8.22 (d, J =8.3hz, 1h), 8.12-7.91 (m, 3H), 7.86 (d, J =7.6hz, 1h), 7.74 (t, J =7.6hz, 1h), 5.46 (s, 1H), 1.61 (d, J =6.7hz, 6H), ESI-MS theoretical calculation C ₁₉ H ₁₈ N ₈ O[M+H] ⁺ =375.2, determined experimentally: 375.4.

end product 272:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (isoquinolin-1-yl) urea (272, YC123)

End product 03 (20mg, 0.062mmol), 1-aminoisoquinoline (26mg, 0.182mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the objective compound YC123 (28.2 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.23 (s, 1H), 8.48 (d, J =8.6hz, 1h), 8.28-8.03 (m, 5H), 8.00-7.78 (m, 3H), 5.63-5.37 (m, 1H), 1.60 (d, J =6.7hz, 6H) ESI-MS theoretical calculation C ₂₀ H ₁₉ N ₇ O[M+H] ⁺ =374.2, experimentally determined: 374.5.

the final product 273:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (7H-pyrrolo [2,3-d ] pyrimidin-2-yl) urea (273, YC124)

The final product 03 (20mg, 0.062mmol), 2-amino-7H-pyrrolo [2,3-d ] was added]Pyrimidine (25mg, 0.186mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the title compound YC124 (18.8 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.36 (s, 1H), 8.73 (s, 1H), 8.26 (dd, J =0.8,8.4hz, 1H), 8.16-8.10 (m, 1H), 7.93 (d, J =4.2hz, 1H), 7.87 (dd, J =0.8,7.6hz, 1H), 6.79 (d, J =4.2hz, 1H), 5.50 (p, J =6.7hz, 1H), 1.62 (d, J =6.7hz, 6H) ESI-MS theoretical calculation C ₁₇ H ₁₇ N ₉ O[M+H] ⁺ =364.2, experimentally determined: 363.6.

end product 274:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (7H-purin-6-yl) urea (274, YC125)

The final product 03 (30mg, 0.093mmol), adenine (38mg, 0.28mmol) and Et ₃ N (38mg, 0.37mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the desired compound YC125 (5.5 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.46 (s, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 8.30 (d, J =8.4hz, 1H), 8.14-7.98 (m, 1H), 7.98-7.77 (m, 1H), 5.64 (p, J =6.8hz, 1H), 1.70 (d, J =6.7hz, 6H), ESI-MS theoretical calculation C ₁₆ H ₁₆ N ₁₀ O[M+H] ⁺ =365.2, experimentally determined: 364.7.

end product 275:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (7H-purin-2-yl) urea (275, YC126)

The final product 03 (20mg, 0.062mmol), 7H-purin-2-amine (25mg, 0.186mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YC126 (7.9 mg). ¹ H NMR(400MHz,DMSO-d ₆ ) δ 12.35 (s, 1H), 10.32 (s, 1H), 9.00 (s, 1H), 8.95 (s, 1H), 8.55 (s, 1H), 8.19 (d, J =8.3hz, 1h), 8.00 (t, J =8.0hz, 1h), 7.80 (d, J =7.5hz, 1h), 5.47 (p, J =6.8hz, 1h), 1.61 (d, J =6.7hz, 6h), ESI-MS theoretical calculation value C ₁₆ H ₁₆ N ₁₀ O[M+H] ⁺ =365.2, experimentally determined: 365.1.

end product 276:1- ([ 1,2,4] triazolo [1,5-a ] pyrazin-2-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -pyridin-2-yl) urea (276, YC127)

The final product 03 (30mg, 0.093mmol), [1,2,4]Triazolo [1,5-a ]]Pyrazin-2-amine (38mg, 0.28mmol) and Et ₃ N (38mg, 0.37mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the title compound YC127 (1.8 mg). ¹ H NMR(400MHz,DMSO-d ₆ ) δ 10.90 (s, 1H), 10.85 (s, 1H), 9.18 (d, J =1.4hz, 1h), 9.01 (dd, J =1.4,4.4hz, 1h), 8.98 (s, 1H), 8.30 (d, J =4.4hz, 1h), 8.15 (d, J =8.3hz, 1h), 8.02 (t, J =8.0hz, 1h), 7.80 (d, J =7.5hz, 1h), 5.40 (p, J =6.7hz, 1h), 1.60 (d, J =6.7hz, 6h), ESI-MS theoretical calculation value C-MS ₁₆ H ₁₆ N ₁₀ O[M+H] ⁺ =365.2, experimentally determined: 365.1.

the final product 277:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (pyrazolo [1,5-a ] pyrimidin-3-yl) urea (277, YC128)

The final product 03 (20mg, 0.062mmol), 3-aminopyrazolo [1,5-a ] was added]Pyrimidine (25mg, 0.186mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the objective compound YC128 (32.2 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.53 (s, 1H), 8.81 (dd, J =1.6,7.1hz, 1h), 8.50 (s, 1H), 8.43 (dd, J =1.6,4.0hz, 1h), 8.05-7.92 (m, 2H), 7.72 (dd, J =1.7,6.6hz, 1h), 6.96 (dd, J =4.0,7.1hz, 1h), 5.60 (p, J =6.7hz, 1h), 1.60 (d, J =6.7hz, 6h) ESI-MS theoretical calculation C-MS ₁₇ H ₁₇ N ₉ O[M+H] ⁺ =364.2, experimentally determined: 364.1.

end products 278 and 279:1- (1H-indazol-3-yl) -3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-3-yl) urea (278, YC135-1) and 3-amino-N- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-3-yl) -1H-indazole-1-carboxamide (279, YC135-2)

YC131 (45mg, 0.139mmol, synthetic step same as end product 03), 3-amino-1H-indazole (37mg, 0.28mmol) and Et ₃ N (38mg, 0.38mmol) was weighed into a bottle, and 2mL of DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the objective compounds YC135-1 (12.9 mg) and YC135-2 (4.9 mg). YC135-1: ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.37 (s, 1H), 8.98 (d, J =2.4hz, 1H), 8.68 (t, J =2.1hz, 1H), 8.60 (s, 1H), 7.88 (d, J =8.3hz, 1H), 7.52-7.39 (m, 2H), 7.18-7.11 (m, 1H), 4.71 (p, J =6.7hz, 1H), 1.60 (d, J =6.7hz, 6H) ESI-MS theoretical calculation C ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.2, experimentally determined: 363.8; YC135-2: ¹ H NMR(400MHz,Methanol-d ₄ ):δ9.40(s,1H),9.17(d,J＝2.4Hz,1H),8.78 (t, J =2.2hz, 1h), 8.64 (d, J =1.9hz, 1h), 8.23 (d, J =8.4hz, 1h), 7.80 (dt, J =1.0,8.0hz, 1h), 7.55 (ddd, J =1.1,7.2,8.3hz, 1h), 7.40-7.21 (m, 1H), 4.75 (p, J =6.7hz, 1h), 1.62 (d, J =6.7hz, 6h) ESI-MS theoretical calculation C ₁₈ H ₁₈ N ₈ O[M+H] ⁺ =363.2, experimentally measured: 363.7.

end products 280 and 281:1- (1H-indazol-3-yl) -3- (2- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-4-yl) urea (280, ztb-86-14 g) and 3-amino-N- (2- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-4-yl) -1H-indazole-1-carboxamide (281, ztb-86-17 g).

Intermediate ZTB-83 (110.9mg, 0.343mmol), 1H-indazol-3-amine (93.7mg, 1.029mmol) and triethylamine (112.8mg, 1.111mmol) were charged to a 50mL reaction flask and the reaction was dissolved by adding 2mL DMF. Stirred at 60 ℃ overnight. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain the objective compounds ZTB-86-14g (22.8 mg) and ZTB-86-17g (11.4 mg). ZTB-86-14g: ¹ h NMR (MeOD-d 4, 400MHz) 9.35 (s, 1H), 8.62 (d, J =5.77Hz, 1H), 8.41 (d, J =1.82Hz, 1H), 7.89 (d, J =8.28Hz, 1H), 7.81 (dd, J =5.77,1.82Hz, 1H), 7.42-7.50 (m, 2H), 7.16 (t, J =7.40Hz, 1H), 5.55-5.65 (m, 1H), 1.63 (s, 3H), 1.61 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₉ N ₈ O[M+H] ⁺ =363.2; the experiment shows that: 363.2; ZTB-86-17g: ¹ h NMR (MeOD-d 4, 400mhz): 9.27 (s, 1H), 8.61 (d, J =5.50hz, 1h), 8.50 (s, 1H), 8.23 (d, J =8.34hz, 1h), 7.94 (d, J =5.40hz, 1h), 7.79 (d, J =7.94hz, 1h), 7.54 (t, J =7.64hz, 1h), 7.30 (t, J =7.52hz, 1h), 5.54-5.64 (m, 1H), 1.61 (s, 3H), 1.60 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₉ N ₈ O[M+H] ⁺ =363.2; the experiment shows that: 363.4.

end products 282 and 283:1- (1H-indazol-3-yl) -3- (4- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (282, ZTB-96-28 g) and 3-amino-N- (4- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indazole-1-carboxamide (283, ZTB-96-32 g).

Intermediate ZTB-84 (156.2mg, 0.483mmol), 1H-indazol-3-amine (193.2mg, 1.46mmol) and triethylamine (158.9mg, 1.57mmol) were added to a 50mL reaction flask and 2mL DMF was added to dissolve the reaction. Stirring was carried out overnight at 60 ℃. After the reaction, 2.0mL of water was added and HPLC purification was performed to obtain 96-28g (21.7 mg) of the objective compound ZTB-96-32g (10.1 mg) of ZTB-A. ZTB-96-28g: ¹ h NMR (MeOD-d 4, 400MHz): 9.34 (s, 1H), 8.56 (d, J =5.22Hz, 1H), 8.12 (s, 1H), 7.91 (d, J =8.09Hz, 1H), 7.42-7.50 (m, 3H), 7.16 (t, J =7.36Hz, 1H), 4.72-4.82 (m, 1H), 1.62 (s, 3H), 1.60 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₉ N ₈ O[M+H] ⁺ =363.2; the test shows that: 363.4; ZTB-96-32g: ¹ h NMR (MeOD-d 4, 400MHz) 9.23 (s, 1H), 8.55-8.57 (m, 2H), 8.25 (d, J =8.28Hz, 1H), 7.82 (d, J =7.92Hz, 1H), 7.57 (t, J =7.65Hz, 1H), 7.47 (t, J =5.24Hz, 1H), 7.32 (t, J =7.49Hz, 1H), 4.76-4.85 (m, 1H), 1.65 (s, 3H), 1.63 (s, 3H). Theoretical calculation of ESI-MS C ₁₈ H ₁₉ N ₈ O[M+H] ⁺ =363.2; the test shows that: 363.4.

synthesis of the Compound SM6:1- (1H-indazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyrazin-2-yl) urea

The starting materials SM1 and hydrazine are refluxed in ethanol to give intermediate SM2. SM3 can be obtained by reacting SM2 with 1, 1-dimethoxy-N, N-dimethylmethylamine following the procedure for the synthesis of intermediate 02/03. The intermediate SM3 can be reacted with isopropylamine following the procedure for the synthesis of intermediate 02/03 to give intermediate SM4. According to the procedure for the synthesis of the final product 03, SM4 is reacted with phenyl chloroformate to give intermediate SM5. SM5 was reacted with 1H-indazol-3-amine according to the procedure for the synthesis of end product 43 to give the target compound SM6.

Synthesis of the Compound SM18:1- (1H-indazol-3-yl) -3- (6- (1-isopropyl-3-methyl-1H-pyrazol-5-yl) pyridin-2-yl) urea

Reaction of cyanoacetone and isopropylhydrazine in an alcohol solution at reflux can afford SM12. Bromination of SM12 can yield intermediate SM13. Suzuki coupling of SM13 with SM14 gives intermediate SM15. And (3) under the catalysis of Pd/C, reducing the nitro substituted intermediate SM15 by hydrogen to obtain SM16. Reaction of SM16 with phenol chloroformate affords intermediate SM17. According to the procedure for the synthesis of the final product 43, SM17 was reacted with 1H-indazol-3-amine to obtain the target compound SM18.

Synthesis of the Compound SM28 1- (1H-indazol-3-yl) -3- (6- (3-isopropyl-1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) urea

SM22 can be obtained by reacting SM21, methylhydrazine and triethyl orthoformate. Hydrolysis of SM22 can yield carboxylic acid SM23.SM23 was reacted with NBS to give intermediate SM24. Suzuki coupling of SM24 with SM14 gives intermediate SM25. Under the catalysis of Pd/C, hydrogen reduces the nitro substituted intermediate SM25 to obtain SM26. Reaction of SM26 with phenol chloroformate affords intermediate SM27. According to the procedure for the synthesis of the final product 43, SM27 was reacted with 1H-indazol-3-amine to obtain the target compound SM28. Synthesis of the Compound SM6:1- (1H-indazol-3-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyrazin-2-yl) urea

Synthesis of the Compound SM36:1- (4-fluoro-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (1H-indazol-3-yl) urea

The starting materials SM31 and hydrazine are refluxed in ethanol to give intermediate SM32. SM33 can be obtained by reacting SM32 with 1, 1-dimethoxy-N, N-dimethylmethylamine following the procedure for the synthesis of intermediate 02/03. SM33 was reacted with isopropylamine following the procedure for the synthesis of intermediate 02/03 to afford intermediate SM34. According to the procedure for the synthesis of end product 03, SM34 is reacted with phenyl chloroformate to give intermediate SM35. The target compound SM36 can be obtained by reacting SM35 with 1H-indazol-3-amine according to the procedure for the synthesis of final product 43.

End product 291:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (pyridin-2-yl) urea (YD 007)

The final product 03 (30mg, 0.0929mmol), 2-aminopyridine (26mg, 0.28mmol) and Et ₃ N (38mg, 0.37mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction was purified directly by reverse phase HPLC to give the desired compound YD007 (22.9 mg). ¹ H NMR (MeOD-d 4, 400MHz): delta 9.48 (s, 1H), 8.31 (dd, J =1.7,6.3Hz, 1H), 8.27-8.22 (m, 1H), 8.22-8.14 (m, 1H), 8.02 (dd, J =7.6,8.4Hz, 1H), 7.88 (dd, J =0.8,7.6Hz, 1H), 7.53 (d, J =8.6Hz, 1H), 7.42-7.30 (m, 1H), 5.88 (p, J =6.7Hz, 1H), 1.63 (d, J =6.1Hz, 6H), 7ESI-MS theoretical calculated values C ₁₆ H ₁₈ N ₇ O[M+H] ⁺ =324.15, determined experimentally: 324.68.

end products 303 and 304:1- (1H-indazol-3-yl) -3- (6- (3-isopropyl-3H-pyrazol-4-yl) pyridin-2-yl) urea (YD 016-1, 303) and 3-amino-N- (5- (3-isopropyl-3H-pyrazol-4-yl) pyridin-3-yl) -1H-indazole-1-carboxamide (YD 016-2, 304)

The method comprises the following steps: synthesis of benzyl (6-bromopyridin-2-yl) carbamate (YC 149)

6-bromo-2-aminopyridine (2g, 11.5 mmol) and sodium carbonate (3.7 g,34.5 mmol) were charged in a reaction flask, dissolved in 1, 4-dioxane (50 mL), cbz-Cl (3.95g, 23.1 mmol) was added, and the mixture was stirred at room temperature overnight. Add a100mL of water was extracted with ethyl acetate 3 times, and the organic phase was dried over anhydrous sodium sulfate and then purified by normal phase silica gel column to obtain YC149 (2.74 g, 77% yield). ¹ H NMR(400MHz,Chloroform-d):δ7.93(d,J＝8.2Hz,1H),7.53(t,J＝8.0Hz,1H),7.41–7.31(m,5H),7.16(dd,J＝0.7,7.7Hz,1H),5.22(s,2H).

Step two: synthesis of 3-isopropyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (YC 157)

Ethyl 4-methyl-3-oxopentanoate (2g, 12.66mmol) and triethyl orthoformate (3.15g, 25.32mmol) were added to a round bottom flask, 6mL of acetic anhydride was added, and the mixture was refluxed overnight. Acetic anhydride was spin dried, dissolved in methanol, and methylhydrazine sulfate (3.65g, 25.32mmol) was added and refluxed for 6h. Cooling to room temperature, vacuum evaporating methanol, dissolving with ethyl acetate, washing the organic phase with water, washing with saturated salt water, drying with anhydrous sodium sulfate, and purifying the organic phase with normal phase silica gel column to obtain YC157. ¹ H NMR(400MHz,Chloroform-d):δ7.80(s,1H),4.26(q,J＝7.1Hz,2H),3.88(s,3H),3.71(p,J＝7.3Hz,1H),1.41–1.31(m,9H).

Step three: synthesis of 3-isopropyl-1-methyl-1H-pyrazole-4-carboxylic acid (YC 160)

YC157 (1.96g, 10mmol) and NaOH (1.6g, 40mmol) were added to a reaction flask, dissolved in ethanol (10 mL) and water (5 mL), and refluxed overnight. Cooling to room temperature, spin-drying the organic solvent, adding water, adjusting pH with 2N hydrochloric acid until solid is precipitated, and filtering to obtain 1.58g of crude YC 160. ¹ H NMR(400MHz,Methanol-d4):δ7.77(s,1H),3.89(s,3H),3.72(p,J＝7.2Hz,1H),1.39(d,J＝7.2Hz,6H).

Step four: synthesis of 3-isopropyl-4-bromo-1-methyl-1H-pyrazole (YD 003)

NBS (1.7g, 9.4mmol) and NaHCO ₃ (2.4g, 28.2mmol) was charged into a reaction flask containing YC160 (1.58g, 9.4mmol), dissolved in 20mL of DMF, and stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and purified with a normal phase silica gel column to obtain YD003 (1.58 g) after spin-drying. ¹ H NMR(400MHz,Chloroform-d)δ7.33(s,1H),3.85(s,3H),3.19(hept,J＝7.2Hz,1H),1.36(d,J＝7.1Hz,6H).

Step five: synthesis of 3-isopropyl-1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (YD 004)

YD003 (1.58g, 7.78mmol) and 2-isopropoxy-4, 5-tetramethyl-1, 3, 2-dioxaborolane (2.17g, 11.67mmol) were added to the reaction flask, dissolved in THF, protected with nitrogen, cooled to-78 deg.C, 1.6M butyllithium (10 mL) was added, and after stirring for one hour, the temperature was raised to-40 deg.C and stirred for 2h. Saturated aqueous ammonium chloride was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and purified with a normal phase silica gel column to obtain YD004 (578 mg).

Step six: synthesis of N-benzyl-6- (3-isopropyl-1-methyl-1H-pyrazol-4-yl) pyridin-2-amine (YD 008)

YD004 (570mg, 2.28mmol) and YC149 (1.4g, 4.56mmol) were weighed into a bottle, and 1, 2-dimethoxyethane (20 mL) and 2M Na were added ₂ CO ₃ Aqueous solution (9 mL). After the reaction system is deoxygenated, pd (dppf) Cl is added ₂ -CH ₂ Cl ₂ (93mg, 0.114mmol). The reaction was heated at 95 ℃ overnight, diluted with water and extracted with ethyl acetate, dried, concentrated and purified with silica gel column to give 398mg of the title compound. ¹ H NMR(400MHz,Chloroform-d):δ7.80(d,J＝8.2Hz,1H),7.66(t,J＝7.9Hz,1H),7.61(s,1H),7.49–7.32(m,5H),7.09(dd,J＝0.9,7.6Hz,1H),5.24(s,2H),3.93(s,3H),3.74(p,J＝7.2Hz,1H),1.35(d,J＝7.2Hz,6H).

Step seven: synthesis of 6- (3-isopropyl-1-methyl-1H-pyrazol-4-yl) pyridin-2-amine (YD 011)

YD008 (398 mg) was dissolved in dry THF, and after evacuation, nitrogen gas was introduced, 10% Pd/C (40 mg) was added, followed by evacuation again, hydrogen gas was introduced, stirring was carried out overnight at room temperature, filtration and spin-drying were carried out, and normal phase silica gel column purification was carried out to obtain YD011 (223 mg, yield 90%). 1H NMR (400MHz, chloroform-d): δ 7.59 (s, 1H), 7.42 (t, J =7.8hz, 1h), 6.74 (dd, J =0.8,7.5hz, 1h), 6.36 (dd, J =0.8,8.1hz, 1h), 3.92 (s, 3H), 3.69 (p, J =7.2hz, 1h), 1.36 (d, J =7.2hz, 6H).

Step eight: synthesis of phenyl (6- (3-isopropyl-1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) carbamate (YD 014)

YD014 can be synthesized by taking YD011 as a reaction raw material and referring to a method for synthesizing an end product 03. ¹ H NMR(400MHz,Chloroform-d):δ7.81(d,J＝8.2Hz,1H),7.69(t,J＝7.9Hz,1H),7.65(s,1H),7.47–7.36(m,2H),7.30–7.18(m,3H),7.14(dd,J＝0.9,7.6Hz,1H),3.95(s,3H),3.77(p,J＝7.2Hz,1H),1.40(d,J＝7.2Hz,6H).

Step nine Synthesis of 1- (1H-indazol-3-yl) -3- (6- (3-isopropyl-3H-pyrazol-4-yl) pyridin-2-yl) Urea (YD 016-1) and 3-amino-N- (5- (3-isopropyl-3H-pyrazol-4-yl) pyridin-3-yl) -1H-indazole-1-carboxamide (YD 016-2)

YD014 (30mg, 0.089mmol), 3-amino-1H indazole (36mg, 0.27mmol) and Et ₃ N (36mg, 0.36mmol) is weighed into a bottle, and DMF is added to dissolve the reaction reagent. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to obtain the target compound YD016-1 (8.5 mg). ¹ H NMR (400MHz, methanol-d 4): delta 8.05 (t, J =8.1Hz, 1H), 7.81 (d, J =8.3Hz, 1H), 7.76 (s, 1H), 7.58-7.39 (m, 3H), 7.32 (d, J =7.7Hz, 1H), 7.20-7.09 (m, 1H), 3.97 (s, 3H), 3.63 (H, J =7.3Hz, 1H), 1.39 (d, J =7.2Hz, 6H), ESI-MS theoretical calculation C ₂₀ H ₂₂ N ₇ O[M+H] ⁺ =376.18, experimentally determined: 376.61; YD016-2 (1.4 mg). ¹ H NMR (400MHz, methanol-d 4) delta 8.24 (dt, J =0.9,8.4Hz, 1H), 8.08-7.98 (m, 2H), 7.82 (dt, J =1.0,8.0Hz, 1H), 7.75 (s, 1H), 7.58 (ddd, J =1.1,7.1,8.4Hz, 1H), 7.38-7.29 (m, 2H), 3.98 (s, 3H), 3.68 (p, J =7.2Hz, 1H), 1.44 (d, J =7.2Hz, 6H), ESI-MS theoretical C ₂₀ H ₂₂ N ₇ O[M+H] ⁺ =376.18, experimentally determined: 376.35.

end products 305 and 306:1- (1H-indazol-3-yl) -3- (6- (pyrazolo [1,5-a ] pyridin-3-yl) pyridin-2-yl) urea (YD 017-1, 305) and 3-amino-N- (5- (pyrazolo [1,5-a ] pyridin-3-yl) -1H-indazole-1-carboxamide (YD 017-2, 306)

The method comprises the following steps: synthesis of 3-bromopyrazolo [1,5-a ] pyridine (YD 002)

YC087 is used as a raw material, and YD002 can be synthesized by referring to the synthesis method of YD 003. ¹ H NMR(400MHz,Chloroform-d):δ8.43(dt,J＝1.1,7.0Hz,1H),7.93(s,1H),7.52(dt,J＝1.2,8.9Hz,1H),7.20(ddd,J＝1.0,6.7,8.9Hz,1H),6.80(td,J＝1.4,6.9Hz,1H).

Step two: synthesis of 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridine (YD 005)

By taking YD002 as a raw material, YD005 can be synthesized by referring to a synthesis method of YD 004.

Step three: synthesis of benzyl (6- (pyrazolo [1,5-a ] pyridin-3-yl) pyridin-2-yl) carbamate (YD 010)

By taking YD005 as a raw material, YD010 can be synthesized by referring to a synthesis method of YD 008. ¹ H NMR(400MHz,Chloroform-d):δ8.49(dt,J＝1.1,7.0Hz,1H),8.44(dt,J＝1.2,9.1Hz,1H),8.36(s,1H),7.77(d,J＝8.2Hz,1H),7.70(t,J＝7.9Hz,1H),7.48–7.32(m,6H),7.29–7.23(m,1H),6.84(td,J＝1.4,6.8Hz,1H),5.25(s,2H).

Step four: synthesis of 6- (pyrazolo [1,5-a ] pyridin-3-yl) pyridin-2-amine (YD 013)

YD010 (480mg, 1.4mmol) and KOH (2.76g, 42mmol) were added to a reaction flask, dissolved in 10mL of ethanol and 5mL of water, and refluxed overnight. Removing ethanol by rotary evaporator, adding water, extracting with ethyl acetate for 3 times, drying the organic phase with anhydrous sodium sulfate, spin-drying, and purifying with normal phase silica gel column to obtain YD013 (263mg, 90%). ¹ H NMR(400MHz,Chloroform-d):δ8.52–8.42(m,2H),8.34(s,1H),7.46(t,J＝7.8Hz,1H),7.23(ddd,J＝1.0,6.7,9.0Hz,1H),7.03(dd,J＝0.8,7.6Hz,1H),6.81(td,J＝1.3,6.9Hz,1H),6.34(dd,J＝0.7,8.1Hz,1H).

Step five: synthesis of phenyl (6- (pyrazolo [1,5-a ] pyridin-3-yl) pyridin-2-yl) carbamate (YD 015)

By taking YD013 as a reaction raw material, YD015 can be synthesized by referring to a method for synthesizing a final product 03. ¹ H NMR(400MHz,Chloroform-d):δ8.57–8.45(m,2H),8.40(s,1H),7.81–7.70(m,2H),7.47–7.37(m,3H),7.35–7.20(m,4H),6.88(td,J＝1.5,6.8Hz,1H).

Step six: synthesis of 1- (1H-indazol-3-yl) -3- (6- (pyrazolo [1,5-a ] pyridin-3-yl) pyridin-2-yl) urea (YD 017-1) and 3-amino-N- (5- (pyrazolo [1,5-a ] pyridin-3-yl) -1H-indazole-1-carboxamide (YD 017-2)

YD015 (30mg, 0.089mmol) and 3-amino-1H indazole (36)mg,0.27 mmol) and Et ₃ N (36mg, 0.36mmol) is weighed into a bottle, and DMF is added to dissolve the reaction reagent. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to obtain the target compound YD017-1 (12.4 mg). ¹ H NMR (400MHz, DMSO-d 6): delta 12.67 (s, 1H), 10.53-10.13 (m, 2H), 8.79 (d, J =7.0Hz, 1H), 8.69 (s, 1H), 8.58 (d, J =8.9Hz, 1H), 8.04 (d, J =8.2Hz, 1H), 7.79 (t, J =7.9Hz, 1H), 7.67 (d, J =8.1Hz, 1H), 7.55 (d, J =7.6Hz, 1H), 7.46 (t, J =8.2Hz, 2H), 7.38 (t, J =7.6Hz, 1H), 7.07 (dt, J =7.2,13.0Hz, 2H), ESI-MS theoretical calculation C ₂₀ H ₁₆ N ₇ O[M+H] ⁺ =370.14, determined experimentally: 369.72; YD017-2 (2.6 mg). ¹ H NMR (400MHz, methanol-d 4): delta 8.63 (dt, J =1.1,7.0Hz, 1H), 8.59-8.50 (m, 2H), 8.29-8.18 (m, 1H), 7.98-7.88 (m, 2H), 7.81 (dt, J =1.0,8.1Hz, 1H), 7.64-7.53 (m, 2H), 7.49 (ddd, J =1.1,6.8,9.0Hz, 1H), 7.31 (ddd, J =0.9,7.2,8.0Hz, 1H), 7.05 (td, J =1.4,6.9Hz, 1H), ESI-MS theoretical calculation value C-MS ₂₀ H ₁₆ N ₇ O[M+H]+ 370.14, experimentally determined: 369.69.

end products 307 and 308:1- (1H-indazol-3-yl) -3- (6- (4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyridin-2-yl) urea (YD 021-1, 307) and 3-amino-N- (5- (4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) -1H-indazole-1-carboxamide (YD 021-2, 308)

The method comprises the following steps: synthesis of 6- (4, 5,6, 7-Tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyridin-2-amine (YD 012)

YD010 (480mg, 1.39mmol) was dissolved in THF, the air was replaced with nitrogen 2 times, pd/C (48 mg) was added, the air was replaced with nitrogen 2 times, vacuum was again applied, hydrogen was replaced, a hydrogen balloon was inserted, and the mixture was left overnight at room temperature. Filtering to obtain crude 92mg. ¹ H NMR(400MHz,Chloroform-d)：δ7.84(s,1H),7.39(t,J＝7.8Hz,1H),6.77(dd,J＝0.7,7.6Hz,1H),6.28(dd,J＝0.8,8.1Hz,1H),4.17(t,J＝6.1Hz,2H),3.12(t,J＝6.4Hz,2H),2.03(td,J＝4.6,7.3,8.4Hz,2H),1.93–1.77(m,2H).

Step two: synthesis of phenyl (6- (4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyridin-2-yl) carbamate (YD 019)

YD019 can be synthesized by taking YD012 as a raw material and referring to a synthesis method of a final product 03. ¹ H NMR(400MHz,Chloroform-d)，δ7.90(s,1H),7.73(d,J＝8.2Hz,1H),7.67(t,J＝7.9Hz,1H),7.56(s,1H),7.46–7.38(m,2H),7.23–7.15(m,3H),4.21(t,J＝6.1Hz,2H),3.18(t,J＝6.4Hz,2H),2.08(ddd,J＝5.0,9.5,12.4Hz,2H),1.94(p,J＝6.2Hz,2H).

Step three: synthesis of 1- (1H-indazol-3-yl) -3- (6- (4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyridin-2-yl) urea (YD 021-1) and 3-amino-N- (5- (4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) -1H-indazole-1-carboxamide (YD 021-2)

YD019 (30mg, 0.089mmol), 3-amino-1H indazole (36mg, 0.27mmol) and Et ₃ N (36mg, 0.36mmol) is weighed into a bottle, and DMF is added to dissolve the reaction reagent. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to obtain the target compound YD021-1 (4 mg). ¹ H NMR(400MHz,DMSO-d ₆ ) δ 8.02 (s, 1H), 7.93 (t, J =8.0hz, 1h), 7.88 (d, J =8.3hz, 1h), 7.48 (d, J =8.5hz, 1h), 7.46-7.39 (m, 1H), 7.37 (d, J =7.8hz, 1h), 7.24 (s, 1H), 7.18-7.10 (m, 1H), 4.19 (t, J =6.1hz, 2h), 3.18 (t, J =6.4hz, 2h), 2.14-2.03 (m, 2H), 1.97-1.80 (m, 2H), ESI-MS theoretical calculation value C-MS ₂₀ H ₂₀ N ₇ O[M+H] ⁺ =374.17, experimentally determined: 374.21; YD021-2 (2.2 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.24 (dt, J =0.9,8.4hz, 1h), 8.07-7.97 (m, 2H), 7.89-7.78 (m, 2H), 7.58 (ddd, J =1.1,7.1,8.3hz, 1h), 7.43 (dd, J =0.9,7.8hz, 1h), 7.33 (ddd, J =0.9,7.2,8.0hz, 1h), 4.21 (t, J =6.1hz, 2h), 3.21 (t, J =6.4hz, 2h), 2.13 (td, J =4.5,7.0,8.2hz, 2h), 2.05-1.88 (m, 2H), ESI-MS theoretical calculation value C ₂₀ H ₂₀ N ₇ O[M+H] ⁺ =374.17, experimentally determined: 374.21.

end product 309:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (5- (1-methyl-1H-pyrazol-4-yl) pyrazin-2-yl) urea (YD 023)

YD020 (49mg, 0.28mmol, synthesis method referenced to that of YC 046), final product 03 (30mg, 0.0929mmol) and Et ₃ N (38mg, 0.37mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the desired compound YD023 (7.9 mg). ¹ H NMR (400MHz, methanol-d 4): delta 9.47 (s, 1H), 8.94 (s, 1H), 8.50 (d, J =1.5Hz, 1H), 8.18-8.07 (m, 2H), 8.04-7.93 (m, 2H), 7.78 (d, J =7.5Hz, 1H), 5.63 (p, J =6.7Hz, 1H), 3.94 (s, 3H), 1.67 (d, J =6.7Hz, 6H), ESI-MS theoretical calculation C ₁₉ H ₂₁ N ₁₀ O[M+H] ⁺ =405.19, determined experimentally: 404.75.

the final product 310:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (quinolin-4-yl) urea (YD 024)

4-aminoquinoline (27mg, 0.19mmol), final product 03 (20mg, 0.062mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD024 (14.2 mg). ¹ H NMR (400MHz, methanol-d 4): delta 9.03-8.96 (m, 2H), 8.92 (d, J =6.8Hz, 1H), 8.36 (d, J =8.7Hz, 1H), 8.16-8.10 (m, 2H), 8.07 (dd, J =7.4,8.4Hz, 1H), 8.02 (s, 1H), 7.87-7.80 (m, 1H), 7.77 (d, J =7.5Hz, 1H), 5.32 (s, 1H), 1.55 (d, J =6.7Hz, 6H) ESI-MS theoretical calculation C ₂₀ H ₂₀ N ₇ O[M+H] ⁺ =374.17, experimentally determined: 374.69. the final product 311:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (isoquinolin-4-yl) urea (YD 028)

4-aminoisoquinoline (27mg, 0.19mmol), final product 03 (20mg, 0.062mmol) and Et ₃ N(25mg, 0.25mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD028 (24.4 mg). ¹ H NMR (400MHz, methanol-d 4): delta 9.45 (d, J =24.3Hz, 2H), 9.11 (s, 1H), 8.49 (d, J =8.2Hz, 1H), 8.34 (d, J =8.6Hz, 1H), 8.15 (ddd, J =1.3,7.0,8.5Hz, 1H), 8.09-7.99 (m, 2H), 7.94 (d, J =8.4Hz, 1H), 7.71 (d, J =7.5Hz, 1H), 5.33 (p, J =6.7Hz, 1H), 1.55 (d, J =6.7Hz, 6H), theoretical calculation of ESI-MS C ₂₀ H ₂₀ N ₇ O[M+H] ⁺ =374.17, experimentally determined: 374.29.

end product 312:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (pyridin-3-yl) urea (YD 030)

3-aminopyridine (18mg, 0.19mmol), final product 03 (20mg, 0.062mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD030 (18.9 mg). ¹ H NMR (400MHz, methanol-d 4): delta 9.36 (d, J =2.4Hz, 1H), 9.15 (s, 1H), 8.57-8.33 (m, 2H), 8.14-8.06 (m, 1H), 8.05-7.93 (m, 2H), 7.78 (dd, J =0.9,7.5Hz, 1H), 5.60 (p, J =6.7Hz, 1H), 1.61 (d, J =6.7Hz, 6H) ESI-MS theoretical calculation C ₁₆ H ₁₈ N ₇ O[M+H] ⁺ =324.15, determined experimentally: 324.29.

end product 313:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (pyridin-4-yl) urea (YD 032)

4-aminopyridine (18mg, 0.19mmol), final product 03 (20mg, 0.062mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product is directly purified by reverse phase HPLC to obtain the target compound YD032 (8.4 mg)。 ¹ H NMR (400MHz, methanol-d 4): delta 9.15 (s, 1H), 8.56 (d, J =7.2Hz, 2H), 8.20-8.09 (m, 3H), 8.02 (dd, J =7.6,8.4Hz, 1H), 7.84 (dd, J =0.8,7.6Hz, 1H), 5.68 (hept, J =6.7Hz, 1H), 1.60 (d, J =6.7Hz, 6H). ESI-MS theoretical calculation C-MS ₁₆ H ₁₈ N ₇ O[M+H] ⁺ =324.15, experimentally determined: 324.55.

the final product 314:1- (1H-indazol-3-yl) -3- (6- (pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) urea (YD 036)

The method comprises the following steps: synthesis of 6- (pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-amine (YD 031)

By taking YD027 as a raw material and hydrogenation of Pd/C and hydrogen, YD031 (23mg, 74%) can be synthesized by referring to a synthesis method of YD 013.

Step two: synthesis of phenyl (6- (pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) carbamate (YD 035)

YD035 (20mg, 56%) was synthesized by using YD031 as the starting material, with reference to the synthesis of end product 03.

Step three: synthesis of 1- (1H-indazol-3-yl) -3- (6- (pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) urea (YD 036)

YD035 (20mg, 0.06mmol), 3-amino-1H indazole (24mg, 0.18mmol) and Et ₃ N (24mg, 0.24mmol) was weighed into a bottle, and DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD036 (14.5 mg). ¹ H NMR(400MHz,DMSO-d ₆ ) δ 9.22 (dd, J =1.7,7.0hz, 1h), 8.91 (s, 1H), 8.47 (s, 1H), 7.95 (t, J =8.0hz, 2h), 7.84 (t, J =7.9hz, 1h), 7.48 (d, J =8.4hz, 1h), 7.40-7.33 (m, 1H), 7.14 (dd, J =4.1,7.0hz, 2h), 7.07 (dd, J =6.8,8.2hz, 1h) ESI-MS theoretical C calculated value ₁₉ H ₁₅ N ₈ O[M+H] ⁺ =371.13, experimentally determined: 371.24 end product 315:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (5- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrazin-2-yl) urea (YD 041)

YD022 (58mg, 0.28mmol, synthesis method referenced to that of YC 046), final product 03 (30mg, 0.0929mmol) and Et ₃ N (56mg, 0.558 mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product is directly purified by reverse phase HPLC, the purified product is dissolved in trifluoroacetic acid/dichloromethane (1 mL/3 mL), stirred overnight at room temperature, dried by spinning, added with 3mL of water and 2mL of methanol, and purified by reverse phase HPLC to obtain the target compound YD041 (2.1 mg). ¹ H NMR (400MHz, methanol-d 4): 9.13-9.01 (m, 1H), 8.91 (s, 1H), 8.49 (d, J =1.5Hz, 1H), 8.06 (d, J =8.4Hz, 1H), 7.98 (dd, J =7.5,8.5Hz, 1H), 7.74 (dd, J =1.0,7.5Hz, 1H), 6.79-6.55 (m, 1H), 5.48 (p, J =6.7Hz, 1H), 3.92 (d, J =3.2Hz, 2H), 3.50 (t, J =6.2Hz, 2H), 2.89 (d, J =22.6Hz, 2H), 1.60 (d, J =6.6Hz,6 Hz), 7H), calculated value of ESI-MS theoretical C ₂₀ H ₂₄ N ₉ O[M+H] ⁺ =406.21, determined experimentally: 406.62.

the final product 316: (R) -1- (6- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -3- (isoquinolin-1-yl) urea (YD 043)

The method comprises the following steps: synthesis of phenyl (R) - (6- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) carbamate (YD 040)

The synthesis of YD040 is described in relation to the synthesis of end product 03. ¹ H NMR(400MHz,Methanol-d ₄ ):δ8.81(s,1H),8.04–7.89(m,2H),7.83(dd,J＝1.3,7.2Hz,1H),7.54–7.38(m,2H),7.33–7.11(m,3H),5.78(dt,J＝5.4,7.4Hz,1H),3.86–3.74(m,2H),1.57(d,J＝7.0Hz,3H).

Step two: synthesis of (R) -1- (6- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -3- (isoquinolin-1-yl) urea (YD 043)

1-aminoisoquinoline (45.4mg, 0.315mmol), YD040 (35.6mg, 0.105mmol) and Et ₃ N(43mg,0.42 mmol) was weighed into a bottle and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the title compound YD043 (12.4 mg). ¹ H NMR (400MHz, methanol-d 4) 9.12 (s, 1H), 8.42 (d, J =8.5Hz, 1H), 8.18-8.05 (m, 4H), 7.95 (d, J =10.9Hz, 1H), 7.90-7.80 (m, 3H), 5.30 (s, 1H), 3.96-3.61 (m, 2H), 1.59 (d, J =7.0Hz, 3H), ESI-MS theoretical calculation C ₂₀ H ₂₀ N ₇ O ₂ [M+H] ⁺ =390.16, experimentally determined: 390.06.

final product 317:1- (6-bromo-pyrazolo [1,5-a ] pyridin-2-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (YD 044)

Reacting 6-bromo-pyrazolo [1,5-a ]]Pyridin-2-amine (25mg, 0.12mmol), end product 03 (20mg, 0.062mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD044 (20.8 mg). ¹ H NMR (400MHz, methanol-d 4): 9.75 (s, 1H), 8.57 (s, 1H), 8.13 (d, J =8.6Hz, 1H), 8.03 (t, J =8.0Hz, 1H), 7.79 (d, J =7.5Hz, 1H), 7.48 (d, J =9.3Hz, 1H), 7.29 (dd, J =1.6,9.5Hz, 1H), 6.76 (s, 1H), 5.68 (p, J =6.7Hz, 1H), 1.68 (d, J =6.7Hz, 6H): ESI-MS calculated value of theoretical C.s, 1H, 1.68 (d, J =6.7Hz, 6H) ₁₈ H ₁₈ ⁷⁹ BrN ₈ O[M+H] ⁺ =442.07, experimentally determined: 442.30.

end product 318:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-2-yl) urea (YD 054)

The method comprises the following steps: synthesis of 6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-2-amine (YD 050)

Synthesis method of YD050 reference to Synthesis method of YD008 (Suzuk)i coupling). ¹ H NMR(400MHz,Methanol-d ₄ ):δ8.31(s,1H),7.83(s,1H),7.74(s,1H),7.28–7.10(m,2H).

Step two: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-2-yl) urea (YD 054)

YD050 (48.8mg, 0.229mmol), final product 03 (20mg, 0.062mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD054 (23 mg). ¹ H NMR(400MHz,DMSO-d ₆ ): δ 10.03 (s, 1H), 9.57 (s, 1H), 9.06 (s, 1H), 8.78 (s, 1H), 8.20 (s, 1H), 8.11-7.88 (m, 3H), 7.71 (d, J =7.4hz, 1h), 7.59 (d, J =9.1hz, 1h), 7.45 (d, J =9.1hz, 1h), 6.71 (s, 1H), 5.41 (p, J =6.8hz, 1h), 3.87 (s, 3H), 1.52 (d, J =6.7hz, 6h), ESI-MS calculated value of theoretical C ₂₂ H ₂₃ N ₁₀ O[M+H] ⁺ =443.20, experimentally determined: 443.42.

end product 319:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1-yl) urea (YD 055)

The method comprises the following steps: synthesis of 4- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1-amine (YD 051)

The synthesis method of YD051 refers to the synthesis method of YD008 (Suzuki coupling), and YD051 (38mg, 68%) is obtained. ¹ H NMR(400MHz,Methanol-d ₄ )：δ8.17(d,J＝8.2Hz,1H),7.92(d,J＝8.4Hz,1H),7.78(s,1H),7.74–7.65(m,2H),7.62(s,1H),7.59–7.50(m,1H),3.97(s,3H).

Step two: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (1-methyl-1H-pyrazol-4-yl) isoquinolin-1-yl) urea (YD 055)

YD051 (38mg, 0.17mmol), final product 03 (30mg, 0.0929mmol) and Et ₃ N (38mg, 0.38mmol) was weighed into a bottle, and DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. Inverse directionThe crude product was purified directly by reverse phase HPLC to give the title compound YD055 (18.3 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.27 (s, 1H), 8.53 (d, J =8.5hz, 1h), 8.32 (d, J =8.4hz, 1h), 8.22-8.05 (m, 4H), 8.03 (s, 1H), 7.92 (t, J =7.8hz, 1h), 7.88-7.83 (m, 1H), 7.82 (s, 1H), 5.48 (s, 1H), 4.05 (s, 3H), 1.61 (d, J =6.7hz, 6H) ESI-MS theoretical calculation C ₂₄ H ₂₄ N ₉ O[M+H] ⁺ =454.21, experimentally determined: 454.61.

the final product 320: (R) -1- (6- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -3- (pyrazolo [1,5-a ] pyridin-2-yl) urea (YD 057)

2-amino pyrazolo [1, 5-a)]Pyridine (24mg, 0.18mmol), YD040 (30mg, 0.088mmol), and Et ₃ N (36mg, 0.35mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD057 (30.2 mg). ¹ H NMR(400MHz,Methanol-d ₄ ): δ 9.55 (s, 1H), 8.35 (dt, J =1.1,7.0hz, 1h), 8.13-7.89 (m, 2H), 7.76 (dd, J =1.1,7.3hz, 1h), 7.49 (dt, J =1.2,9.0hz, 1h), 7.18 (ddd, J =1.1,6.8,8.9hz, 1h), 6.78 (td, J =1.3,6.9hz, 1h), 5.63 (dq, J =6.7,10.7hz, 1h), 3.97 (dd, J =3.9,12.0hz, 1h), 3.87 (dd, J =5.8,11.9hz, 1h), 1.66 (d, J =6.9hz, ESI-MS theoretical calculated value C-C) ₁₈ H ₁₉ N ₈ O ₂ [M+H] ⁺ =379.16, experimentally determined: 378.64.

the final product 321: (R) -1- (6- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -3- (pyrazolo [1,5-a ] pyridin-2-yl) urea (YD 058)

2-aminoquinoline (26mg, 0.18mmol), YD040 (30mg, 0.088mmol) and Et ₃ N (36mg, 0.35mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. Reaction system 50Heating at deg.C overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD058 (2.2 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.31 (s, 1H), 8.41 (d, J =8.9hz, 1h), 8.28 (d, J =8.4hz, 1h), 8.04 (dd, J =7.6,8.5hz, 1h), 8.00-7.91 (m, 2H), 7.88 (d, J =7.6hz, 1h), 7.85-7.78 (m, 1H), 7.57 (t, J =7.6hz, 1h), 7.35 (d, J =8.9hz, 1h), 5.82 (dd, J =6.0,11.0hz, 1h), 3.96 (dd, J =3.9,11.9hz, 1h), 3.87 (dd, J =5.9,11.9hz, 1h), 1.69 (d, J =6.9hz, ESI), theoretical calculated values of C-1h), 1.69 (d, J = 6.3h), and ESI ₂₀ H ₂₀ N ₇ O ₂ [M+H] ⁺ =390.16, determined experimentally: 389.68.

the final product 322: (R) -1- (2- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyrimidin-4-yl) -3- (quinazolin-2-yl) urea (YD 059)

2-aminoquinazoline (38mg, 0.26mmol), YD040 (30mg, 0.088mmol) and Et ₃ N (36mg, 0.35mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD059 (0.6 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.41 (s, 1H), 9.22 (s, 1H), 8.36 (d, J =8.4hz, 1h), 8.09-7.94 (m, 3H), 7.91 (d, J =8.5hz, 1h), 7.86 (dd, J =0.9,7.6hz, 1h), 7.61 (ddd, J =1.2,6.8,8.0hz, 1h), 5.74 (q, J =6.4hz, 1h), 4.01 (dd, J =4.1,11.8hz, 1h), 3.91 (dd, J =6.0,11.8hz, 1h), 1.71 (d, J =7.0hz, 3h), ESI-MS theoretically calculated value C-MS ₁₉ H ₁₉ N ₈ O ₂ [M+H] ⁺ =391.16, determined experimentally: 391.02.

the final product 323: (R) -1- (6- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -3- (quinoxalin-2-yl) urea (YD 060)

2-aminoquinoxaline (26mg, 0.18mmol), YD040 (30mg, 0.088mmol) and Et ₃ N (36mg, 0.35mmol) is calledThe mixture is bottled and DMF is added to dissolve the reaction reagent. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to obtain the target compound YD060 (3.1 mg). ¹ H NMR(400MHz,DMSO-d ₆ ) δ 11.29 (s, 1H), 10.72 (s, 1H), 9.10 (s, 1H), 8.85 (s, 1H), 8.16 (d, J =8.3hz, 1h), 8.08-7.97 (m, 2H), 7.90-7.79 (m, 3H), 7.73-7.65 (m, 1H), 5.53 (q, J =6.2hz, 1h), 3.81-3.64 (m, 2H), 1.55 (d, J =6.9hz, 3h), ESI-MS theoretical calculation value C ₁₉ H ₁₉ N ₈ O ₂ [M+H] ⁺ =391.16, determined experimentally: 391.76.

the final product 324: (R) -1- (6- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -3- (1-methyl-1H-indazol-3-yl) urea (YD 062)

1-methyl-3-amino-1H-indazole (22mg, 0.15mmol), YD040 (25mg, 0.074mmol) and Et ₃ N (30mg, 0.296 mmol) was weighed into a bottle, and DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YD062 (7.1 mg). Theoretical calculation of ESI-MS C ₁₉ H ₂₁ N ₈ O ₂ [M+H] ⁺ =393.17, determined experimentally: 392.81.

the final product 325:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (6- (prop-1-en-2-yl) pyrazolo [1,5-a ] pyridin-2-yl) urea (YD 063)

The method comprises the following steps: synthesis of 2-amino-6- (prop-1-en-2-yl) pyrazolo [1,5-a ] pyridine (YD 052)

The synthesis method of YD052 refers to the synthesis method of YD008 (Suzuki coupling), and YD052 (22mg, 43%) is obtained. ¹ H NMR(400MHz,Chloroform-d)：δ8.21(d,J＝1.6Hz,1H),7.26–7.21(m,1H),7.15(d,J＝9.3Hz,1H),5.72(s,1H),5.36(s,1H),5.05(t,J＝1.5Hz,1H),2.11(d,J＝1.3Hz,3H).

Step two: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (6- (prop-1-en-2-yl) pyrazolo [1,5-a ] pyridin-2-yl) urea (YD 063)

YD052 (22mg, 0.127mmol), final 03 (20mg, 0.062mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD063 (3.4 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.22 (s, 1H), 8.37 (s, 1H), 8.08 (d, J =8.5hz, 1h), 7.99 (t, J =7.9hz, 1h), 7.75 (d, J =7.5hz, 1h), 7.56-7.34 (m, 2H), 5.64-5.40 (m, 2H), 5.17 (s, 1H), 2.18 (s, 3H), 1.65 (d, J =6.7hz, 6h), ESI-MS theoretical calculation C ₂₁ H ₂₃ N ₈ O[M+H] ⁺ =403.20, determined experimentally: 403.22.

the final product 326:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (prop-1-en-2-yl) isoquinolin-1-yl) urea (YD 064)

The method comprises the following steps: synthesis of 4- (prop-1-en-2-yl) isoquinolin-1-amine (YD 053)

Synthetic method referring to the synthetic method of YD008 (Suzuki coupling), YD053 (82.1mg, 89%) was obtained. ¹ H NMR(400MHz,Methanol-d ₄ )：δ8.08(t,J＝9.5Hz,1H),7.82(d,J＝8.4Hz,1H),7.67–7.54(m,2H),7.51–7.43(m,1H),5.33(t,J＝1.9Hz,1H),4.99(d,J＝2.2Hz,1H),2.10(s,3H).

Step two: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (prop-1-en-2-yl) isoquinolin-1-yl) urea (YD 064)

YD053 (24mg, 0.13mmol), end product 03 (20mg, 0.062mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD064 (29 mg). ¹ H NMR(400MHz,Methanol-d ₄ )δ9.18(s,1H),8.50(d,J＝8.5Hz,1H),8.22(d,J＝8.4Hz,1H),8.18–8.04(m,3H) Theoretical calculation of C, 7.96-7.80 (m, 3H), 5.74-5.57 (m, 1H), 5.45 (s, 1H), 5.26 (s, 1H), 2.25 (s, 3H), 1.60 (d, J =6.7hz, 6H) ESI-MS ₂₃ H ₂₄ N ₇ O[M+H] ⁺ =414.20, determined experimentally: 414.37.

end product 327:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (6- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-2-yl) urea (YD 071)

The method comprises the following steps: synthesis of 4- (2-Aminopyrazolo [1,5-a ] pyridin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (YD 066)

The synthesis method refers to the synthesis method of YD008 (Suzuki coupling), and YD066 (92mg, 71%) is obtained. ¹ H NMR(400MHz,Chloroform-d):δ8.11(s,1H),7.17–7.08(m,2H),5.98(s,1H),5.70(s,1H),4.06(p,J＝2.4,2.9Hz,2H),3.61(t,J＝5.7Hz,2H),2.43(s,2H),1.47(s,9H).

Step two: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (6- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-2-yl) urea (YD 071)

YD066 (92.4mg, 0.29mmol), final product 03 (50mg, 0.155mmol) and Et ₃ N (63mg, 0.62mmol) was weighed into a bottle, and DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. Adding water, extracting with ethyl acetate, washing an organic phase with water, spin-drying, dissolving a crude product in dichloromethane (4 mL), adding trifluoroacetic acid (1 mL), stirring at room temperature for 3 hours, and directly purifying the reaction crude product by using reverse phase HPLC to obtain a target compound YD071 (46.5 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.46 (s, 1H), 8.34 (s, 1H), 8.07 (d, J =8.5hz, 1h), 7.95 (dd, J =7.5,8.5hz, 1h), 7.73 (d, J =7.4hz, 1h), 7.48-7.42 (m, 1H), 7.37 (dd, J =1.6,9.3hz, 1h), 6.22 (dd, J =1.5,3.5hz, 1h), 5.61 (p, J =6.7hz, 1h), 3.88 (q, J =2.6hz, 2h), 3.49 (t, J =6.1hz, 2h), 2.79 (ddt, J =2.1,4.6,6.6hz, 2h), 1.64 (d, J =6.6hz, ESI) theoretical calculated value of C-7H), theoretical calculated value of d, J = 6.6.6.6H ₂₃ H ₂₆ N ₉ O[M+H] ⁺ =444.22, determined experimentally: 444.00.

the final product 328:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (1, 2,3, 6-tetrahydropyridin-4-yl) isoquinolin-1-yl) urea (YD 072)

The method comprises the following steps: synthesis of 4- (1-aminoisoquinolin-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (YD 068)

YD068 synthesis method YD068 (134mg, 83%) was obtained with reference to the synthesis method of YD008 (Suzuki coupling).

Step two: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4- (1, 2,3, 6-tetrahydropyridin-4-yl) isoquinolin-1-yl) urea (YD 072)

YD068 (134mg, 0.41mmol), final product 03 (50mg, 0.15mmol) and Et ₃ N (64mg, 0.63mmol) was weighed into a bottle, and DMF was added to dissolve the reagents. The reaction was heated at 50 ℃ overnight. Adding water, extracting with ethyl acetate, washing an organic phase with water, spin-drying, dissolving a crude product in dichloromethane (4 mL), adding trifluoroacetic acid (1 mL), stirring at room temperature for 3h, and directly purifying the reaction crude product by using reverse phase HPLC to obtain a target compound YD072 (7.5 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.26 (s, 1H), 8.54 (d, J =8.4hz, 1h), 8.20 (d, J =8.3hz, 1h), 8.11 (p, J =7.5hz, 3h), 8.00-7.77 (m, 3H), 6.07 (dt, J =1.9,3.8hz, 1h), 5.49 (s, 1H), 3.98 (q, J =2.7hz, 2h), 3.60 (t, J =6.0hz, 2h), 2.79 (q, J =4.1,4.5hz, 2h), 1.61 (d, J =6.6hz, 6h), ESI-MS theoretical calculation value C-MS ₂₅ H ₂₇ N ₈ O[M+H] ⁺ =455.23, experimental determination: 455.07.

end product 329:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4-isopropylisoquinolin-1-yl) urea (YD 073)

The method comprises the following steps: synthesis of 4-isopropylisoquinolin-1-amine (YD 067)

Pd/C hydrogenated YD053, the synthetic method of which refers to the synthetic method of YD011, and YD067 (63mg, 99%) is obtained.

Step two: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4-isopropylisoquinolin-1-yl) urea (YD 073)

YD067 (54mg, 0.186mmol), final product 03 (20mg, 0.062mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD073 (10.2 mg). ¹ H NMR(400MHz,Methanol-d ₄ ): δ 9.21 (d, J =3.7hz, 1h), 8.49 (d, J =8.5hz, 1h), 8.43 (d, J =8.6hz, 1h), 8.20 (t, J =7.8hz, 1h), 8.09 (d, J =7.0hz, 2h), 7.92 (d, J =8.7hz, 2h), 7.84 (d, J =6.9hz, 1h), 5.35 (d, J =69.3hz, 1h), 3.74 (p, J =6.8hz, 1h), 1.59 (d, J =6.7hz, 6h), 1.47 (dd, J =2.0,6.8hz, 6h), ESI-MS theoretical calculation value C-MS ₂₃ H ₂₆ N ₇ O[M+H] ⁺ =416.22, experimentally determined: 416.03.

the final product 330:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4-phenyliso-1-yl) urea (YD 074)

The method comprises the following steps: synthesis of 4-phenyliso-1-amine (YD 069)

The synthetic method refers to the synthetic method of YD008 (Suzuki coupling), and YD069 (65.3mg, 59%) is obtained. ¹ H NMR(400MHz,Methanol-d ₄ ):δ8.19–8.12(m,1H),7.71–7.65(m,1H),7.64(s,1H),7.55(ddd,J＝1.4,6.8,8.4Hz,1H),7.48(ddd,J＝1.4,6.9,8.2Hz,1H),7.45–7.38(m,2H),7.34(ddq,J＝1.4,1.9,3.4,6.8Hz,3H).

Step two: synthesis of 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (4-phenyliso-1-yl) urea (YD 074)

YD069 (65mg, 0.295mmol), final product 03 (20mg, 0.062mmol) and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD074 (20.5 mg). ¹ H NMR(400MHz,Methanol-d ₄ ): δ 9.45 (s, 1H), 8.58 (d, J =8.3hz, 1h), 8.24-8.09 (m, 3H), 8.06 (d, J =8.3hz, 1h), 8.01 (s, 1H), 7.96 (t, J =7.6hz, 1h), 7.90 (d, J =7.2hz, 1h), 7.68-7.50 (m, 5H), 5.55 (s, 1H), 1.64 (d, J =6.7hz, 6H) ESI-MS theoretical calculation C, J =6.7hz, 6H) ₂₆ H ₂₄ N ₇ O[M+H] ⁺ =450.20, experimentally determined: 450.16.

end product 331:1, 3-bis (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (YD 092)

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6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (25mg, 0.124mmol), end product 03 (20mg, 0.062mmol), and Et ₃ N (25mg, 0.25mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the target compound YD092 (5.6 mg). ¹ H NMR(400MHz,Methanol-d ₄ ): δ 9.21 (s, 2H), 8.19 (dd, J =0.8,8.5hz, 2h), 8.00 (dd, J =7.6,8.5hz, 2h), 7.76 (dd, J =0.8,7.6hz, 2h), 5.55 (hept, J =6.8hz, 2h), 1.55 (d, J =6.7hz, 12h), ESI-MS theoretical calculation C ₂₁ H ₂₅ N ₁₀ O[M+H] ⁺ =433.22, experimentally determined: 432.83.

the final product 332:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3- (1-phenyl-1H-indazol-3-yl) urea (YD 134)

1-phenyl-1H-indazol-3-amino (50mg, 0.24mmol), final product 03 (30mg, 0.093mmol) and Et ₃ N (38mg, 0.37mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the desired compound YD134 (9.7 mg). ¹ H NMR(400MHz,Methanol-d ₄ )：δ9.56(s,1H),8.33(d,J＝8.3Hz,1H),8.04(t,J＝8.1Hz,2H),7.83(d,J＝7.4Hz,1H),7.78–7.68(m,3H),7.59(t,J＝7.8Hz,2H),7.53(t,J＝7.6hz, 1h), 7.42 (t, J =7.4hz, 1h), 7.27 (t, J =7.5hz, 1h), 5.53 (p, J =6.8hz, 1h), 1.41 (d, J =6.7hz,6 h) ESI-MS theoretical calculation C ₂₄ H ₂₃ N ₈ O[M+H] ⁺ =439.20, experimentally determined: 439.78.

end product 334:1- (5- (3-cyclopropyl-1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) urea (YD 145)

YD144 (15.5mg, 0.0724mmol, synthesis method refer to that of YC 046), final product 03 (20mg, 0.0724mmol) and Et ₃ N (22mg, 0.217mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was purified directly by reverse phase HPLC to give the title compound YD145 (8.1 mg). ¹ H NMR(400MHz,DMSO-d ₆ ) δ 9.28 (s, 1H), 8.41 (dd, J =0.7,2.3hz, 1H), 8.24-8.10 (m, 2H), 8.01 (dd, J =7.5,8.5hz, 1H), 7.87-7.76 (m, 1H), 7.66 (s, 1H), 7.51 (d, J =8.8hz, 1H), 5.66 (H, J =6.7hz, 1H), 3.97 (s, 3H), 1.97 (tt, J =5.4,8.3hz, 1H), 1.65 (d, J =6.7hz, 6H), 1.20-1.04 (m, 2H), 0.53-0.40 (m, 2H), ESI-MS theoretical calculation C ₂₃ H ₂₆ N ₉ O[M+H] ⁺ =444.22, experimentally determined: 444.15.

end product 335:1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 3-dimethyl-3- (pyrazolo [1,5- α ] pyridin-2-yl) urea (YF 037)

YC107 (67.6 mg, 0.14mmol) was dissolved in 2mL DMF, cooled in an ice-water bath, naH (60% in oil,23mg, 0.56mmol) was added, after stirring for 15min MeI (48mg, 0.34mmol) was added and stirring was carried out overnight at room temperature. After the reaction, 4mL of water was added, the mixture was acidified with trifluoroacetic acid, and purified by HPLC to obtain YF037 (34.2 mg). ¹ H NMR(400MHz,Methanol-d ₄ )δ9.40(s,1H),8.26(dt,J＝1.1,7.0Hz,1H),7.80(dd,J＝7.6,8.3Hz,1H),7.66 (dd, J =0.8,7.6hz, 1h), 7.45-7.24 (m, 2H), 7.11 (ddd, J =1.1,6.8,9.0hz, 1h), 6.74 (td, J =1.4,6.9hz, 1h), 5.52 (hept, J =6.7hz, 1h), 3.41 (s, 3H), 3.37 (s, 3H), 1.50 (d, J =6.8hz, 6H), ESI-MS theoretical calculation C ₂₀ H ₂₃ N ₈ O[M+H] ⁺ =391.20, determined experimentally: 389.86.

end product 336:3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-methyl-1- (quinolin-2-yl) urea (YF 042)

2- (methylamino) quinoline (44mg, 0.28mmol), end product 03 (30mg, 0.0929mmol) and Et ₃ N (38mg, 0.37mmol) was weighed into a bottle, and DMF was added to dissolve the reaction reagents. The reaction was heated at 50 ℃ overnight. The crude reaction product was directly purified by reverse phase HPLC to give the title compound YF042 (8.1 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.27 (s, 1H), 8.27 (d, J =8.9hz, 2h), 7.90 (t, J =8.0hz, 1h), 7.86-7.70 (m, 3H), 7.70-7.62 (m, 1H), 7.47 (t, J =7.5hz, 1h), 7.40 (d, J =9.0hz, 1h), 5.77 (p, J =6.8hz, 1h), 3.49 (s, 3H), 1.53 (d, J =6.7hz, H), ESI-MS theoretical calculation value C ₂₁ H ₂₂ N ₇ O[M+H] ⁺ =388.18, experimentally determined: 388.80.

the following compounds can be synthesized by selecting corresponding raw materials:

TABLE 1

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Experimental example 2: ASK1 kinase Activity assay

The screening method comprises the following steps: apoptosis Signal-regulating kinase 1 (ASK 1) Activity Screen

The instrument comprises: envision of enzyme-linked plate reader ^TM (PerkinElmer,USA)。

Materials: human recombinant ASK1, purchased from Carna Bioscience, GST-fused ASK1 protein fragment (aa 654-971);

ASK1 activity detection kit

KinEASE ^TM STK S3, available from Cisbio.

The principle is as follows: the method adopts specific biotin-labeled polypeptide S3 as a substrate, ASK1 starts reaction under the participation of ATP, and phosphorylation modification of the polypeptide substrate S3 can be catalyzed. The Eu-labeled S3-specific phosphorylated antibody can be bound to the substrate by an antigen-antibody reaction, while the streptavidin-labeled receptor is bound by the specific interaction of streptavidin and biotin. Thereby enabling the Eu-labeled donor to interact with the streptavidin-labeled receptor. In fluorescence resonance energy transfer, when two fluorophores are close due to biomolecular interaction, part of the energy captured by the cryptate upon excitation will be released, with an emission wavelength of 620nm; another part of the energy is transferred to the acceptor (acceptor), which emits at 665nm. The emission at 665nm is generated only by FRET by the donor (donor). Therefore, when biomolecules interact, there are two excitation lights 620nm and 665nm; when there is no interaction, there is only 620nm excitation light. ASK1 phosphorylation activity can be reflected by measuring the ratio of the fluorescence signals at two emission wavelengths of 665nm and 620 nm. Meanwhile, a blank control is arranged to judge the strength of the enzyme activity. GS-4997 was used as a positive inhibitor for the experiment.

Sample treatment: the samples were dissolved in DMSO, stored at low temperature, and the concentration of DMSO in the final system was controlled within a range that did not affect the detection activity.

ASK1 and substrate were diluted with HTRF Kinase buffer solution (1X Kinase buffer,5mM MgCl2,1mM DTT). mu.L of enzyme, 4. Mu.L of substrate and 2. Mu.L of test compound at different concentrations were added to 384 reaction plates (ProxiPlate. TM. -384plus, perkinElmer) at 2% DMSO, 3ng/. Mu.L ASK1, 1. Mu.M STK3, 40. Mu.M ATP. After incubation for 1 hour at room temperature, the antibody was added for detection. And simultaneously setting a solvent control group, a GS-4997 positive control group and a blank control group which replace the compound to be detected by DMSO, and setting 3 multiple wells for each concentration of each sample. The activity of the sample is tested under a single concentration condition, e.g., 10. Mu.M, selected for the primary screen. For samples exhibiting activity under certain conditions, e.g.,% inhibition greater than 50, the activity is tested for dose dependence, i.e., IC ₅₀ Values, obtained by nonlinear fitting of sample concentrations by sample activity, were calculated as Graphpad Prism 5, the model used for fitting was sigmoidal dose-response (variable slope), and for most inhibitor screening models, the bottom and top of the fitted curve were set at 0 and 100.

TABLE 2

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(in the table,. Indicates IC) ₅₀ Is 50-500nM; * Denotes IC ₅₀ Is 501-2000nM; * Denotes IC ₅₀ 2001nM; * Denotes<50nM)

Of these, GS4997 is a clinical compound from Gilead, which has very high inhibitory activity against ASK1 kinase, and the specific values are shown in the table above.

YD140 is PCT patent WO2018157857 reporting the compound of example 20, which the inventors synthesized and named YD140. IC of YD140 for ASK1 kinase inhibitory Activity by Activity assay ₅₀ =2585nM, activity in μ M interval. In accordance therewith, part of the compounds of the present application have IC for ASK1 kinase inhibitory activity ₅₀ <50nM, active>A 50-fold improvement.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the appended claims of the present application.

Claims

1. A compound represented by formula Ia:

wherein R is ₃ Is a substituted or unsubstituted triazolyl, said substitution being such that one or more hydrogen atoms on the group are substituted with a group selected from the group consisting of: halogen, hydroxy substituted or unsubstituted C1-C6 alkyl;

m is hydrogen, or C1-C4 alkyl;

and Y represents a nitrogen atom or an oxygen atom;

wherein,

when Y represents an oxygen atom, R ₁ Is absent; r ₂ Is C1-C6 alkyl;

when Y represents a nitrogen atom, the compound represented by formula (I),

R ₁ is hydrogen or C1-C6 alkyl;

R ₂ is substituted phenyl, substituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, substituted 5-14 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;

wherein said substitution means that one or more hydrogen atoms on the group are substituted by a group selected from the group consisting of: amino, C1-C4 alkyl substituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, C1-C4 alkyl substituted or unsubstituted 5-13 membered heterocycle containing 1-4 heteroatoms selected from N, O and S, C2-C4 alkenyl;

wherein ring D represents a substituted or unsubstituted partially unsaturated 5-14 membered heterocycle containing 1 to 4 atoms selected from N, O and S, or a 5-12 membered heteroaryl ring containing 1 to 4 atoms selected from N, O and S, and these heterocycles or heteroaryl rings are linked by the N atom and the carbonyl group within the ring;

wherein said substitution means that one or more hydrogen atoms of the above ring D are substituted by a group selected from the group consisting of: halogen, amino, substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted 5-13 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy; wherein one or more hydrogen atoms of said substituent group are substituted with a group selected from the group consisting of: C1-C4 alkoxy, C1-C4 alkyl, halogenated C1-C4 alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula I-3:

wherein, the rings D and R ₃ And M is as defined in claim 1;

wherein R is ₄ 、R _4a Each independently halogen, amino, substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy; wherein one or more hydrogen atoms of said substituent group are substituted with a group selected from the group consisting of: C1-C4 alkyl, halogenated C1-C4 alkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, having a structure according to formula I-4, I-5, or I-6:

wherein R is ₄ 、R _4a 、R ₃ And M is as defined in claim 2;

x represents-CH ₂ -、-O-、-NR ₅ -or-S-; wherein R is ₅ Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is ₃ Is composed of

5. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula I-1, I-2, I-21, or I-22 below:

wherein ring A, ring B and ring C each independently represent a 5-to 6-membered aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from N, O and S, a 5-to 7-membered heterocyclic ring containing 1 to 4 hetero atoms selected from N, O and S, or a 5-to 7-membered aliphatic ring; and ring A and ring B are fused ring systems, and ring A, ring B and ring C are fused ring systems;

m represents hydrogen, halogen, or C1-C4 alkyl;

R ₃ is a substituted or unsubstituted triazolyl, said substitution being such that one or more hydrogen atoms on the group are substituted with a group selected from the group consisting of: halogen, hydroxy substituted or unsubstituted C1-C6 alkyl;

R ₁ represents hydrogen or C1-C6 alkyl;

wherein R is ₄ 、R _4a 、R _4b Each independently a halogen, deuterium atom, cyano, amino, substituted or unsubstituted phenyl ring, substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted 5-13 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl; wherein one or more hydrogen atoms of said substituent group are substituted with a group selected from the group consisting of: halogen, C1-C4 alkyl, C3-C6 cycloalkyl.

6. The compound or pharmaceutically acceptable salt thereof of claim 5, wherein R is ₃ Is composed of

7. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

8. a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

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9. an ASK1 kinase inhibitor, comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition, comprising: (A) A therapeutically effective amount of one or more of the compounds of any one of claims 1-8, or a pharmaceutically acceptable salt thereof; and (B) a pharmaceutically acceptable carrier.

11. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with activity or expression of ASK1 kinase.

12. The use according to claim 11, wherein the ASK1 kinase related disease is selected from the group consisting of: liver diseases, lung diseases, cardiovascular diseases, kidney diseases and metabolic diseases.

13. The use according to claim 12, wherein the liver disease is selected from the group consisting of: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, chronic liver disease, metabolic liver disease, hepatic fibrosis, primary sclerosing cholangitis, hepatic ischemia-reperfusion injury, primary biliary cirrhosis, and liver disease related to diabetes;

the pulmonary disease is selected from the group consisting of: pulmonary hypertension, pulmonary fibrosis;

the cardiovascular disease is selected from the group consisting of: heart failure;

the kidney disease is selected from the group consisting of: glomerulonephritis, diabetic nephropathy, hypertensive nephropathy; and/or

The metabolic disease is selected from the group consisting of: type ii diabetes, type one diabetes.

14. A process for preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof,

wherein M, R3, R1 and R2 are defined in claim 1;

z represents H or a substituent on the benzene ring, the substituent being selected from the group consisting of: nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl.

15. A process for preparing a compound of claim 2, or a pharmaceutically acceptable salt thereof,

the compound is of formula (I-3), the method comprising the steps of:

the method comprises the following steps: reacting compound SS1 with compound S5 in an inert solvent, thereby forming final product I-3;

wherein, M and R ₃ R4 and R4a are as defined in claim 2;

16. A process for the preparation of a compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-4), said process comprising the steps of:

step four: reacting intermediate S15 and compound S5 in an inert solvent to form the final product I-4; wherein, M and R ₃ 、R ₄ And R _4a The definition of claim 3;

z represents H or a substituent on the benzene ring, the substituent being selected from the group consisting of: nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl,

the method comprises the following steps: reacting compound S16 with compound S5 in an inert solvent, thereby forming the final product I-5; wherein, M and R ₃ 、R ₄ And R _4a As defined in claim 3;

z represents H or a substituent on the benzene ring, the substituent being selected from the group consisting of: nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl;

the method comprises the following steps: reacting compound S17 with compound S5 in an inert solvent to form the final product I-6; wherein, M and R ₃ 、R ₄ And R _4a The definition of which is the same as that of claim 4;

z represents H or a substituent on the benzene ring, and the substituent is selected from the following group: nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl.

17. A process for preparing a compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-21) or (I-22), the process comprising the steps of:

the method comprises the following steps: reacting compound I-5 with a compound lawson's reagent in an inert solvent to give compound I-22;

step two: reacting compound I-22 with aqueous ammonia in an inert solvent to give compound I-21; wherein, ring A, ring B, M, R ₁ 、R ₃ 、R ₄ 、R _4a The definition is the same as before.