CN113135896B

CN113135896B - Methylpyrazole derivatives as RET inhibitors

Info

Publication number: CN113135896B
Application number: CN202110061785.3A
Authority: CN
Inventors: 张寅生; 陆鹏; 秦慧; 叶嘉炜; 陶亮; 陈璞舟; 刘戌时; 施伟; 徐宏江
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2020-01-18
Filing date: 2021-01-18
Publication date: 2024-12-06
Anticipated expiration: 2041-01-18
Also published as: CN113135896A

Abstract

本申请涉及作为RET抑制剂的甲基吡唑类衍生物，具体涉及式(I)所示化合物、其立体异构体及其药学上可接受的盐，其制备方法及其药物组合物。本申请所述式(I)化合物可用于预防或治疗由异常RET活性介导的疾病。 The present application relates to methylpyrazole derivatives as RET inhibitors, and specifically to compounds represented by formula (I), stereoisomers thereof, and pharmaceutically acceptable salts thereof, preparation methods thereof, and pharmaceutical compositions thereof. The compounds of formula (I) described in the present application can be used to prevent or treat diseases mediated by abnormal RET activity.

Description

Methylpyrazole derivatives as RET inhibitors

Technical Field

The application relates to a methylpyrazole derivative used as RET inhibitor, in particular to a compound shown in a formula (I), a stereoisomer and a pharmaceutically acceptable salt thereof, a preparation method, a pharmaceutical composition and application thereof in preparing medicines for preventing or treating diseases mediated by abnormal RET activity.

Background

RET (Rearranged during Transfection) is a membrane receptor tyrosine kinase encoded by the proto-oncogene RET gene located on chromosome 10, and its ligand is GNDF family protein (GFLs), such as GDNF, NTRN, ARTN and PSPN. But unlike other receptor tyrosine kinases RET does not bind directly to its ligand. GDNF, NTRN, ARTN and PSPN bind to the co-receptor GFRα of RET to form a GFL-GFRα complex which mediates dimerization of RET and autophosphorylation of tyrosine residues of intracellular domains of RET, activates cascade reactions of downstream pathways such as MAPK, PI3K, JAK-STAT, PKA and PKC, and finally regulates proliferation and differentiation levels of cells. Thus, abnormal upregulation of RET activity will cause diseases such as cancer.

RET can be activated abnormally by two pathways, point mutation and gene fusion. Point mutations at the kinase end of the intracellular domain of RET cause an increase in the catalytic phosphorylation activity of RET, such as E768D, L790,790, 790F, V804M, and point mutations in the extracellular domain promote intermolecular disulfide bond formation, causing ligand-independent dimerization of RET, resulting in autophosphorylation of RET. The gene fusion of RET is easy to lead RET kinase end and chaperone protein with dimer end to fuse to form hybrid protein with RET catalytic activity, lead RET to be dimerized independent of ligand, and excite RET catalytic activity. RET fusion genes which have been found at present are RET-CCDC6, RET-PRKAR1A, RET-GOLGA5, RET-RFG9 and the like. Clinical studies have shown that various cancers such as thyroid cancer, non-small cell lung cancer, colon cancer and breast cancer are all driven by RET, with the RET driven papillary thyroid cancer, medullary thyroid cancer and non-small cell lung cancer being present in relatively high proportions, 11%, 60% and 2% respectively.

The first-generation RET inhibitors such as Vandatinib and cabatinib can inhibit RET activity at low nM concentration, but can also effectively inhibit various non-RET kinases, and the inhibiting activity on the non-RET kinase is superior to that on RET. Therefore, the medicament shows dose-dependent off-target related side effects in clinical experiments, such as hypertension, hand-foot syndrome and urine protein related to VEGFR inhibition, rash related to BRAF inhibition, hypopigmentation related to KIT inhibition, diarrhea related to EGFR inhibition and the like. The incidence of the drug dose reduction caused by the problem of dose tolerance is 23% -79% and the incidence of treatment suspension is 6% -21%. In addition, when the first generation RET inhibitor is used for treating RET-driven NSCLC, the problems of low overall response rate and short median progression-free survival time still exist, and patients benefit far less than NSCLC patients with EGFR mutation, ALK and ROS1 gene fusion positive and the like. As with other targeted drugs, the occurrence of drug-resistant mutations greatly reduces the efficacy of first-generation RET inhibitors, leading to rapid progression of the cancer condition. RET GATEKEEPER mutations (e.g., V804L, V804M) are the predominant drug resistance mutations. Val is mutated into Leu or Met with larger branched chain volume, so that the steric hindrance of the RET inhibitor hydrophobic fragment extending into a hydrophobic pocket behind an ATP binding point is increased, and the affinity with the inhibitor is reduced, thereby leading to the generation of drug resistance. Another major type of drug resistance mutation is solvent front domain mutations (solvent-front mutation) G810R and G810A, which are similar to ALKG1202R, ROS G2032R, NTRK G595R and NTRK3G623R, and RET solvent region Gl810 is mutated to a more bulky amino acid residue, which creates steric hindrance with the solvent region fragment of the drug, reducing affinity.

Therefore, the first generation RET inhibitors are of limited clinical use. However, as a second-generation RET inhibitor effective against drug-resistant mutations, which has not been highly selective, has been approved to be marketed, there is still a need to develop an excellent second-generation RET inhibitor effective against drug-resistant mutations.

Disclosure of Invention

A compound shown in a formula (I), a stereoisomer and a pharmaceutically acceptable salt thereof,

Wherein,

X is selected from NH;

U, V, W are each independently selected from C (R ¹) or N;

Q is selected from C (R ²) or N;

ring A is a 6-8 membered single heterocyclic ring, a 6-10 membered bridged heterocyclic ring, a benzene ring, a naphthalene ring, a 7-12 membered condensed ring or condensed heterocyclic ring, or a 7-12 membered condensed heteroaromatic ring, wherein the single heterocyclic ring contains at least one N atom;

ring B is benzene ring, naphthalene ring, 5-6 membered heteroaromatic ring, 7-12 membered fused heterocycle or 7-12 membered fused heteroaromatic ring;

-L ¹ -selected from single bond, -O-, -S-, -C (O) -, -C (S) -, -S (O) ₂ -, or-N (R ^A0) -;

-L ² -selected from -O-、-S-、-C(S)-、-S(O)₂-、-(CR^A2R^B2)_q-、-N(R^A1)-、-C(O)-N(R^A1)-、-N(R^A1)-C(S)-、-(CR^A2R^B2)_q-C(S)-、-(CR^A2R^B2)_q-S(O)₂-、-C(O)-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-C(O)-(CR^A2R^B2)_q-、-C(S)-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-C(S)-(CR^A2R^B2)_q-、-S(O)₂-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-S(O)₂-(CR^A2R^B2)_q-、-C(O)-N(R^A1)-C(O)-、-N(R^A1)-C(O)-N(R^A1)-、-N(R^A1)-C(O)-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-C(O)-(CR^A2R^B2)_q-N(R^A1)-、-N(R^A1)-C(O)-(CR^A2R^B2)_q-C(O)-、-N(R^A1)-C(O)-N(R^A1)-C(O)-、-C(O)-N(R^A1)-C(O)-(CR^A2R^B2)_q-、-C(S)-N(R^A1)-C(O)-(CR^A2R^B2)_q-、-C(O)-N(R^A1)-(CR^A2R^B2)_q-C(O)-、-C(S)-N(R^A1)-(CR^A2R^B2)_q-C(O)-、-N(R^A1)-C(O)-(CR^A2R^B2)_q-C(O)-N(R^A1)-、-C(O)-N(R^A1)-(CR^A2R^B2)_q-C(O)-N(R^A1)- or-C (O) -N (R ^A1)-(CR^A2R^B2)_q-N(R^A1) -C (O) -;

R ^A0 is selected from C _1-6 alkyl, C _3-6 cycloalkyl or 3-to 6-membered heterocycloalkyl, said C _1-6 alkyl, C _3-6 cycloalkyl and 3-to 6-membered heterocycloalkyl optionally being substituted by one, two or three substituents selected from halogen, hydroxy, cyano or amino;

R ^A1 is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or 3-to 6-membered heterocycloalkyl, said C _1-6 alkyl, C _3-6 cycloalkyl and 3-to 6-membered heterocycloalkyl optionally being substituted by one, two or three substituents selected from halogen, hydroxy, cyano or amino;

R ^A2 and R ^B2 are each independently selected from H, halogen, hydroxy, cyano, amino, COOH, nitro, C _1-6 alkyl, C _1-6 alkyl-NH-, C _1-6 alkoxy, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl optionally being substituted by one, two or three substituents selected from halogen, hydroxy, cyano or amino, or R ^A2、R^B2 taken together with the C to which it is attached forms a three-, four-or five-membered saturated monocyclic or mono-heterocyclic ring with no substituent, said mono-heterocyclic ring comprising 1 or 2 heteroatoms selected from O or N;

r ¹、R² and R ⁵ are each independently selected from H, halogen, hydroxy, amino, cyano, COOH, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, methoxy, C _3-6 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, or R ¹、R² together with the C atom to which it is attached form a 3-6 membered monocyclic ring or a 3-6 membered monocyclic ring, said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, methoxy, C _3-6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered monocyclic ring and 3-6 membered monocyclic ring being optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino;

R ³ is selected from halogen, hydroxy, amino, cyano, COOH, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, 3-to 6-membered cycloalkyl, said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy and 3-to 6-membered cycloalkyl optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino;

R ⁴ is selected from H, halogen, hydroxy, amino, cyano, COOH, nitro, C _2-6 alkenyl, C _2-6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, pyrazolyl, 6-10 membered bridged heterocycle, 3-6 membered heterocycloalkyl-C _1-6 alkylene, wherein the C _2-6 alkenyl, C _2-6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered bridged heterocycle, 3-6 membered heterocycloalkyl-C _1-6 alkylene are optionally substituted with one, two or three substituents selected from R ⁶, and the pyrazolyl is substituted with one, two or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro;

R ⁶ is independently halogen, hydroxy, amino, cyano, COOH, nitro, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkyl-NH-, N-di (C _1-6 alkyl) -N-, C _1-6 alkyl-O-, C _1-6 alkyl-S-, C _1-6 alkyl-C (O) -, said C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkyl-NH-, N-di (C _1-6 alkyl) -N-, C _1-6 alkyl-O-, C _1-6 alkyl-S-, and C _1-6 alkyl-C (O) -being optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino;

n is 0 or 1;

p is 1,2 or 3;

q is 1, 2, 3, 4 or 5;

And when ring A is a piperidine ring, L ² is not-C (O) -N (R ^A1)-(CR^A2R^B2)_q -and-N (R ^A1)-C(O)-(CR^A2R^B2)_q -;

And when none and only 1 of U, V, W are N, Q is C (CH ₃), and ring a is a piperazine ring, N is not 0;

And the present application does not include the following specific compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof:

In some embodiments, each R ¹ is independently selected from H, halogen, hydroxy, amino, cyano, COOH, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, methoxy, C _3-6 alkoxy, 3-to 6-membered cycloalkyl, or 3-to 6-membered heterocycloalkyl, which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, methoxy, C _3-6 alkoxy, 3-to 6-membered cycloalkyl, and 3-to 6-membered heterocycloalkyl may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino.

In some embodiments, R ¹ is each independently selected from H, halogen, or C _1-6 alkyl, which C _1-6 alkyl may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino, and in some embodiments, R ¹ is each independently selected from H, halogen, or C _1-4 alkyl, which C _1-4 alkyl may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino.

In some embodiments, each R ¹ is independently selected from H or halogen.

In some embodiments, R ¹ is H.

In some embodiments U, V, W are both CH.

In some embodiments, at least one of U, V, W is selected from N.

In some embodiments, U is CH, V is N, and W is N.

In some embodiments, U is CH, V is CH, and W is N.

In some embodiments, U is CH, V is N, and W is CH.

In some embodiments, U is N, V is CH, and W is N.

In some embodiments, Q is C (R ²).

In some embodiments, R ² is selected from H, halogen, hydroxy, amino, cyano, COOH, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, methoxy, C _3-6 alkoxy, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, methoxy, C _3-6 alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl being optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino.

In some embodiments, R ² is selected from H or C _1-6 alkyl, which C _1-6 alkyl may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino, and in some embodiments, R ² is selected from H or C _1-4 alkyl, which C _1-4 alkyl may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino.

In some embodiments, R ² is selected from H, methyl, ethyl, isopropyl, or tert-butyl, which may be optionally substituted with one, two, or three substituents selected from halogen.

In some embodiments, R ² is selected from H or methyl, which methyl may be optionally substituted with one, two, or three substituents selected from halogen.

In some embodiments, R ² is selected from H, methyl, difluoromethyl, or trifluoromethyl.

In some embodiments, R ² is selected from methyl.

In some embodiments, U is CH, V is N, W is N, and Q is C (R ²).

In some embodiments, U is CH, V is N, W is N, and Q is C (CH ₃).

In some embodiments, U is CH, V is CH, W is N, and Q is N.

In some embodiments, R ¹、R² together with the C atom to which it is attached form a 5-membered monocyclic ring.

In some embodiments, R ^A0 is independently selected from C _1-6 alkyl, which C _1-6 alkyl may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino, and in some embodiments, R ^A0 is independently selected from C _1-4 alkyl, which C _1-4 alkyl may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino.

In some embodiments, R ^A0 is independently selected from methyl, ethyl, isopropyl, or tert-butyl.

In some embodiments, R ^A0 is independently selected from methyl.

In some embodiments, L ¹ is selected from a single bond, -O-, -S-, -C (O) -or-N (R ^A0) -, and in some embodiments, L ¹ is selected from a single bond, -C (O) -or-N (R ^A0) -.

In some embodiments, L ¹ is selected from a single bond, -C (O) -, -N (CH ₃)-、-N(CH₂CH₃) -or-N (CH ₃)₂) -.

In some embodiments, L ¹ is selected from a single bond, -C (O) -or-N (CH ₃) -.

In some embodiments, L ¹ is selected from a single bond.

In some embodiments, ring A is a 6-8 membered monocyclic ring, a 6-10 membered bridged heterocyclic ring, a benzene ring, an 8-10 membered fused or fused ring, the monocyclic ring containing at least one N atom, and in some embodiments, ring A is a 6-8 membered saturated monocyclic ring, a 6-10 membered saturated bridged heterocyclic ring, an 8-10 membered fused or fused ring, a benzene ring, the monocyclic ring containing at least one N atom.

In some embodiments, ring a is In some embodiments, ring a is

In some embodiments, ring a is

In some embodiments of the present invention, in some embodiments,Is that

In some embodiments, R ³ is independently selected from halogen, hydroxy, amino,Or C _1-6 alkyl, which C _1-6 alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino, in some embodiments R ³ is independently selected from halogen,Or C _1-4 alkyl, which C _1-4 alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.

In some embodiments, R ³ is independently selected from F,Methyl, ethyl, isopropyl or tert-butyl.

In some embodiments, R ³ is independently selected from F,Or methyl.

In some embodiments, n is 0.

In some embodiments, -L ² -is selected from -O-、-S-、-C(S)-、-S(O)₂-、-(CR^A2R^B2)_q-、-N(R^A1)-、-C(O)-N(R^A1)-、-N(R^A1)-C(S)-、-(CR^A2R^B2)_q-C(S)-、-(CR^A2R^B2)_q-S(O)₂-、-C(O)-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-C(O)-(CR^A2R^B2)_q-、-C(S)-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-C(S)-(CR^A2R^B2)_q-、-S(O)₂-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-S(O)₂-(CR^A2R^B2)_q-、-C(O)-N(R^A1)-C(O)-、-N(R^A1)-C(O)-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-C(O)-(CR^A2R^B2)_q-N(R^A1)-、-N(R^A1)-C(O)-(CR^A2R^B2)_q-C(O)-、-N(R^A1)-C(O)-N(R^A1)-C(O)-、-C(O)-N(R^A1)-C(O)-(CR^A2R^B2)_q-、-C(S)-N(R^A1)-C(O)-(CR^A2R^B2)_q-、-C(O)-N(R^A1)-(CR^A2R^B2)_q-C(O)-、-C(S)-N(R^A1)-(CR^A2R^B2)_q-C(O)-、-N(R^A1)-C(O)-(CR^A2R^B2)_q-C(O)-N(R^A1)-、-C(O)-N(R^A1)-(CR^A2R^B2)_q-C(O)-N(R^A1)- or-C (O) -N (R ^A1)-(CR^A2R^B2)_q-N(R^A1) -C (O) -.

In some embodiments, L ² is selected from -O-、-S-、-(CR^A2R^B2)_q-、-N(R^A1)-、-C(O)-N(R^A1)-、-C(S)-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-C(S)-(CR^A2R^B2)_q-、-C(O)-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-C(O)-(CR^A2R^B2)_q-、-S(O)₂-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-S(O)₂-(CR^A2R^B2)_q-、-N(R^A1)-C(O)-N(R^A1)-、-N(R^A1)-C(O)-N(R^A1)-(CR^A2R^B2)_q- or-N (R ^A1)-C(O)-(CR^A2R^B2)_q-C(O)-N(R^A1) -;

In some embodiments, L ² is selected from -O-、-C(O)-N(R^A1)-、-C(O)-N(R^A1)-(CR^A2R^B2)_q-、-S(O)₂-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-C(O)-(CR^A2R^B2)_q-、-C(S)-N(R^A1)-(CR^A2R^B2)_q-、-N(R^A1)-C(O)-N(R^A1)-、-N(R^A1)-C(O)-N(R^A1)-(CR^A2R^B2)_q- or-N (R ^A1)-C(O)-(CR^A2R^B2)_q-C(O)-N(R^A1) -;

in some embodiments, L ² is selected from -O-、-C(O)-N(R^A1)-、-C(O)-N(R^A1)-(CR^A2R^B2)-、-S(O)₂-N(R^A1)-(CR^A2R^B2)-、-N(R^A1)-C(O)-(CR^A2R^B2)-、-C(S)-N(R^A1)-(CR^A2R^B2)-、-N(R^A1)-C(O)-N(R^A1)-(CR^A2R^B2)- or-N (R ^A1)-C(O)-(CR^A2R^B2)-C(O)-N(R^A1) -.

In some embodiments, R ^A1 is independently selected from H or C _1-6 alkyl, which C _1-6 alkyl may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino, and in some embodiments, R ^A1 is independently selected from H or C _1-4 alkyl, which C _1-4 alkyl may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino.

In some embodiments, R ^A1 is independently selected from H, methyl, ethyl, isopropyl, or tert-butyl.

In some embodiments, R ^A1 is independently selected from H or methyl.

In some embodiments, R ^A1 is independently selected from H.

In some embodiments, R ^A2 and R ^B2 are each independently selected from H, halogen, hydroxy, C _1-6 alkyl, or C _1-6 alkyl-NH-, said C _1-6 alkyl and C _1-6 alkyl-NH-may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino, or R ^A2、R^B2 together with the C to which it is attached form a three-, four-, or five-membered saturated monocyclic or mono-heterocyclic ring comprising 1 or 2 heteroatoms selected from O or N, and in some embodiments, R ^A2 and R ^B2 are each independently selected from H, C _1-4 alkyl or C _1-4 alkyl-NH-, said C _1-4 alkyl and C _1-4 alkyl-NH-may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino, or R ^A2、R^B2 taken together with the C to which it is attached form a three-membered saturated monocyclic or mono-heterocyclic ring comprising 1 or 2 heteroatoms selected from O or N.

In some embodiments, R ^A2 and R ^B2 are each independently selected from H, methyl, ethyl, or methyl-NH-.

In some embodiments, R ^A2 and R ^B2 are each independently selected from H or methyl.

In some embodiments, R ^A2 and R ^B2 are both H.

In some embodiments, R ^A2 is selected from methyl, R ^B2 is selected from methyl, or R ^A2、R^B2 is taken together with the C to which it is attached to form a cyclopropane ring.

In some embodiments, R ^A2 is selected from H, R ^B2 is selected from methyl, or R ^A2 is selected from methyl, R ^B2 is selected from H.

In some embodiments of the present invention, in some embodiments, L ² is selected from the group consisting of-O-, -CH ₂-、-C(O)-NH-、-C(O)-NH-CH(CH₃)-、-C(O)-NH-CH₂ -; -NH-C (O) -NH-,-S(O)₂-NH-CH(CH₃)-、-NH-C(O)-CH(CH₃)-、-C(S)-NH-CH(CH₃)-、-NH-C(O)-NH-CH(CH₃)-、-N(CH₃)-C(O)-NH-CH(CH₃)- Or (b)

In some embodiments of the present invention, in some embodiments, L ² is selected from the group consisting of-O-, -C (O) -NH-, -C (O) -NH-CH (CH ₃)-、-C(O)-NH-CH₂ -; -NH-C (O) -NH-,-S(O)₂-NH-CH(CH₃)-、-NH-C(O)-CH(CH₃)-、-C(S)-NH-CH(CH₃)-、-NH-C(O)-NH-CH(CH₃)-、-N(CH₃)-C(O)-NH-CH(CH₃)- Or (b)

In some embodiments of the present invention, in some embodiments, L ² is selected from the group consisting of-C (O) -NH-and-C (O) -NH-CH (CH ₃) -.

In some embodiments, L ² is selected from the group consisting of-C (O) -NH-CH (CH ₃) -.

In some embodiments, ring B is a benzene ring, a 5-6 membered heteroaromatic ring, a 7-10 membered fused heterocyclic ring, or a 7-10 membered fused heteroaromatic ring containing 1,2, or 3 heteroatoms selected from O, N, S, in some embodiments, ring B is a benzene ring, a 5-6 membered heteroaromatic ring, a 9-10 membered fused heterocyclic ring, or a 9-10 membered fused heteroaromatic ring containing 1,2, or 3 heteroatoms selected from O, N, S.

In some embodiments of the present invention, in some embodiments, ring B is furan ring, pyrrole ring, pyrazole ring, imidazole ring, oxazole ring, isoxazole ring, thiophene ring, thiazole ring, isothiazole ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, indole ring, benzimidazole ring, benzothiazole ring, benzoxazole ring, quinoline ring, isoquinoline ring, quinazoline ring,In some embodiments, ring B is a benzene ring, a pyridine ring, a benzimidazole ring, or a benzothiazole ring.

In some embodiments, ring B is

In some embodiments of the present invention, in some embodiments,Is that

In some embodiments, R ⁵ is independently selected from H, halogen, hydroxy, amino, cyano, C _1-6 alkyl, methoxy, or C _3-6 alkoxy, which C _1-6 alkyl, methoxy, or C _3-6 alkoxy may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino.

In some embodiments, R ⁵ is independently selected from H, halogen, hydroxy, amino, cyano, or C _1-6 alkyl, which C _1-6 alkyl may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino.

In some embodiments, R ⁵ is independently selected from H, halogen, hydroxy, C _1-4 alkyl, methoxy, or C _3-6 alkoxy, which C _1-4 alkyl, methoxy, or C _3-6 alkoxy may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino.

In some embodiments, R ⁵ is independently selected from H, halogen, hydroxy, or C _1-4 alkyl, which C _1-4 alkyl may be optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino.

In some embodiments, R ⁵ is independently selected from H, halogen, hydroxy, methyl, ethyl, isopropyl, tert-butyl, methoxy, propoxy, isopropoxy, butyl-2-oxo, tert-butyloxy, or pentan-2-yloxy, which methyl, ethyl, isopropyl, tert-butyl, methoxy, propoxy, isopropoxy, butyl-2-oxy, tert-butyloxy, or pentan-2-yloxy may be optionally substituted with one, two, or three substituents selected from halogen or cyano.

In some embodiments, R ⁵ is independently selected from H, halogen, hydroxy, methyl, ethyl, isopropyl, or tert-butyl, which methyl, ethyl, isopropyl, or tert-butyl may be substituted with one, two, or three substituents selected from halogen.

In some embodiments, R ⁵ is independently selected from H, F, hydroxy, trifluoromethyl,Methoxy, trifluoromethyloxy, isopropyloxy, butyl-2-oxy, and pentan-2-yloxy.

In some embodiments, R ⁵ is independently selected from H, F, hydroxy, trifluoromethyl.

In some embodiments, p is 1 or 2.

In some embodiments, R ⁵ is independently selected from H.

In some embodiments, R ⁴ is selected from H, halogen, hydroxy, amino, cyano, C _2-6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, pyrazolyl, 6-8 membered bridged heterocycle, or 3-6 membered heterocycloalkyl-C _1-6 alkylene, which C _2-6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered bridged heterocycle, or 3-6 membered heterocycloalkyl-C _1-6 alkylene may be optionally substituted with one, two, or three substituents selected from R ⁶, and the pyrazolyl is substituted with one, two, or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro.

In some embodiments, R ⁴ is selected from H, halogen, cyano, C _2-4 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, pyrazolyl, 6-7 membered bridged heterocycle, or 5-6 membered heterocycloalkyl-C _1-4 alkylene, said C _2-4 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-7 membered bridged heterocycle, or 5-6 membered heterocycloalkyl-C _1-4 alkylene being optionally substituted with one, two, or three substituents selected from R ⁶, said pyrazolyl being substituted with one, two, or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro.

In some embodiments, R ⁴ is selected from H, halogen, cyano, ethynyl, 1-propynyl, 2-propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl,Tetrahydropyrrolyl-1-methylene, tetrahydropyrrolyl-2-methylene, tetrahydropyrrolyl-3-methylene, piperidinyl-1-methylene, piperidinyl-2-methylene, piperidinyl-3-methylene, piperidinyl-4-methylene, piperazinyl-1-methylene or piperazinyl-2-methylene, the stated ethynyl, 1-propynyl, 2-propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl,Tetrahydropyrrolyl-1-methylene, tetrahydropyrrolyl-2-methylene, tetrahydropyrrolyl-3-methylene, piperidinyl-1-methylene, piperidinyl-2-methylene, piperidinyl-3-methylene, piperidinyl-4-methylene, piperazinyl-1-methylene or piperazinyl-2-methylene may be optionally substituted with one, two or three substituents selected from R ⁶, said pyrazolyl being substituted with one, two or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro.

In some embodiments, R ⁴ is selected from H, F, cyano, ethynyl, cyclopropyl, cyclopentyl, azetidinyl, tetrahydropyrrolyl, pyrazolyl,Tetrahydropyrrolyl-1-methylene or piperazinyl-1-methylene, said ethynyl, cyclopropyl, cyclopentyl, azetidinyl, tetrahydropyrrolyl,The tetrahydropyrrolyl-1-methylene or piperazinyl-1-methylene may be optionally substituted with one, two or three substituents selected from R ⁶, and the pyrazolyl is substituted with one, two or three substituents selected from halogen.

In some embodiments, R ⁶ is independently selected from halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkyl-NH-, N-di (C _1-6 alkyl) -N-, said C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkyl-NH-, and N, N-di (C _1-6 alkyl) -N-, optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino, and in some embodiments, R ⁶ is independently selected from halogen, cyano, C _1-4 alkyl, C _2-4 alkynyl, or N, N-di (C _1-4 alkyl) -N-, said C _1-4 alkyl, C _2-4 alkynyl, and N, N-di (C _1-4 alkyl) -N-, optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, or amino.

In some embodiments, R ⁶ is independently selected from halogen, cyano, methyl, ethynyl, or N, N-dimethylamino.

In some embodiments, R ⁶ is independently selected from F.

In some embodiments, R ⁴ is selected from H, F, cyano, ethynyl,

In some embodiments, R ⁴ is selected from

In some embodiments, the aforementioned compounds of formula (I) have the structure shown in formula (II),

Wherein R ²、R³、R⁴、R⁵, ring A, ring B, L ², n, p are as defined for the compounds of formula (I) above.

In some embodiments, the aforementioned compounds of formula (I) have the structure shown in formula (III),

Wherein R ³、R⁴、R⁵, ring A, ring B, L ², n, p are as defined for the compounds of formula (I) above.

In some embodiments, the aforementioned compounds of formula (I) have a structure represented by formula (IV),

Wherein R ³、R⁴、R⁵, ring A, ring B, n, p are as defined above for the compound of formula (I), and ring A is not a piperidine ring.

In some embodiments, the aforementioned compounds of formula (I) have a structure represented by formula (IV-a),

In some embodiments, the aforementioned compounds of formula (I) have the structure shown in formula (V),

Wherein R ³、R⁴、R⁵, ring A, L ², n, p are as defined for the compounds of formula (I) above.

In some embodiments, the aforementioned compounds of formula (I) have the structure shown in formula (VII),

Wherein R ³、R⁵, ring A, L ², n, p are as defined for the compounds of formula (I) above.

In some embodiments, the aforementioned compounds of formula (I) have the structure shown in formula (VIII),

Wherein R ³、R⁵, ring A, n, p are as defined above for the compound of formula (I), and ring A is not a piperidine ring.

In some embodiments, the aforementioned compounds of formula (I) have a structure represented by formula (VIII-a),

In some embodiments, the application is selected from the following compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof:

In another aspect, the present application relates to pharmaceutical compositions comprising the compounds of formula (I) of the present application, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In some embodiments, the pharmaceutical compositions of the present application comprise a therapeutically effective amount of a compound of formula (I) of the present application, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In some embodiments, the pharmaceutical compositions of the present application further comprise pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.

Typical routes of administration of the compounds of the application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.

The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, this can be achieved by mixing the active compound with solid auxiliary substances, optionally grinding the resulting mixture, adding further suitable auxiliary substances if desired, and processing the mixture into granules, giving tablets or dragee cores. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents and the like.

In another aspect, the present application relates to a method of treating a disorder mediated by aberrant RET activity in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) of the present application, stereoisomers and pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

In all methods of administration of the compounds of formula (I), stereoisomers or pharmaceutically acceptable salts thereof, of the application, the dosages administered daily are from 0.01 to 100mg/kg body weight, preferably from 0.05 to 50mg/kg body weight, more preferably from 0.1 to 5mg/kg body weight, either as individual or divided dosages.

In another aspect, the present application relates to the use of a compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of a disease mediated by aberrant RET activity.

In another aspect, the present application relates to the use of a compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of a disease mediated by aberrant RET activity.

In another aspect, the present application relates to compounds of formula (I), stereoisomers thereof, and pharmaceutically acceptable salts thereof, for the prevention or treatment of diseases mediated by aberrant RET activity.

Diseases mediated by the aberrant RET activity described herein include cancer.

In some embodiments, the cancer in the present application is selected from Papillary Thyroid Cancer (PTC), medullary Thyroid Cancer (MTC), pheochromocytoma (PC), pancreatic cancer, multiple endocrine tumors (MEN 2A and MEN 2B), breast cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, hematological tumor, colorectal cancer, ovarian cancer, cervical cancer, gastric cancer, prostate cancer, salivary gland cancer.

Definition of the definition

The following terms used in the present application have the following meanings unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present application prepared from the compounds of the present application which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present application contain relatively acidic functional groups, base addition salts may be obtained by contacting a suitable base with the neutral form of such compounds. When the compounds of the present application contain relatively basic functional groups, the acid addition salts may be obtained by contacting a suitable acid with a neutral form of such compounds. Certain specific compounds of the application contain basic and acidic functionalities that can be converted to either base or acid addition salts.

Certain compounds of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present application.

When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E, Z geometric isomers unless specified otherwise. Likewise, all tautomeric forms are included within the scope of the application, e.g.,And (3) withIn tautomeric form.

The compounds of the application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present application. For example, inclusion in the structure of the compoundAre diastereomers, e.g. comprised in the structure of the compoundAre the (R) -and (S) -enantiomers.

Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the application is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Or when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), forms a diastereomeric salt with an appropriate optically active acid or base, and then undergoes diastereomeric resolution by conventional methods well known in the art, followed by recovery of the pure enantiomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).

The compounds of the present application may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with a radioisotope, such as deuterium (² H), tritium (³ H), iodine-125 (¹²⁵ I) or C-14 (¹⁴ C). All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.

The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent to achieve a desired effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.

The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl can be unsubstituted (CH ₂CH₃), monosubstituted (e.g., CH ₂CH₂ F), polysubstituted (e.g., CHFCH ₂F、CH₂CHF₂, etc.), or fully substituted (CF ₂CF₃). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.

As used herein C _m-n refers to having m-n carbon atoms in this moiety. For example, "C _3-10 cycloalkyl" means that the cycloalkyl has 3 to 10 carbon atoms. "C _0-6 alkylene" means that the alkylene has 0 to 6 carbon atoms, and when the alkylene has 0 carbon atoms, the group is a bond.

Numerical ranges herein refer to individual integers within a given range. For example, "C _1-10" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =o) (also referred to as oxo), meaning that both hydrogen atoms are substituted, ketone substitution does not occur on the aromatic group.

When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.

When one of the variables is selected from a bond, the two groups representing its attachment are directly linked, e.g., when L in A-L-Z represents a bond, it is meant that the structure is actually A-Z.

When a substituent is absent, it is meant that the substituent is absent, e.g., X in A-X is absent, meaning that the structure is actually A. Where a bond of a substituent may cross-connect to two atoms on a ring, the substituent may be bonded to any atom on the ring. When none of the listed substituents indicates through which atom it is attached to a compound included in the chemical formula but not specifically mentioned, such substituents may be bonded through any of their atoms. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, structural unitsMeaning that it may be substituted at any one position on the cyclohexyl or cyclohexadiene. For example structural unitsRepresentation of

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

The term "hydroxy" refers to-OH.

The term "cyano" refers to-CN.

The term "amino" refers to-NH ₂.

The term "nitro" refers to-NO ₂.

The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. The term "C _1-6 alkyl" as used herein, including all isomeric forms thereof, e.g., propyl includes-CH ₂CH₂CH₃、-CH(CH₃)₂, and butyl includes -CH₂CH₂CH₂CH₃、-CH(CH₃)(CH₂CH₃)、-C(CH₃)₃、-CH₂CH(CH₃)₂., refers to an alkyl group having from 1 to 6 carbon atoms. The term "C _1-4 alkyl" refers to an alkyl group having 1 to 4 carbon atoms. The term "C _1-3 alkyl" refers to an alkyl group having 1 to 3 carbon atoms. The "alkyl", "C _1-8 alkyl", "C _1-6 alkyl" or "C _1-3 alkyl" may be unsubstituted or substituted with one or more substituents selected from hydroxy, halogen or amino.

The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means-CH ₂ -, and "ethylene" means-CH ₂-CH₂ -, "propylene" means-CH ₂-CH₂-CH₂ -, and "butylene" means-CH ₂-CH₂-CH₂-CH₂ -, etc.

The term "alkoxy" refers to an alkyl group as described above having a specified number of carbon atoms attached through an oxygen bridge. C _1-6 alkoxy includes the alkoxy groups of C ₁、C₂、C₃、C₄、C₅ and C ₆. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy.

The term "alkyleneoxy" refers to an alkoxy group in which one hydrogen atom is further substituted.

The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2 to 12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, and 3-hexenyl. One of the double bond carbons may optionally be the attachment point for an alkenyl substituent.

The term "alkynyl" refers to a straight or branched hydrocarbon chain containing from 2 to 12 carbon atoms and characterized by having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the attachment point of an alkynyl substituent.

Unless otherwise specified, the term "hetero" means a heteroatom or a heteroatom group (i.e., a heteroatom-containing group) including atoms other than carbon (C) and hydrogen (H) as well as groups containing such heteroatoms, including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S- = O, = S, -C (=o) O-, -C (=o) -, -C (=s) -, -S (=o) ₂ -, and-C (=o) N (H) -, -C (=nh) -, -S (=o) ₂ N (H) -, or-S (=o) N (H) -.

Unless otherwise specified, the term "monocyclic" denotes a saturated or partially saturated monocyclic cyclic hydrocarbon, the monocyclic ring containing 3 to 12 carbon atoms, preferably containing 3 to 8 carbon atoms, more preferably containing 3 to 6 carbon atoms. Non-limiting examples of monocyclic rings include cyclopropane ring, cyclobutane ring, cyclopentene ring, cyclohexane ring, cyclohexene ring, cyclohexadiene ring, cycloheptane ring, cycloheptatriene ring, cyclooctane ring, and the like.

The term "cycloalkyl" refers to a saturated monocyclic ring.

The term "mono-heterocyclic" refers to a single ring having 3-12 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from N, O, S (O) _n (wherein n is 0,1 or 2) and the remaining ring atoms are C. Such rings may be saturated or unsaturated (e.g., having one or more double bonds), but do not have a fully conjugated pi-electron system. Examples of 3-membered saturated mono-heterocycles include, but are not limited toExamples of 4-membered saturated mono-heterocycles include, but are not limited toExamples of 5-membered saturated mono-heterocycles include, but are not limited to Examples of 6-membered saturated mono-heterocycles include, but are not limited to Examples of 7-membered saturated mono-heterocycles include, but are not limited toExamples of 5-membered unsaturated mono-heterocycles include, but are not limited toExamples of 6-membered unsaturated mono-heterocycles include, but are not limited to

The term "heterocycloalkyl" refers to a saturated mono-heterocycle.

The term "bridged heterocyclic ring" refers to a 5-14 membered, polycyclic ring in which two or more rings share two or more atoms, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system, wherein one or more ring atoms are selected from heteroatoms of N, O, S (O) _n (where n is 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14-membered, more preferably 6 to 10-membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycle, preferably bicyclic or tricyclic, more preferably bicyclic. Non-limiting examples of bridged heterocycles include:

The term "fused ring" refers to an all-carbon polycyclic ring of 7-20 membered in which two rings share two adjacent carbon atoms, at least one of the rings having a fully conjugated pi-electron system. Preferably 6 to 14-membered, more preferably 6 to 10-membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic ring, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic ring. Non-limiting examples of fused rings include:

The term "fused heterocycle" refers to a 5-20 membered ring in which two rings share multiple rings of adjacent two ring atoms, at least one of which has a fully conjugated pi electron system, wherein one or more ring atoms are selected from the group consisting of heteroatoms of N, O, S (O) _n (where n is 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14-membered, more preferably 6 to 10-membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic ring, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic ring. Non-limiting examples of fused heterocycles include:

The term "fused heteroaryl ring" refers to a fused heterocycle having a ring system with a fully conjugated pi electron system, non-limiting examples of fused heteroaryl rings include:

The term "heteroaryl ring" or "heteroaryl" refers to a single ring having a conjugated pi-electron system comprising 1 to 4 heteroatoms, 5 to 8 ring atoms, wherein the heteroatoms are selected from O, N, S and the remaining ring atoms are C. Heteroaryl is preferably 5 to 6 membered, containing 1 to 3 heteroatoms, more preferably 5 or 6 membered, containing 1 to 2 heteroatoms, preferably such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, and the like, preferably imidazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, or pyrazinyl.

In the present application, the connection mode of L ¹、L² to the ring a and the ring B indicates a sequential connection from left to right. For example, -L ² -is selected from-N (R ^A1)-C(O)-(CR^A2R^B2)_q -only represents ring A-N (R ^A1)-C(O)-(CR^A2R^B2)_q -ring B).

"EA" refers to ethyl acetate.

"TFA" refers to trifluoroacetic acid.

"DCM" refers to dichloromethane.

"DMF" refers to N, N-dimethylformamide.

"HATU" refers to 2- (7-oxo-benzotriazol) -N, N' -tetramethyluronium hexafluorophosphate.

"DMSO" refers to dimethyl sulfoxide.

"EDTA" refers to ethylenediamine tetraacetic acid.

"BINAP" refers to 1,1 '-binaphthyl-2, 2' -diphenylphosphine.

"Dioxane" refers to Dioxane.

"Pd ₂dba₃" refers to tris (dibenzylideneacetone) dipalladium.

"DavePhos" refers to 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl.

"LiHMDS" refers to lithium hexamethyldisilazide.

"THF" refers to tetrahydrofuran.

"DIPEA" refers to N, N' -diisopropylethylamine.

"Triphosgene" refers to triphosgene.

"CDI" refers to N' N-carbonyldiimidazole.

The room temperature is 20-30 ℃.

Description of the preferred embodiments

The present application is described in detail below by way of examples, but is not meant to be limiting in any way. The present disclosure has been described in detail herein, and specific embodiments thereof are disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the disclosed embodiments without departing from the spirit and scope of the application.

Example 1 preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

step A preparation of 1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethanone

To a 250 mL-sealed tube were added 10g (71.88 mmol) of 2-fluoro-5-acetylpyridine, 100mL of DMF, 6.18g (71.88 mmol) of 4-fluoro-1H-pyrazole and 9.93g (71.88 mmol) of potassium carbonate, and the mixture was heated to 100℃and stirred for 10 hours. The heating was turned off, and the reaction solution was cooled to room temperature, poured into 400mL of water, and stirred for 30min. The mixture was filtered, and the cake was washed with water, collected and dried to give 13.7g of a beige target product. The crude product was used directly in the next reaction without purification.

Step B preparation of (R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide

A500 mL three-necked round bottom flask was charged with 150mL anhydrous tetrahydrofuran, 13.7g (66.7 mmol) of 1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethanone, 8.09g (66.7 mmol) of R-t-butylsulfinamide, 17.92g (133.4 mmol) of diethylene glycol dimethyl ether and 30.46g (133.4 mmol) of tetraethyl titanate, and the reaction mixture was heated to reflux for 5 hours. The reaction solution was cooled to-78℃and 200.3mL of a 1M solution of lithium tri-sec-butylborohydride in tetrahydrofuran was slowly added dropwise under nitrogen protection, and the reaction was continued under stirring at-78℃for 40min after the completion of the addition. The reaction was quenched by dropwise addition of 20mL of methanol, and the reaction mixture was naturally warmed to 0℃and poured into 500mL of water with stirring. The mixture was filtered, and the filter cake was washed with ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give crude product as a yellow oil. 150mL of petroleum ether was added to the crude product, and the mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with petroleum ether to give 12.1g of an off-white target. The product was used directly in the next reaction without purification.

Step C preparation of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethanamine dihydrochloride

Into a 250mL round bottom flask was added 12.1g of (R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide and 50mL of methanol. After dissolution by stirring, 100mL of a 1M solution of 1, 4-dioxane in hydrogen chloride was added under the same conditions, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated to give a crude product as a pale yellow oil, to which 30mL of ethyl acetate was added and left to stir at room temperature for 1.5 hours. The mixture was filtered, and the filter cake was washed with a small amount of ethyl acetate, and the filter cake was collected and dried to obtain 9.4g of a pale yellow target product.

MS(ESI,[M+H]⁺)m/z:207.1.

Step D preparation of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

To a 100mL round bottom flask was added 12g (73.6 mmol) of 2, 4-dichloro-6-methylpyridine, 50mL of DMSO, 7.86g (73.6 mmol) of 5-methyl-1H-pyrazol-3-amine, and 14.2g (1.10 mmol) of diisopropylethylamine, and the reaction was heated to 60℃and reacted overnight. The reaction solution was cooled to room temperature, poured into 400mL of water, extracted with methyl tert-butyl ether, and the combined organic phases were washed with saturated aqueous NaCl solution and dried. The organic phase was concentrated and the resulting crude product was added to 50mL of dichloromethane and slurried overnight with stirring. The mixture was filtered, and the filter cake was washed with a small amount of methylene chloride, collected and dried to give 9.9g of a white target.

MS(ESI,[M+H]⁺)m/z:224.1.

Preparation of 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester

In a 100mL round bottom flask, 0.5g (2.235 mmol) of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, 5mL of DMF and 0.833g (4.47 mmol) of tert-butyl piperazine-1-carboxylate were added sequentially, and the mixture was heated to 100℃under N ₂ protection to react for 7H. The reaction solution was poured directly into 50mL of ice water, and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave 1.5g of colorless oil. Purification by column chromatography gave 0.8g of an off-white powdery solid.

MS(ESI,[M+H]⁺)m/z:374.4。

Step F preparation of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate

In a 50mL round bottom flask, 0.78g (1.938 mmol) of tert-butyl 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxylate, 10mL of DCM and 1.105g (9.69 mmol) of trifluoroacetic acid were successively added, stirred at room temperature overnight, and after completion of the reaction, the reaction solution was concentrated to give 0.8g of a white solid product which was directly used for the next reaction without purification.

¹H-NMR(500MHz,DMSO-d₆):δ10.85(s,1H),9.31(s,2H),6.38(s,1H),6.24(s,1H),3.99(s,4H),3.29(s,4H),2.33(s,3H),2.35(s,3H);

MS(ESI,[M+H]⁺)m/z:274.4。

Step G preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

Triphosgene 0.011g (0.037 mmol) was dissolved in 3mL of dichloromethane, the ice salt bath was cooled to 0℃under N ₂, and 2mL of a dichloromethane solution containing (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethan-1-amine dihydrochloride 0.030g (0.107 mmol) and triethylamine 0.086g (0.852 mmol) was added dropwise. After the reaction solution was stirred at 0℃for 5 minutes, 0.05g (0.107 mmol) of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate and triethylamine were added thereto, and the mixture was stirred at room temperature for 20 minutes. After completion of the reaction, 50mL of methylene chloride was added to the reaction mixture to dilute it, and the mixture was washed with 10mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the obtained crude product was purified by column chromatography to obtain 32mg of the target product as a white powdery solid.

¹H NMR(500MHz,DMSO-d₆):δ11.82(s,1H),9.25(s,1H),8.66(d,J＝4.5Hz,1H),8.42(s,1H),7.96(d,J＝8.5Hz,1H),7.89(m,2H),6.97(d,J＝7.5Hz,1H),6.22(br,1H),6.14(br,1H),4.94(m,1H),3.68(s,4H),3.40(s,4H),2.21(s,3H),2.13(s,3H),1.45(d,J＝7.0Hz,3H);

MS(ESI,[M+H]⁺)m/z:506.5。

EXAMPLE 2 preparation of (1S, 4S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -5- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,DMSO-d₆):δ11.88(s,1H),9.30(br,1H),8.63(s,1H),8.39(s,1H),7.89(m,3H),6.74(s,1H),6.23(br,2H),4.86(m,1H),3.65(m,3H),3.07(m,3H),2.21(s,3H),2.12(s,3H),1.40(d,J＝7.0Hz,3H),1.26(t,J＝7.0Hz,2H);

MS(ESI,[M+H]⁺)m/z:518.34。

Example 3 preparation of (1R, 4R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -5- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H-NMR(500MHz,DMSO-d₆):δ11.88(s,1H),9.97(s,1H),8.64(d,J＝5.0Hz,1H),8.37(d,J＝5.0Hz,1H),7.85(m,3H),6.73(s,1H),6.23(br,2H),4.89(m,1H),3.43(m,2H),3.07(m,4H),2.19(s,3H),2.13(s,3H),1.42(d,J＝10.0Hz,3H),1.24(s,2H);

MS(ESI,[M+H]⁺)m/z:518.29。

EXAMPLE 4 preparation of N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -6- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-3-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,DMSO-d₆):δ12.30(s,1H),10.51(s,1H),8.64(d,J＝3.5Hz,1H),8.35(s,1H),7.90(d,J＝4.5Hz,2H),7.81(d,J＝8.5Hz,1H),6.76(s,1H),6.31(m,2H),4.88(m,1H),3.90(m,2H),3.46(m,2H),3.05(m,2H),2.37(s,3H),2.29(s,3H),1.59(s,2H),1.40(m,3H);

MS(ESI,[M+H]⁺)m/z:518.5。

EXAMPLE 5 preparation of N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,DMSO-d₆):δ11.92(s,1H),10.45(s,1H),8.55(m,1H),8.29(s,1H),7.88(m,1H),7.79(d,J＝8Hz,1H),7.66(d,J＝9Hz,1H),7.22(m,1H),6.31(s,1H),6.18(s,1H),4.82(m,1H),4.31(m,2H),4.10(m,2H),3.48(m,2H),2.21(s,3H),2.15(s,3H),1.43(m,3H),1.36(m,2H);

MS(ESI,[M+H]⁺)m/z:518.5。

Example 6:N preparation of- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -8- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H-NMR(500MHz,DMSO-d₆):δ11.87(s,1H),9.32(s,1H),8.67(d,J＝5.0Hz,1H),8.39(s,1H),7.90(m,3H),6.77(d,J＝5.0Hz,1H),6.15(m,2H),4.91(m,1H),4.66(s,2H),3.74(d,J＝10.0Hz,2H),3.00(d,J＝10.0Hz,2H),2.21(s,3H),2.14(s,3H),1.84(s,2H),1.69(d,J＝5.0Hz,2H),1.42(d,J＝10.0Hz,3H);

MS(ESI,[M+H]⁺)m/z:532.30。

EXAMPLE 7 preparation of N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H-NMR(500MHz,DMSO-d₆):δ11.88(s,1H),9.90(s,1H),8.67(d,J＝5.0Hz,1H),8.42(s,1H),7.92(m,3H),7.13(d,J＝5.0Hz,1H),6.15(m,2H),4.96(m,1H),4.42(d,J＝5.0Hz,2H),4.29(d,J＝5.0Hz,2H),3.08(d,J＝5.0Hz,2H),2.21(s,3H),2.13(s,3H),1.75(s,2H),1.59(d,J＝10.0Hz,2H),1.46(d,J＝5.0Hz,3H);

MS(ESI,[M+H]⁺)m/z:532.30。

EXAMPLE 8 preparation of (R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,CDCl₃)δ8.37–8.38(m,2H),7.89(d,J＝8.5Hz,1H),7.77(d,J＝7.7Hz,1H),7.56(d,J＝4.0Hz,1H),7.19(s,1H),6.06(d,J＝21.0Hz,2H),5.06–5.11(m,1H),4.75(d,J＝6.0Hz,1H),4.54(d,J＝12.5Hz,1H),4.45(d,J＝13.0Hz,1H),4.15(s,1H),3.76(d,J＝12.5Hz,1H),3.20–3.27(m,2H),3.05–3.11(m,1H),2.29(s,3H),2.23(s,3H),1.54(d,J＝7.0Hz,3H),1.19(d,J＝6.5Hz,3H);

MS(ESI,[M+H]⁺)m/z:520.27。

Example 9 preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,CDCl₃)δ8.38–8.40(m,2H),7.90(d,J＝8.5Hz,1H),7.79(dd,J＝8.5,2.5Hz,1H),7.58(d,J＝4.0Hz,1H),7.31(s,1H),6.07(d,J＝17.0Hz,2H),5.08–5.18(m,1H),4.81(d,J＝7.0Hz,1H),4.55(d,J＝12.5Hz,1H),4.47(d,J＝13.0Hz,1H),4.13–4.18(m,1H),3.80(d,J＝13.0Hz,1H),3.21–3.27(m,2H),3.07–3.13(m,1H),2.30(s,3H),2.24(s,3H),1.56(d,J＝7.0Hz,3H),1.21(d,J＝7.0Hz,3H);

MS(ESI,[M+H]⁺)m/z:520.25。

Example 10 (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -7- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -4, 7-diazaspiro [2.5] octane-4-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,CDCl₃)δ8.36–8.37(m,2H),7.88(d,J＝8.5Hz,1H),7.75(d,J＝8.5Hz,1H),7.56(d,J＝4.5Hz,2H),6.03(s,2H),5.66(d,J＝7.0Hz,1H),5.07–5.20(m,1H),3.67(s,6H),2.26(s,3H),2.19(s,3H),1.56(d,J＝7.0Hz,3H),1.01(d,J＝15.5Hz,4H);

MS(ESI,[M+H]⁺)m/z:532.28。

EXAMPLE 11 preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,CDCl₃)δ8.39–8.40(m,2H),7.90(d,J＝8.5Hz,1H),7.79(d,J＝8.5Hz,1H),7.58(d,J＝4.5Hz,1H),7.18(s,1H),6.07(d,J＝18.0Hz,2H),5.07–5.14(m,1H),4.87(s,1H),4.77(d,J＝6.5Hz,1H),4.46(d,J＝13.5Hz,1H),3.90(d,J＝12.0Hz,1H),3.69(d,J＝13.0Hz,1H),3.29–3.35(m,2H),3.05–3.11(m,1H),2.30(s,3H),2.25(s,3H),1.57(d,J＝7.0Hz,3H),1.23(d,J＝6.5Hz,3H);

MS(ESI,[M+H]⁺)m/z:520.5。

EXAMPLE 12 preparation of (R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,CDCl₃)δ8.40–8.41(m,2H),7.92(d,J＝8.5Hz,1H),7.81(d,J＝8.5Hz,1H),7.59(d,J＝4.0Hz,1H),6.97(s,1H),6.09(d,J＝25.0Hz,2H),5.10–5.15(m,1H),4.88(s,1H),4.68(d,J＝6.6Hz,1H),4.50(d,J＝13.3Hz,1H),3.89(d,J＝12.0Hz,1H),3.69(d,J＝13.0Hz,1H),3.30–3.38(m,2H),3.07–3.13(m,1H),2.33(s,3H),2.27(s,3H),1.57(d,J＝7.0Hz,3H),1.25(s,3H).

MS(ESI,[M+H]⁺)m/z:520.5。

EXAMPLE 13 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N-phenylpiperazine-1-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,CDCl₃)δ7.39(d,J＝8.0Hz,2H),7.29(t,J＝8.0Hz,2H),7.04(t,J＝7.5Hz,1H),6.96(s,1H),6.50(s,1H),6.14(s,1H),6.02(s,1H),3.87(s,4H),3.58(s,4H),2.31(s,3H),2.25(s,3H).

MS(ESI,[M+H]⁺)m/z:393.3。

Example 14 (S) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (pyridin-3-yl) ethyl) -1-carboxamide

The synthesis method is described in example 1.

¹H NMR(500MHz,CDCl₃)δ8.63(s,1H),8.50(s,1H),7.66(d,J＝10.0Hz,1H),6.84(s,1H),6.15(s,1H),6.01(s,1H),5.34(s,1H),5.08(m,1H),4.72(d,J＝7.0Hz,1H),3.82(s,4H),3.57(s,4H),2.31(s,3H),2.26(s,3H),1.54(d,J＝7.0Hz,3H).

MS(ESI,[M+H]⁺)m/z:422.4。

EXAMPLE 15 preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -2-aza-spiro [3.3] heptane-6-carboxamide

The reaction flow is as follows:

step A preparation of (S) -6- ((1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) carbamoyl) -2-azaspiro [3.3] heptane-2-tert-butyl carboxylate

To a 50mL round bottom flask were successively added 0.4g (1.658 mmol) of 2- (tert-butoxycarbonyl) -2-azaspiro [3.3] heptane-6-carboxylic acid, 5mL of tetrahydrofuran, (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethanamine dihydrochloride 0.463g (1.658 mmol), HATU0.693g (1.824 mmol) and 0.857g (6.63 mmol) of N, N-diisopropylethylamine, and after completion of the reaction, the reaction was stirred at room temperature, and stirring was stopped to add 100mL of ethyl acetate and 20mL of water to the reaction system. The organic phase was collected, washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated, and the crude product was purified by column chromatography to give 0.7g of a white powdery solid product.

MS(ESI,[M+Na]⁺)m/z:452.4。

Step B preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-aza-spiro [3.3] heptane-6-carboxamide

To a 50mL round bottom flask was added successively 0.27g (0.624 mmol) of (S) -6- ((1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) carbamoyl) -2-azaspiro [3.3] heptane-2-tert-butylcarboxylate, 5mL of acetonitrile and 0.764g (4.99 mmol) of trimethylbromosilane and stirred at room temperature for 3H. After the completion of the reaction, 20mL of water was added to the reaction system, followed by extraction with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave 0.13g of a grayish oil. Without further purification, it was used directly in the next reaction.

MS(ESI,[M+H]⁺)m/z:330.2。

Step C preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -2-aza-spiro [3.3] heptane-6-carboxamide

To a 35mL microwave tube, 0.12g (0.364 mmol) of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-aza-spiro [3.3] heptane-6-carboxamide, 10mL of isopropanol, 0.147g (1.457 mmol) of triethylamine, 0.081g (0.364 mmol) of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine were successively added, and the reaction was heated at 120℃for 2 hours using a microwave reactor. After the reaction was completed, the reaction solution was poured into 50mL of water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine three times and then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated, and the crude product was subjected to column chromatography to give 82mg of the target product as a white powdery solid.

¹H NMR(500MHz,DMSO-d₆):δ12.04(s,1H),8.67(d,J＝4.5Hz,1H),8.36(m,2H),7.95(m,3H),6.25(m,2H),4.99(t,J＝7.5Hz,1H),4.11(s,2H),3.99(s,2H),2.98(t,J＝8.0Hz,1H),2.36(d,J＝8.0Hz,3H),2.19(m,7H),1.40(d,J＝7.0Hz,3H);

MS(ESI,[M+H]⁺)m/z:517.5。

Example 16 preparation of (1R, 5S, 6R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide

The reaction flow is as follows:

The synthesis method is described in example 15.

¹H NMR(500MHz,DMSO-d₆):δ12.00(s,1H),8.67(s,1H),8.59(d,J＝6.5Hz,1H),8.40(s,1H),7.90(m,4H),6.25(m,2H),5.00(d,J＝6.0Hz,1H),3.91(s,2H),3.56(s,2H),3.10(s,1H),2.21(m,3H),2.03(m,3H),1.42(s,2H),1.24(s,3H);

MS(ESI,[M+H]⁺)m/z:503.4。

Example 17 preparation of (1R, 3R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -8- (4-methyl-6- (5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -8-azabicyclo [3.2.1] octane-3-carboxamide

The reaction flow is as follows:

The synthesis method is described in example 15.

¹H-NMR(500MHz,DMSO-d₆)：δ11.83(s,1H),9.22(br,1H),8.65(d,J＝4.5Hz,1H),8.33(m,2H),7.91-7.85(m.3H),6.15(br,2H),4.90(t,J＝7.5Hz,1H),4.60(m,2H),2.88(m,1H),2.18(s,3H),2.11(s,3H),1.37(d,J＝7Hz,3H),1.97(m,2H),1.78(m,2H),1.51(m,3H);

MS(ESI,[M+H]⁺)m/z:531.4。

EXAMPLE 18 preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidine-4-sulfonamide

The reaction flow is as follows:

Step A preparation of (S) -tert-butyl 4- (N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) sulfanyl) piperidine-1-carboxylate

To a 25mL round bottom flask was added 0.17g (0.71 mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethanamine dihydrochloride, 5mL of dichloromethane, 0.14g (1.41 mmol) of triethylamine, 0.2g (0.71 mmol) of N-t-butoxycarbonyl-4-chlorosulfonylpiperidine in this order, and the reaction was stirred at room temperature overnight. After completion of the reaction, 50mL of methylene chloride was added thereto for dilution, and the mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was collected and concentrated, and the resulting crude product was purified by column chromatography to give 0.36g of an off-white solid.

¹H-NMR(500MHz,DMSO-d₆)：δ8.68(d,J＝4.5Hz,1H),8.46(d,J＝1Hz,1H),8.02(dd,J＝1.5Hz,8.5Hz,1H),7.93-7.88(m,3H),4.62(m,1H),4.00(m,2H),3.07(m,1H),2.03-1.94(m,2H),1.46(m,4H),1.36(m,12H);

MS(ESI,[M+Na]⁺)m/z:476.5。

Step B preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylpiperidine-4-sulfonylamine hydrochloride

(S) -4- (N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) sulfanyl) piperidine-1-carboxylic acid tert-butyl ester 0.36g (0.81 mmol) was dissolved in 10mL of 1mol/L HCl in methanol, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated to obtain 0.27g of a crude product. The obtained product was used directly in the next reaction without purification.

Step C preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidine-4-sulfonamide

In a 35mL microwave tube, 0.13g (0.33 mmol) of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylpiperidine-4-sulfonamide hydrochloride, 10mL of isopropyl alcohol, 0.14g (1.33 mmol) of triethylamine, 0.075g (0.33 mmol) of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine were sequentially added, and after the completion of the reaction, the reaction solution was poured into 50mL of water, extracted twice with ethyl acetate, and the organic phase was combined, and after the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 43mg of a white powdery solid target product by column chromatography.

¹H-NMR(500MHz,DMSO-d₆)：δ11.85(s,1H),9.20(s,1H),8.67(d,J＝4.5Hz,1H),8.47(s,1H),8.01(d,J＝8.5Hz,1H),7.92-7.85(m,3H),6.22(br,1H),6.09(br,1H),4.71(t,J＝8.5Hz,1H),4.63(t,J＝7Hz,1H),3.14(t,J＝8.5Hz,1H),2.81(t,1H),2.81(t,J＝12Hz,1H),2.71(t,J＝12Hz,1H),2.20(s,3H),2.10(s,3H),2.00(d,J＝12.5Hz,1H),1.90(d,J＝12.5Hz,1H),1.46(m,4H);

MS(ESI,[M+H]⁺)m/z:541.4。

EXAMPLE 19 preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

step A preparation of tert-butyl (S) -4- (6-chloro-4-methylpyridin-2-yl) -2-methylpiperazine-1-carboxylate

To a 30 mL-sealed tube was successively added 2, 6-dichloro-4-methylpyridine (1 g,6.17 mmol), tert-butyl (S) -2-methylpiperazine-1-carboxylate (1.236 g,6.17 mmol), palladium acetate (0.069 g,0.309 mmol), BINAP (0.284 g, 0.627 mmol), cesium carbonate (3.02 g,9.26 mmol) and Dioxane, and after blowing off air with nitrogen, the mixture was placed in a microwave reactor and heated to 120℃for 2 hours. The filtrate was filtered, collected and concentrated, and the resulting crude product was purified by column chromatography to give 0.44g of the target product as a brown solid.

MS(ESI,[M+H]⁺)m/z:326.1.

Step B preparation of tert-butyl (S) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate

To a 20 mL-sealed tube was added tert-butyl (S) -4- (6-chloro-4-methylpyridin-2-yl) -2-methylpiperazine-1-carboxylate (439 mg,1.349 mmol), 5-methyl-1H-pyrazol-3-amine (131mg,1.349mmol),Pd₂dba₃(61.8mg,0.067mmol),DavePhos(53.1mg,0.135mmol),LiHMDS(564mg,3.37mmol) and THF (3 mL) in this order, and the air was purged with nitrogen, placed in a microwave reactor, and heated to 130℃for 30 minutes at 100W for reaction. The reaction was quenched by dropwise addition of 2mL of 1M saturated ammonium chloride solution in ice bath and diluted with 20mL ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was concentrated and the crude product was purified by column chromatography to give 0.320g of the target yellow solid.

MS(ESI,[M+H]⁺)m/z:387.2.

Step C preparation of (S) -4-methyl-N- (5-methyl-1H-pyrazol-3-yl) -6- (3-methylpiperazin-1-yl) pyridin-2-amine trifluoroacetate salt

In a 50mL round bottom flask, tert-butyl (S) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate 0.320g (0.83 mmol), DCM 10mL and trifluoroacetic acid 0.473g (4.15 mmol) were added sequentially, stirred at room temperature overnight, and after the reaction was completed, the reaction solution was concentrated to give 0.31g of a white solid product which was used directly in the next reaction without purification.

MS(ESI,[M+H]⁺)m/z:287.1.

Step D preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

Triphosgene 0.011g (0.037 mmol) was dissolved in 5mL of dichloromethane, the ice salt bath was cooled to 0℃under nitrogen, and 2mL of a dichloromethane solution containing (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethanamine dihydrochloride 0.226g (0.807 mmol) and triethylamine 0.716g (6.456 mmol) was added dropwise. After the reaction solution was stirred at 0℃for 5 minutes, 0.31g (0.807 mmol) of (S) -4-methyl-N- (5-methyl-1H-pyrazol-3-yl) -6- (3-methylpiperazin-1-yl) pyridin-2-amine trifluoroacetate and triethylamine were added thereto, and the mixture was stirred at room temperature for 20 minutes. After completion of the reaction, 50mL of methylene chloride was added to the reaction mixture to dilute it, and the mixture was washed with 20mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the obtained crude product was purified by column chromatography to obtain 131mg of the target product as a white powdery solid.

¹H-NMR(500MHz,DMSO-d₆):8.39(d,J＝12.5Hz,2H),7.84(d,J＝30.1Hz,2H),7.57(s,1H),7.38(s,1H),6.92(s,2H),6.07(s,1H),5.88(d,J＝17.4Hz,2H),5.17(s,1H),4.18(s,1H),3.97-3.99(m,1H),3.78-3.89(m,2H),3.19–3.29(m,2H),2.99–3.03(m,1H),2.26(s,3H),2.18(s,3H),1.56(s,3H),1.23(s,3H);

MS(ESI,[M+H]⁺)m/z:519.3.

EXAMPLE 20 preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

step A preparation of tert-butyl (S) -4- (4-chloro-6-methylpyridin-2-yl) -2-methylpiperazine-1-carboxylate

In a25 mL single-necked flask, 2, 4-dichloro-6-methylpyridine (2 g,12.34 mmol), tert-butyl (S) -2-methylpiperazine-1-carboxylate (2.72 g,13.58 mmol), et ₃ N (1.499 g,2.065mL,14.81 mmol) and DMSO (20 mL) were added sequentially, and the mixture was heated to 100℃under nitrogen to react for 16h. To the reaction solution was added 10mL of water, and extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown oil, which was purified by column chromatography to obtain 1.24g of the target compound as a brown solid.

MS(ESI,[M+H]⁺)m/z:326.3.

Step B preparation of tert-butyl (S) -2-methyl-4- (6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate

To a 20 mL-sealed tube was added tert-butyl (S) -4- (6-chloro-4-methylpyridin-2-yl) -2-methylpiperazine-1-carboxylate (439 mg,1.349 mmol), 5-methyl-1H-pyrazol-3-amine (131mg,1.349mmol),Pd₂dba₃(61.8mg,0.067mmol),DavePhos(53.1mg,0.135mmol),LiHMDS(564mg,3.37mmol) and THF (3 mL) in this order, and the air was purged with nitrogen, placed in a microwave reactor, and heated to 130℃for 30 minutes at 100W for reaction. The reaction was quenched by dropwise addition of 2mL of 1M saturated ammonium chloride solution in ice bath and diluted with 20mL ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was concentrated and the crude product was purified by column chromatography to yield 0.309g of the target yellow solid.

MS(ESI,[M+H]⁺)m/z:387.4.

Step C preparation of (S) -2-methyl-N- (5-methyl-1H-pyrazol-3-yl) -6- (3-methylpiperazin-1-yl) pyridin-4-amine

In a 50mL round bottom flask, tert-butyl (S) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate 0.309g (0.801 mmol), DCM 10mL and trifluoroacetic acid 0.456g (4.01 mmol) were added sequentially, stirred at room temperature overnight, and after completion of the reaction was concentrated to give 0.30g of a white solid product which was used directly in the next reaction without purification.

MS(ESI,[M+H]⁺)m/z:287.1.

Step D preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

Triphosgene 0.011g (0.037 mmol) was dissolved in 5mL of dichloromethane, the ice salt bath was cooled to 0℃under nitrogen, and 2mL of a dichloromethane solution containing (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethan-1-amine dihydrochloride 0.218g (0.807 mmol) and triethylamine 0.717g (6.456 mmol) was added dropwise. After the reaction solution was stirred at 0℃for 5 minutes, 0.30g (0.780 mmol) of (S) -4-methyl-N- (5-methyl-1H-pyrazol-3-yl) -6- (3-methylpiperazin-1-yl) pyridin-2-amine trifluoroacetate and triethylamine were added thereto, and the mixture was stirred at room temperature for 20 minutes. After completion of the reaction, 50mL of methylene chloride was added to the reaction mixture to dilute it, and the mixture was washed with 20mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the obtained crude product was purified by column chromatography to obtain 120mg of the target product as a white powdery solid.

¹H-NMR(500MHz,CDCl₃)δ12.05(s,1H),8.35(d,J＝20.2Hz,2H),7.80(s,2H),7.54(s,1H),6.88(s,1H),5.89(s,1H),5.84(s,1H),5.80(s,1H),5.05(s,1H),4.28(s,1H),3.83–3.85(m,1H),3.62–3.64(m,1H),3.51–3.53(m,1H),3.25–3.33(m,2H),3.13–3.15(m,1H),2.32(s,3H),2.17(s,3H),1.53(s,3H),1.13(s,3H);

MS(ESI,[M+H]⁺)m/z:519.6.

Example 21 preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-thiocarboxamide

The reaction flow is as follows:

Step A preparation of (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

In a 100mL single vial was added 0.3g (1.341 mmol) of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, 5mL of DMF, 0.43g (2.012 mmol) of 3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester. The reaction was carried out for 10h at 100℃under nitrogen. After the completion of the reaction, 50ml of water was added to the reaction mixture to dilute it, followed by extraction with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 380mg of a transparent granular solid.

MS(ESI,[M+H]⁺)m/z:400.5.

Step B preparation of 2- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine trifluoroacetate

In a 100mL single vial was added (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 0.38g (0.951 mmol), dichloromethane 10mL, trifluoroacetic acid 0.868g (7.61 mmol). The reaction was carried out at room temperature for 12 hours. After the reaction, the reaction solution was directly concentrated to obtain a white oil, and after the reaction solution was slurried with ethyl acetate, the mixture was filtered to obtain 0.52g of a white powdery solid.

MS(ESI,[M+H]⁺)m/z:300.4.

Step C preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-thiocarboxamide

In a 50mL single port flask, 0.16g (0.573 mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethan-1-amine dihydrochloride, 5mL of chloroform, 0.23g (2.293 mmol) of triethylamine and 0.079g (0.688 mmol) of thiophosgene were added. Then 2mL of water was added to cover the reaction liquid surface. The reaction was carried out at room temperature for 20min. The aqueous layer was removed and a solution of 2- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine trifluoroacetate 0.302g (0.573 mmol), triethylamine 0.23g (2.293 mmol) in 4mL chloroform was then added. The reaction was carried out at room temperature for 2 hours. After the completion of the reaction, 50mL of methylene chloride was added to the reaction mixture, which was washed with saturated brine, and the organic phase was collected. Dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 140mg of a yellow solid.

¹H-NMR(500MHz,CDCl3):δ12.10(s,1H),8.45(s,1H),8.36(d,J＝4.5Hz,1H),7.87(s,2H),7.56(d,J＝4.2Hz,1H),6.45(s,1H),6.11(s,1H),6.04(s,1H),5.89(p,J＝7.2Hz,1H),3.14(q,J＝7.3Hz,4H),2.27(m,6H),1.65(d,J＝7.0Hz,3H),1.34(t,J＝7.3Hz,6H),0.89(dd,J＝12.7,9.5Hz,1H);

MS(ESI,[M+H]⁺)m/z:548.2.

EXAMPLE 22 preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-thiocarboxamide

The reaction flow is as follows:

Synthetic method reference example 21

¹H NMR(500MHz,CDCl₃):δ8.44(s,1H),8.39(d,J＝4.5Hz,1H),7.91(d,J＝8.5Hz,1H),7.84(d,J＝8.0Hz,1H),7.58(d,J＝8.5Hz,1H),7.22(s,1H),6.10(s,1H),6.04(s,1H),5.93(m,1H),5.86(s,1H),4.79(s,1H),4.38(m,3H),3.49(m,4H),2.32(s,3H),2.25(s,3H),1.67(d,J＝8.0Hz,3H),1.29(m,3H);

MS(ESI,[M+H]⁺)m/z:536.2.

Example 23 preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-amide

The reaction flow is as follows:

Step A preparation of (1R, 5S) -3- (4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

In a 100mL single vial was added 0.3g (1.431 mmol) of 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, 5mL of DMF, 0.456g (2.147 mmol) of tert-butyl 3, 2.1] octane-8-carboxylate. The reaction was carried out for 10h at 100℃under nitrogen. After completion of the reaction, 50mL of water was added to the reaction mixture to dilute the mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 0.52g of brown solid.

MS(ESI,[M+H]⁺)m/z:386.5.

Step B preparation of 2- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine trifluoroacetate salt

In a 100ml single vial was added (1R, 5S) -3- (4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 0.52g (1.341 mmol), dichloromethane 10ml, trifluoroacetic acid 1.223g (10.73 mmol). The reaction was carried out at room temperature for 12 hours. After the reaction was completed, the reaction mixture was directly concentrated to give a white oil, and after adding 20ml of ethyl acetate, the mixture was slurried and filtered to give 0.76g of a yellowish white powdery solid.

MS(ESI,[M+H]⁺)m/z:286.4.

Step C preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-amide

Triphosgene 0.064g (0.217 mol) was dissolved in 3mL methylene chloride in a 50mL three-necked flask and cooled to 0℃in an ice salt bath under nitrogen. 3mL of a methylene chloride solution containing 0.055g (0.197 mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethan-1-amine dihydrochloride and 0.160g (1.576 mmol) of triethylamine was added dropwise. The reaction solution was stirred at 0℃for 5 min. 3mL of a dichloromethane solution of 0.100g (0.197 mmol) of 2- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine trifluoroacetate and 0.160g (1.576 mmol) of triethylamine was added. The reaction was carried out at room temperature for 30min. After the completion of the reaction, 50mL of methylene chloride was added to the reaction mixture to dilute it, and the mixture was washed with saturated brine to collect an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 54mg of a yellow solid.

¹H-NMR(500MHz,CDCl₃):δ12.05(s,1H),11.21(s,4H),8.43(s,1H),8.36(d,J＝4.7Hz,1H),7.88(m,3H),7.55(d,J＝4.4Hz,1H),3.67(m,7H),3.37–3.17(m,3H),2.32(s,3H),1.92(s,2H),1.72(s,2H);

MS(ESI,[M+H]⁺)m/z:518.3.

EXAMPLE 24 preparation of N- (4-fluorophenyl) -N- (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-yl) cyclopropane-1, 1-dicarboxamide

The reaction flow is as follows:

step A preparation of methyl 1- ((4-fluorophenyl) amidomethyl) cyclopropyl-1-carboxylate

Into a100 mL three-necked flask, 20mL of toluene, 2.22g (19.98 mmol) of 4-fluoroaniline and 4.32g (19.98 mmol) of sodium methoxide were successively added. And (3) reacting for 30min at 100 ℃ under the protection of nitrogen, cooling to 66 ℃, and steaming to remove methanol in the reaction system under the nitrogen flow. After complete evaporation of the methanol, 3.79g (23.97 mmol) of dimethyl 1, 1-cyclopropanedicarboxylate was added. The reaction was carried out under the protection of nitrogen at 66 ℃ and the operation of steaming methanol with nitrogen flow was carried out every 1 hour until the reaction was completed. The reaction mixture was concentrated to give an oil, 100mL of water was added and the pH of the system was adjusted to weak acidity with 1.2M dilute hydrochloric acid. Extracting with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 2.07g of a yellowish green solid.

MS(ESI,[M-H]^-)m/z:236.2.

Step B preparation of 1- ((4-fluorophenyl) amidomethyl) cyclopropyl-1-carboxylic acid.

In a 50mL single-necked flask, 5mL of methanol, 0.13g (0.548 mmol) of methyl 1- ((4-fluorophenyl) amidomethyl) cyclopropyl-1-carboxylate and 1.1mL of 1N aqueous sodium hydroxide solution were added. The reaction was carried out at room temperature overnight. The phase reaction solution was poured into 50mL of ice water, 1M diluted hydrochloric acid was added dropwise to adjust the pH of the system to weak acidity, extraction was performed with methylene chloride, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 0.12g of white powdery solid.

MS(ESI,[M-H]^-)m/z:222.2.

Step C preparation of tert-butyl (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-yl) aminocarboxylate

To a 100mL single flask was added 1g (4.47 mmol) of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, 10mL of DMF and 0.985g (4.92 mmol) of 4-t-butoxycarbonylaminopiperidine in sequence. And reacting for 8 hours at 100 ℃ under the protection of nitrogen. The reaction mixture was diluted with 80mL of water, extracted with methylene chloride, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 1.54g of a white powdery solid.

MS(ESI,[M+H]⁺)m/z:388.5.

Step D preparation of 2- (4-aminopiperidin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidine-4-aminotrifluoroacetate

In a 100mL single vial was added 1.54g (3.97 mmol) of tert-butyl (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-yl) carbamate, 20mL of dichloromethane, and 4.53g (39.7 mmol) of trifluoroacetic acid. The reaction was carried out at room temperature for 12 hours. After the reaction, the reaction mixture was concentrated directly, and after adding 20mL of ethyl acetate, the mixture was slurried and filtered to obtain 2.1g of a white powdery solid.

MS(ESI,[M+H]⁺)m/z:288.3.

Step E preparation of N- (4-fluorophenyl) -N- (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-yl) cyclopropane-1, 1-dicarboxamide

In a 100mL single vial was added 0.12g (0.538 mmol) of 1- ((4-fluorophenyl) amidomethyl) cyclopropyl-1-carboxylic acid, 5mL of DMF, and 0.307g (0.645 mmol) of HATU. To the reaction system was added 0.33g (0.645 mmol) of 2- (4-aminopiperidin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidine-4-aminotrifluoroacetate and 0.554 g (4.3 mmol) of DIPEA in 5mL of DMF. The reaction was carried out at room temperature for 4 hours. After the reaction is completed. To the reaction mixture was poured 80ml of purified water, followed by extraction with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 0.15g of a white solid.

¹H-NMR(500MHz,CDCl₃):δ10.43(s,1H),7.52(dd,J＝8.8,4.8Hz,2H),7.12(s,1H),7.02(t,J＝8.5Hz,2H),6.10(s,1H),6.03(d,J＝8.2Hz,2H),4.66(dd,J＝13.8,3.9Hz,2H),4.05(m,1H),3.11–2.99(m,2H),2.31(s,3H),2.24(s,3H),1.98(d,J＝15Hz,2H),1.70(q,J＝4.7Hz,2H),1.46–1.39(m,3H),1.32(q,J＝4.6Hz,2H);

MS(ESI,[M+H]⁺)m/z:493.2.

Example 25 preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide

The reaction flow is as follows:

Step A preparation of 2-chloro-4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidine

A100 mL round bottom flask was charged with 1.309g (8.03 mmol) of 2, 4-dichloro-6-methylpyrimidine, 20mL of DMF, 0.876g (8.93 mmol) of 5-methyl-1H-pyrazol-3-ol, and 5g (10.17 mmol) of DIPEA1.315g were stirred uniformly and heated to 85℃and reacted for 20H with stirring. Heating was stopped, cooled to room temperature, 50mL of water was added to the reaction solution to dilute it, and extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 0.718g of a white solid.

MS(ESI,[M+Na]⁺)m/z:247.1.

Step B preparation of (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8 carboxylic acid tert-butyl ester

To a 100mL single flask was added 0.2g (0.890 mmol) of 2-chloro-4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidine, 10mL of (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 0.227g (1.068 mmol) and 0.246g (1.781 mmol) of potassium carbonate in this order, and the mixture was heated to 100℃under N ₂ for 7H of reaction. The reaction mixture was poured directly into 50mL of ice water, and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography gave 0.26g of an off-white powdery solid.

MS(ESI,[M+H]⁺)m/z:401.4.

Step C preparation of trifluoroacetate salt of (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) -6-pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane

To a 100mL single vial was added successively 0.39g (0.974 mmol) of tert-butyl (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8 carboxylate, 10mL of DCM, and 1.105g (0.746 mL,9.69 mmol) of trifluoroacetic acid, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give a colorless oil, and 10mL of ethyl acetate was added and stirred at room temperature for 30min. Filtration gave 0.32g of a white powdery solid.

MS(ESI,[M+H]⁺)m/z:301.3.

Step D preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide

To a 50mL three-necked flask, 179mg (0.602 mmol) of triphosgene, 5mL of methylene chloride and 5mL of methylene chloride solution containing 210mg (0.753 mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl-1-amine dihydrochloride and 0.4mL of triethylamine were sequentially added dropwise under the protection of N ₂ and the ice salt bath condition was cooled to 0 ℃. After the reaction mixture was stirred at 0℃for 5 minutes, 300mg (0.753 mmol) of trifluoroacetate salt containing (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) -6-pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane and 0.8mL of DCM 10mL of triethylamine were added to the reaction mixture. The reaction solution is stirred for 5-10 min at low temperature, and is transferred to room temperature for stirring for 20min. 50mL of methylene chloride was added to the reaction mixture to dilute it, and the mixture was washed with a saturated aqueous sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by column chromatography to obtain 250mg of a white powdery solid.

¹H-NMR(500MHz,DMSO-d₆):δ12.17(s,1H),8.66(d,J＝5Hz,1H),8.41(s,1H),7.91(m,3H),7.08(d,J＝10.0Hz,1H),6.01(s,1H),5.83(s,1H),4.95(m,1H),4.30(m,4H),2.97(d,J＝10.0Hz,2H),2.23(d,J＝5Hz,6H),1.75(s,2H),1.54(d,J＝10.0Hz,2H),1.45(d,J＝5.0Hz,3H).

MS(ESI,[M+H]⁺)m/z:533.4.

Example 26 preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (6-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide

The reaction flow is as follows:

Step A preparation of (1R, 5S) -3- (2-chloro-6-methylpyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

In a 50mL single-necked flask, 90mg (0.552 mmol) of 2, 4-dichloro-6-methylpyrimidine, 10mL of n-butanol, 129mg (0.607 mmol) of tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate and 107mg (0.145 mL,0.828 mmol) of diisopropylethylamine were successively added, and the mixture was heated to 100℃for reaction for 15 hours. After the reaction was completed, 50mL of ethyl acetate was added to the reaction system, and the mixture was washed twice with 20mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting crude product was purified by column chromatography to give 154mg of a beige solid target.

MS(ESI,[M+H]⁺)m/z:339.4.

Step B preparation of (1R, 5S) -3- (6-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] ] octane-8-carboxylic acid tert-butyl ester

In a 50mL single-necked flask, 122mg (0.360 mmol) of tert-butyl (1R, 5S) -3- (2-chloro-6-methylpyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, 5mL of isopropyl alcohol and 175mg (1.800 mmol) of 5-methyl-1H-pyrazol-3-amine were successively added, and the mixture was heated to 100℃under nitrogen protection to react for 36 hours. The solvent was removed by concentration, and 5mL of a mixed solution of ethanol and water (ethanol: water=1:3) was added to the reaction system. 59.7mg (0.432 mmol) of potassium carbonate was added to the reaction system, and the mixture was stirred at room temperature for 1.5 hours. To the reaction system were added 50mL of ethyl acetate and 20mL of water. The organic phase was separated, collected, dried over anhydrous sodium sulfate, filtered, and concentrated to a pale yellow oil. Purification by column chromatography gave a total of 0.2g of colorless oil.

MS(ESI,[M+H]⁺)m/z:400.4.

Step C preparation of 4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-2-amine trifluoroacetate

In a 100mL single vial was added (1R, 5S) -3- (6-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] ] octane-8-carboxylic acid tert-butyl ester 0.2g (0.5 mmol), dichloromethane 5mL, trifluoroacetic acid 0.868g (2.50 mmol). The reaction was carried out at room temperature for 12 hours. After the reaction is finished, the reaction solution is directly concentrated to obtain white oily matter, and ethyl acetate is added to the oily matter to be pulped and filtered to obtain 0.218g of white powdery solid.

MS(ESI,[M+H]⁺)m/z:300.4.

Step D preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (6-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide

In a 50mL three-necked flask, 0.043g (0.145 mmol) of triphosgene was dissolved in 3mL of methylene chloride, the ice-salt bath was cooled to about 0℃under nitrogen, a 35mL microwave tube was taken, and 0.090g (0.440 mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl-1-amine dihydrochloride was dissolved in 2mL of methylene chloride, and 0.137g (1.23 mmol) of triethylamine was added. The neutralized raw material was slowly added dropwise to a methylene chloride solution of triphosgene for about 2 minutes, and the addition was completed. The reaction solution was stirred at 0℃for 5min. 3mL of a dichloromethane solution containing 0.09g (0.44 mmol) of 4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-2-amine trifluoroacetate and 0.08g (0.72 mmol) of triethylamine was added. The reaction mixture was stirred at 0℃for 5min, and then warmed to room temperature and stirred for 20min. 50mL of methylene chloride was added to the reaction mixture to dilute it, and the mixture was washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give 49mg of a white powdery solid.

¹H-NMR(500MHz,DMSO-d₆):δ12.23(s,1H),10.34(s,1H),8.66(d,J＝3.5Hz,1H),8.43(s,1H),7.91(m,3H),7.31(d,J＝7.5Hz,1H),6.35(s,1H),6.09(s,1H),4.95(d,J＝7.0Hz,1H),4.49(m,2H),4.43(m,2H),3.01(m,2H),2.28(s,3H),2.22(s,3H),1.80(s,2H),1.57(d,J＝3.0Hz,2H),1.46(d,J＝6.5Hz,3H);

MS(ESI,[M+H]⁺)m/z:532.5.

Example 27 preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 19.

¹H NMR(500MHz,CDCl₃):δ11.64(s,1H),8.61(m,2H),8.42(s,1H),7.88(m,3H),7.13(d,J＝7.5Hz,1H),6.33(s,1H),6.23(s,1H),5.86(s,1H),4.95(m,1H),4.44(m,2H),3.84(m,2H),2.89(m,2H),2.18(s,3H),2.11(s,3H),1.77(d,J＝3.5Hz,2H),1.67(d,J＝7.5Hz,2H),1.45(d,J＝7Hz,3H).

MS(ESI,[M+H]⁺)m/z:531.3.

EXAMPLE 28 preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4- (3-methyl-5- ((5-methyl-1H-pyrazol-3-yl) amino) phenyl) piperazine-1-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 19.

¹H NMR(500MHz,DMSO-d₆):δ11.60(s,1H),10.27(s,1H),8.66(d,J＝4.5Hz,1H),8.41(m,1H),7.93(m,4H),7.04(d,J＝7.5Hz,1H),6.78(s,1H),6.16(s,1H),5.58(s,1H),4.93(m,1H),3.47(d,J＝4.5Hz,4H),3.33(s,4H),2.17(s,6H),1.44(d,J＝7.0Hz,3H).

MS(ESI,[M+H]⁺)m/z:504.3.

EXAMPLE 29 preparation of N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) cyclopropyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

Step A preparation of 1- (6-bromopyridin-3-yl) cyclopropan-1-amine

In a 25mL three-necked flask, 6.99g (24.59 mmol) of tetraisopropyl titanate and THF (3 mL) were sequentially added, and the mixture was heated to 50℃under N ₂. Subsequently, 3g (16.39 mmol) of 2-bromo-5-cyanopyridine was added thereto, and 5.46g (41.0 mmol) of ethylmagnesium bromide was slowly added dropwise at 50 ℃. The reaction was heated at 50 ℃ for 4h. After the reaction, the reaction solution was concentrated and purified by column chromatography to obtain 0.8g of a yellow solid product.

MS(ESI,[M+H]⁺)m/z:213.0,215.0.

Step B preparation of N- (1- (6-bromopyridin-3-yl) cyclopropyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The synthesis method is described in example 1, step G.

MS(ESI,[M+H]⁺)m/z:512.1,514.1.

Step C preparation of tert-butyl N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) cyclopropyl) - (S) -4- (4-methyl-6- ((methyl-1H-pyrazol-3-yl) -2-yl) -N- (1- (6- ((trimethylsilyl) ethynyl) pyrimidin-3-yl) ethyl) piperazine-1-carboxylate-1-carboxamide

To a 30mL microwave tube, 300mg (0.585 mmol) of N- (1- (6-bromopyridin-3-yl) cyclopropyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide, 252mg (2.93 mmol) of 4-fluoro-1H-pyrazole, 572mg (1.756 mmol) of cesium carbonate, 112mg (0.585 mmol) of trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine, 83mg (0.585 mmol) of cuprous iodide and N, N-dimethylformamide (10 mL) were added sequentially, and N2 was blown off of air and placed in a microwave reactor and heated to 120℃for reaction for 60 minutes at 200W. The reaction solution was poured directly into 50mL of ice water, and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated and purified by column chromatography to obtain 36mg of the objective product.

¹H NMR(500MHz,Chloroform-d)δ8.38(s,2H),7.87(d,J＝8.5Hz,1H),7.78(d,J＝10.4Hz,1H),7.58(d,J＝4.0Hz,1H),6.85(s,1H),6.16(s,1H),6.04(s,1H),5.35(s,1H),3.85(s,4H),3.48(s,4H),2.33(s,3H),2.28(s,3H),1.32(d,J＝14.6Hz,4H).

MS(ESI,[M+H]⁺)m/z:518.5.

EXAMPLE 30 preparation of (S) -N- (1- (6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

Step A preparation of (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide

The synthesis method is described in example 1, step B.

MS(ESI,[M+H]⁺)m/z:306.3.

Step B preparation of (R) -2-methyl-N- ((S) -1- (6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl) ethyl) propane-2-sulfinamide to a 30mL tube enclosure under nitrogen protection, (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide (350 mg,1.147 mmol), DMF (10 mL), 4-methylimidazole (284 mg,3.46 mmol), cesium carbonate (112mg, 3.44 mmol), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (163 mg,1.147 mmol), cuprous iodide (219 mg,1.147 mmol) were added in sequence, the air was purged with nitrogen, and placed in a microwave reactor and heated to 120℃for 60min at 100W.

The filtrate was collected by filtration and concentrated, 40mL of EA and 60mL of H ₂ O were added, the mixture was shaken to separate the solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give 140mg of a white solid.

MS(ESI,[M+H]⁺)m/z:307.1.

Step C preparation of (S) -1- (6- (4- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl) ethan-1-amine hydrochloride

The synthesis is described in example 1, step C.

MS(ESI,[M+H]⁺)m/z:203.2.

Step D preparation of (S) -N- (1- (6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The synthesis method is described in example 1, step G.

¹H NMR(500MHz,DMSO-d₆)δ11.86(s,1H),9.25(s,1H),8.41(d,J＝2.3Hz,1H),8.36(d,J＝1.3Hz,1H),7.91(dd,J＝8.5,2.3Hz,1H),7.67(d,J＝8.4Hz,1H),7.61(s,1H),6.95(d,J＝7.6Hz,1H),6.54–5.98(m,2H),4.92(p,J＝7.1Hz,1H),3.74–3.59(m,4H),3.44–3.37(m,4H),2.22–2.10(m,9H),1.43(d,J＝7.1Hz,3H).

MS(ESI,[M+H]⁺)m/z:502.3.

Example 31 preparation of (S) -N- (1- (6-cyanopyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

The synthesis method is described in example 1, step B.

MS(ESI,[M+H]⁺)m/z:306.3.

Step B preparation of (R) -N- ((S) -1- (6-cyanopyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide

(R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide (1000 mg,3.28 mmol), DMA (10 mL), dppf (150 mg, 0.271mmol), zinc powder (80 mg,1.224 mmol), zinc cyanide (300 mg,2.56 mmol), pd ₂(dba)₃ (150 mg,0.164 mmol) were added in sequence to a 30mL tube under nitrogen atmosphere, and the mixture was placed in a microwave reactor and reacted at 100W to 100℃for 120min. The filtrate was collected by filtration and concentrated, 30mL of EA and 50mL of H ₂ O were added, the mixture was shaken to separate the solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained was purified by column chromatography to give 700mg of yellow solid.

MS(ESI,[M+H]⁺)m/z:252.1.

Step C preparation of (S) -5- (1-aminoethyl) pyridinoline hydrochloride

The synthesis is described in example 1, step C.

MS(ESI,[M+H]⁺)m/z:148.0.

Step D preparation of (S) -N- (1- (6-cyanopyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The synthesis method is described in example 1, step G.

¹H NMR(500MHz,DMSO-d₆)δ11.86(s,1H),9.26(s,1H),8.76–8.70(m,1H),7.98(qd,J＝8.1,1.4Hz,2H),7.04(d,J＝7.3Hz,1H),6.18(d,J＝41.0Hz,2H),4.95(p,J＝7.1Hz,1H),3.73–3.63(m,4H),3.44–3.36(m,4H),2.21(s,3H),2.13(s,3H),1.43(d,J＝7.1Hz,3H).

MS(ESI,[M+H]⁺)m/z:447.3.

EXAMPLE 32 preparation of (S) -N- (1- (6-ethynylpyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) pyridin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

The synthesis method is described in example 1, step B.

MS(ESI,[M+H]⁺)m/z:305.0

Step B preparation of (R) -2-methyl-N- ((S) -1- (6- ((trimethylsilyl) ethynyl) pyrimidin-3-yl) ethyl) propane-2-sulfinamide

To a 30mL microwave tube were added 404mg (1.324 mmol) of (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide, 260mg (2.65 mmol) of trimethylethynyl silicon, 46.5mg (0.066 mmol) of ditriphenylphosphine palladium dichloride, 25mg (0.132 mmol) of cuprous iodide and 670mg (6.62 mmol) of triethylamine in this order, acetonitrile (10 mL) was added and the mixture was heated to 120℃under protection of N ₂ to react for 10min. After the reaction, the reaction mixture was concentrated and purified by column chromatography to obtain 0.38g of a yellow solid product.

MS(ESI,[M+H]⁺)m/z:323.1.

Step C preparation of (S) -1- (6- ((trimethylsilyl) ethynyl) pyrimidin-3-yl) ethan-1-amine

The synthesis is described in example 1, step C.

MS(ESI,[M+H]⁺)m/z:219.2.

Step D preparation of (S) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- ((trimethylsilyl) ethynyl) pyridin-3-yl) ethyl) piperazine-1-carboxamide

The synthesis method is described in example 1, step G.

MS(ESI,[M+H]⁺)m/z:518.4.

Step E preparation of (S) -N- (1- (6-ethynylpyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

To a 50mL eggplant-shaped flask, 660mg (1.275 mmol) of (S) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- ((trimethylsilyl) ethynyl) pyridin-3-yl) ethyl) piperazine-1-carboxamide, dichloromethane (2 mL) and methanol (3 mL) were added sequentially, followed by 881mg (6.37 mmol) of potassium carbonate and the reaction was carried out at room temperature under the protection of N ₂ for 3H. After the reaction, the reaction solution was concentrated and purified by column chromatography to obtain 58mg of the objective product.

¹H NMR(500MHz,Chloroform-d)δ8.61(s,1H),7.66(d,J＝7.8Hz,1H),7.46(d,J＝7.7Hz,1H),7.29(s,1H),7.12(s,1H),6.09(d,J＝55.0Hz,2H),5.07-5.10(m,1H),4.88(d,J＝6.2Hz,1H),3.83(s,4H),3.48(s,4H),2.29(d,J＝27.2Hz,6H),1.55(s,3H).

MS(ESI,[M+H]⁺)m/z:446.2.

Example 33 preparation of (S) -N- (1- (2-cyanopropan-2-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

step A preparation of 2- (5-bromopyridin-2-yl) -2-methylpropanenitrile

To a 25mL three-necked flask, 2g (10.15 mmol) of 2- (5-bromopyridin-2-yl) acetonitrile, 2.285g (25.4 mmol) of potassium t-butoxide, 402mg (1.523 mmol) of 18-crown-6 and tetrahydrofuran (10 mL) were successively added, and the mixture was stirred at room temperature under the protection of N ₂. 11.53g (81 mmol) of methyl iodide was then added and the reaction was carried out overnight at room temperature. The reaction solution was distilled off under reduced pressure by means of a rotary evaporator, and purified by column chromatography to obtain 1.66g of a white solid product.

MS(ESI,[M+H]⁺)m/z:225.0

Step B preparation of 2- (5-Acetylpyridin-2-yl) -2-methylpropanenitrile

A25 ml three-necked flask was taken and charged with 1.2g (5.33 mmol) of 2- (5-bromopyridin-2-yl) -2-methylpropanenitrile and 10ml of tetrahydrofuran, and the temperature was lowered to-78℃under nitrogen. 0.41g (6.4 mmol) of n-butyllithium was added dropwise to the reaction liquid system using a syringe, keeping the internal temperature below-65 ℃. Stirring at low temperature for 15min after the addition is completed. N, N-dimethylacetamide 0.715g (6.93 mmol) was dissolved in 5ml THF and added dropwise to the reaction system using a syringe, keeping the internal temperature below-65 ℃. Stirring and reacting for 2h at low temperature after the addition is finished. The reaction solution was distilled off under reduced pressure by means of a rotary evaporator, and purified by column chromatography to obtain 1.66g of a white solid product.

MS(ESI,[M+H]⁺)m/z:189.3.

Step C preparation of (R) -N- ((S) -2- (5- (1-aminoethyl) pyridin-2-yl) -2-methylpropanenitrile) -2-methylpropane-2-sulfinamide

The synthesis method is described in example 1, step B.

MS(ESI,[M+H]⁺)m/z:294.3.

Step D preparation of (S) -2- (5- (1-aminoethyl) pyridin-2-yl) -2-methylpropanenitrile

The synthesis is described in example 1, step C.

MS(ESI,[M+H]⁺)m/z:190.2.

Step E preparation of (S) -N- (1- (2-cyanopropan-2-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The synthesis method is described in example 1, step G.

¹H NMR(500MHz,Chloroform-d)δ10.98(s,1H),8.60(s,1H),8.27(s,1H),7.70(s,1H),7.51(s,1H),6.10(d,J＝26.0Hz,2H),5.21(s,1H),5.04-5.06(m,1H),3.81(s,4H),3.50(s,4H),2.27(d,J＝19.5Hz,6H),1.75(s,6H),1.52(d,J＝6.8Hz,3H).

MS(ESI,[M+H]⁺)m/z:489.3.

Example 34 preparation of (S) -N- (1- (6-cyclopropylpyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

The synthesis method is described in example 1, step B.

MS (ESI, [ M-H ] ^-) M/z:303.0. Step B preparation of (R) -N- ((S) -1- (6-cyclopropylpyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide

In a 50mL eggplant-shaped bottle, 405mg (1.327 mmol) of (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide, 228mg (2.65 mmol) of cyclopropylboronic acid, 74mg (0.265 mmol) of tricyclohexylphosphine, 925mg (5.31 mmol) of potassium phosphate and 30mg (0.133 mmol) of palladium acetate were sequentially added, water (1 mL) and toluene (5 mL) were added, and the mixture was heated to 110℃under the protection of N ₂ to react for 6h. The stirring was stopped, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure by a rotary evaporator, and the mixture was purified by column chromatography to obtain 220mg of a brown oil.

MS(ESI,[M+H]⁺)m/z:267.1

Step C preparation of (S) -1- (6-cyclopropylpyridin-3-yl) ethane-1-amine

The synthesis is described in example 1, step C.

MS(ESI,[M+H]⁺)m/z:163.1.

Step D preparation of (S) -N- (1- (6-cyclopropylpyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The synthesis method is described in example 1, step G.

¹H NMR(500MHz,Chloroform-d)δ8.46(s,1H),7.53(d,J＝10.1Hz,1H),7.10(d,J＝8.1Hz,1H),7.05(s,1H),6.13(s,1H),6.04(s,1H),5.01-5.06(m,1H),4.73(d,J＝6.8Hz,1H),3.81-3.83(m,4H),3.45-3.50(m,4H),2.32(s,3H),2.26(s,3H),2.01-2.06(m,1H),1.52(d,J＝6.9Hz,3H),0.98-1.01(m,4H).

MS(ESI,[M+H]⁺)m/z:462.3.

Example 35 preparation of (S) -N- (1- (6- (methoxypyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The synthesis method is described in example 1.

¹H NMR(500MHz,DMSO-d₆)δ11.84(s,1H),9.24(s,1H),8.09(d,J＝2.4Hz,1H),7.68(dd,J＝8.6,2.5Hz,1H),6.83(d,J＝7.8Hz,1H),6.76(d,J＝8.5Hz,1H),4.83(p,J＝7.2Hz,1H),3.81(s,3H),3.69–3.61(m,4H),3.41–3.35(m,4H),2.20(s,3H),2.12(s,3H),1.38(d,J＝7.1Hz,3H).

MS(ESI,[M+H]⁺)m/z:452.3.

Example 36 preparation of (S) -N- (1- (6-isopropoxypyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-amide

The reaction flow is as follows:

step A preparation of 1- (6-isopropoxypyridin-3-yl) ethanone

In a 50mL three-necked flask, 2.0g (9.26 mmol) of 2-isopropoxy-5-bromopyridine and 20mL of THF were placed. And cooling to-78 ℃ under the protection of nitrogen. Subsequently, 0.72g (2.5 mol/L,11.24 mmol) of n-butyllithium was slowly added dropwise. Stirring at low temperature for a moment after the dripping is finished. 1.241g (12.03 mmol) of N-methoxy-N-methylacetamide was dissolved in 5ml of THF and slowly added to the reaction system. After the reaction is completed, 20mL of saturated ammonium chloride solution is added into the reaction solution to quench the reaction. The reaction solution was then poured into 100mL of purified water. EA extraction, combining organic phases and drying over anhydrous sodium sulfate. Filtration and concentration gave 1.59g of yellow oil.

MS(ESI,[M+H]⁺)m/z:180.1.

Step B preparation of (S, Z) -N- (1- (6-isopropoxypyridin-3-yl) ethylene) -2-methylpropan-2-sulfinamide

1.59G (8.87 mmol) of 1- (6-isopropoxypyridin-3-yl) ethanone, 25mL of THF, 2.98g (22.18 mmol) of diethylene glycol dimethyl ether, 5.06g (22.18 mmol) of tetraethyl titanate, and 2.69g (22.28 mmol) of (R) - (+) -tert-butylsulfinamide were sequentially added to a 50mL single-port bottle. The reaction was carried out at 80℃under nitrogen. After the reaction was completed, the reaction solution was poured into 100mL of purified water, and at this time, a large amount of white solid was precipitated. After suction filtration, the filter cake was washed with EA, and the organic phases were combined and dried by adding anhydrous sodium sulfate. Followed by filtration, concentration and purification by column chromatography gave 1.8g of yellow liquid.

MS(ESI,[M+H]⁺)m/z:283.3.

Step C preparation of (S) -N- ((S) -1- (6-isopropoxypyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide

In a 100mL three-necked flask, 1.8g (6.39 mmol) of (S, Z) -N- (1- (6-isopropoxypyridin-3-yl) ethylene) -2-methylpropan-2-sulfinamide and 20mL of THF were added. Cooling to-80 ℃. Subsequently, 2.43g (1 mol/L,12.78 mmol) of lithium tri-sec-butylborohydride was slowly added dropwise to the reaction system. After the completion of the dropwise addition, the reaction is carried out at a low temperature of-80 ℃. After the reaction was completed, 10mL of methanol was added to the reaction system to quench the reaction. The reaction solution was then poured into 100mL of ice water, at which time a large amount of solid precipitated. And washing the filter cake by EA after suction filtration. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give 0.6g of a white solid.

MS(ESI,[M+H]⁺)m/z:285.2.

Step D preparation of (S) -1- (6-isopropoxypyridin-3-yl) ethylamine hydrochloride

In a 100mL single-necked flask, 0.672g (2.363 mmol) of (S) -N- ((S) -1- (6-isopropoxypyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide, 20mL of methanol, and 5.9mL (4 mol/L,23.62 mmol) of hydrogen chloride dioxane solution were sequentially added. The reaction was carried out at room temperature under nitrogen atmosphere. And after the reaction is finished, evaporating the reaction solvent. After 20mLEA was added, white solid was precipitated, and after beating, the filter cake was collected and dried in vacuo to give 470mg of white solid.

MS(ESI,[M+H]⁺)m/z:181.1.

Step E preparation of (S) -N- (1- (6-isopropoxypyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

To a 50mL three-necked flask was added CDI 0.142g (0.878 mmol) and DCM 10mL. The ice salt bath is cooled to 0 ℃ under the protection of nitrogen. A10 mL tube was taken and 0.202g (0.798 mmol) of (S) -1- (6-isopropoxypyridin-3-yl) ethylamine hydrochloride, 0.485g (4.79 mmol) of triethylamine, 5mL of DCM was added slowly to the reaction. After about 30min of low temperature reaction, 5mL of DCM solution containing 0.4g (0.798 mmol) of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate and 0.485g (4.79 mmol) of triethylamine was added to the reaction system. After the reaction was completed, the reaction solution was poured into 100mL of purified water and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate. Followed by filtration, concentration and purification by column chromatography gave 120mg of a white solid.

¹H NMR(500MHz,DMSO-d₆)δ11.86(s,1H),9.25(s,1H),8.07(d,J＝2.1Hz,1H),7.65(s,2H),7.02(s,1H),6.82(d,J＝7.7Hz,1H),6.68(d,J＝8.5Hz,1H),5.21(hept,J＝6.2Hz,1H),4.83(p,J＝7.0Hz,1H),3.66(t,J＝5.0Hz,4H),3.38(t,J＝5.0Hz,4H),2.21(s,3H),2.13(s,3H),1.38(d,J＝7.0Hz,3H),1.27(d,J＝6.2Hz,6H).

MS(ESI,[M+H]⁺)m/z:480.3.

EXAMPLE 37 preparation of (S) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- (pyrrolidin-1-yl) pyridin-3-yl) ethyl) piperazine-1-carboxamide

The reaction flow is as follows:

To a 250mL three-necked flask, 1- (6-bromopyridin-3-yl) ethan-1-one (5.26 g,26.3 mmol), THF (100 mL), tetraethyltitanate (12.00 g,52.6 mmol), (R) - (+) -tert-butylsulfinamide (6.37 g,52.6 mmol), diethylene glycol dimethyl ether (3.53 g,26.3 mmol), were sequentially added, the nitrogen was replaced three times, the temperature was raised to 75℃and the reaction was heated at controlled temperature for 7h. The reaction system was cooled to-78 ℃, air was purged with nitrogen, lithium tri-sec-butylborohydride (15.00 g,79 mmol) was measured under nitrogen protection, and the temperature was controlled to not higher than-70 ℃ and added dropwise to the flask. And controlling the temperature to be not higher than-40 ℃ for 4 hours. To the reaction solution was added 30mL of MeOH for quenching, and after quenching, the mixture was poured into 300mL of ice water for pulping for 30min, suction filtration was performed, the filtrate was collected and concentrated, 100mL of EA was added, and the mixture was shaken to separate the solution. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried by spinning to give 6.86g of a yellow oily liquid.

MS(ESI,[M+H]⁺)m/z:305.3.

Step B preparation of (R) -2-methyl-N- ((S) -1- (6- (pyrrolidinyl-1-yl) pyridin-3-yl) ethyl) propane-2-sulfinamide

To a 30mL tube was added successively (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide (1000 mg,3.28 mmol), THF (8 mL), tetrahydropyrrole (500 mg,7.03 mmol), davephos (260 mg,0.661 mmol), pd2 (dba) 3 (300 mg,0.328 mmol), liHMDS (1372 mg,8.20mL,8.20 mmol) under nitrogen blanket, and the mixture was placed in a microwave reactor and reacted at 100W to 130℃for 30min. 2mL of a 1M saturated ammonium chloride solution was added dropwise under ice-bath conditions to quench the reaction, and the reaction was diluted with 20mL of ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was concentrated and the crude product was purified by column chromatography to give 135mg of the target product as a yellow solid.

MS(ESI,[M+H]⁺)m/z:296.1.

Step C preparation of (S) -1- (6- (pyrrolidin-1-yl) pyridin-3-yl) ethan-1-amine hydrochloride

In a 50mL round bottom flask, (R) -2-methyl-N- ((S) -1- (6- (pyrrolidinyl-1-yl) pyridin-3-yl) ethyl) propane-2-sulfinamide (280 mg,0.948 mmol), meOH (50 mL), a solution of HCl in Dioxane (348 mg,0.288mL,9.48 mmol) was added sequentially, stirred overnight at room temperature, after the reaction was completed the reaction was concentrated to give 0.26g of a white solid product which was used directly in the next reaction without purification.

MS(ESI,[M+H]⁺)m/z:192.2.

Step D preparation of (S) -4- (4-methyl-6- (((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- (pyrrolidin-1-yl) pyridin-3-yl) ethyl) piperazine-1-carboxamide

To a 50mL eggplant-shaped bottle was added sequentially (S) -1- (6- (pyrrolidin-1-yl) pyridin-3-yl) ethan-1-amine hydrochloride (225 mg,0.988 mmol), DCM (10 mL), TEA (1000 mg,9.88 mmol), CDI (160 mg,0.988 mmol). The reaction was carried out at room temperature for 1h. Another 25mL single-necked flask was charged with 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate (367 mg,0.988 mmol), DCM (10 mL), TEA (1000 mg,9.88 mmol) in sequence. After stirring until the solid was completely dissolved, the mixture was added to a 50mL eggplant-shaped bottle and stirred at room temperature overnight. After completion of the reaction, 50mL of methylene chloride was added to the reaction mixture to dilute it, and the mixture was washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained was purified by column chromatography to give 290mg of white powdery solid.

¹H NMR(500MHz,DMSO-d₆)δ9.32(s,1H),7.97(d,J＝2.4Hz,1H),7.54(dd,J＝8.8,2.4Hz,2H),6.75(d,J＝7.9Hz,1H),6.47(d,J＝8.8Hz,1H),4.75(p,J＝7.2Hz,1H),3.76–3.58(m,4H),3.06(q,J＝7.3Hz,6H),2.20(s,3H),2.13(s,3H),1.95–1.88(m,4H),1.35(d,J＝7.0Hz,3H).

MS(ESI,[M+H]⁺)m/z:491.4.

EXAMPLE 38 preparation of 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (3- ((4-methylpiperazin-1-yl) methyl) phenyl) piperazine-1-carboxamide

The reaction flow is as follows:

Step A preparation of 1-methyl-4- (3-nitrobenzyl) piperazine

In a 100mL single-necked flask, 2g (9.26 mmol) of 3-nitrobenzyl bromide, 0.928g (9.26 mmol) of N-methylpiperazine, 1.28g (9.26 mmol) of potassium carbonate and 15mL of DMF were successively added. The reaction was stirred at room temperature. After the reaction, 100mL of purified water was added to the reaction system, and EA was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 2.08g of a yellow oil.

MS(ESI,[M+H]⁺)m/z:236.1.

Step B preparation of 3- ((4-methylpiperazin-1-yl) methyl) aniline

1G of 1-methyl-4- (3-nitrobenzyl) piperazine and 0.1g (10% m/c) of palladium on carbon were placed in a 100mL single flask. The mixture was stirred at room temperature under a hydrogen atmosphere for about 1 hour. After the reaction is finished, filtering and separating palladium carbon, washing filter cake by EA

. The combined organic phases were concentrated to give 0.75g of a yellow oil.

MS(ESI,[M+H]⁺)m/z:206.2.

Step C preparation of 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (3- ((4-methylpiperazin-1-yl) methyl) phenyl) piperazine-1-carboxamide

Triphosgene 0.118g (0.399 mol) was dissolved in 3mL methylene chloride in a 50mL three-necked flask, and the ice salt bath was cooled to 0℃under N ₂. 3mL of a dichloromethane solution containing 0.082g (0.399 mmol) of 3- ((4-methylpiperazin-1-yl) methyl) aniline and 0.242g (2.4 mmol) of triethylamine was added dropwise. The reaction solution was stirred at 0℃for 5 min. A solution of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate 0.200g (0.399 mmol) and triethylamine 0.242g (2.4 mmol) in dichloromethane 3ml was added. The reaction was carried out at room temperature for 30min. After the completion of the reaction, 50mL of methylene chloride was added to the reaction mixture to dilute it, and the mixture was washed with saturated brine to collect an organic phase. Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 57mg of a white solid.

¹H NMR(500MHz,DMSO-d₆)δ11.88(s,1H),9.27(s,1H),8.58(s,1H),7.42(d,J＝9.6Hz,2H),7.17(t,J＝7.7Hz,1H),6.86(d,J＝7.5Hz,1H),6.19(d,J＝49.0Hz,2H),3.74(t,J＝5.1Hz,4H),3.52(t,J＝5.1Hz,4H),3.41(s,2H),2.43(s,8H),2.23(d,J＝11.9Hz,6H),2.14(s,3H).

MS(ESI,[M+H]⁺)m/z:505.3.

EXAMPLE 39 preparation of 4- (4-methyl-6- (((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) piperazine-1-carboxamide

The reaction flow is as follows:

The synthesis method is described in example 1, step G.

¹H NMR(500MHz,DMSO-d₆):δ11.72(s,1H),9.26(s,1H),8.86(s,1H),7.90(s,1H),7.75(d,J＝8.0Hz,1H),7.57(d,J＝8.5Hz,1H),6.20(m,2H),3.75(d,J＝5.0Hz,4H),3.53(m,6H),2.38(s,8H),2.21(s,3H),2.17(s,3H),2.14(s,3H).

MS(ESI,[M+H]⁺)m/z:573.3.

EXAMPLE 40 preparation of (S) -4- (4-methyl-6- (((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) ethyl) piperazine-1-carboxamide

The reaction flow is as follows:

Step A preparation of benzyl (S) - (1- ((2-amino-5- (trifluoromethyl) phenyl) amino) -1-oxopropan-2-yl) carbamate

In a 50mL single-necked flask, ((benzyloxy) carbonyl) -L-alanine (1 g,4.48 mmol), methylene chloride (20 mL), 4- (trifluoromethyl) benzene-1, 2-diamine (0.789 g,4.48 mmol), triethylamine (1.36 g, 13.44 mmol) and EDCI (0.859 g,4.48 mmol) were sequentially added, and the mixture was stirred at room temperature for 1.5h. To the reaction system was added 20mL of methylene chloride to dilute, and washed once with 20mL of saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1.4g of brown oil. Without further purification, the subsequent reaction was continued.

MS(ESI,[M+H]⁺)m/z:382.1.

Step B preparation of benzyl (S) - (1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) ethyl) carbamate

In a 50mL single vial, benzyl (S) - (1- ((2-amino-5- (trifluoromethyl) phenyl) amino) -1-oxopropan-2-yl) carbamate (1.4 g,3.67 mmol) and glacial acetic acid (15 mL) were added sequentially and the mixture was heated to 70℃and stirred for 1.5h. After the reaction is completed, concentrating half of glacial acetic acid under reduced pressure to obtain brown glacial acetic acid solution. The subsequent reaction was continued without further purification.

MS(ESI,[M+H]⁺)m/z:364.1.

Step C preparation of (S) -1- (5- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) ethan-1-amine hydrobromide

To the brown glacial acetic acid solution obtained in step B, 20mL of 48% aqueous HBr was added, and the mixture was stirred at room temperature for 24h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, to obtain a crude brown oily product. To the crude product, 5mL of water was added, pH was adjusted to about 8 with a saturated aqueous sodium carbonate solution, extraction was performed with ethyl acetate (30 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 780mg of white crystals.

MS(ESI,[M+H]⁺)m/z:230.1.

Step D preparation of (S) -4- (4-methyl-6- (((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- (trifluoromethyl) -1H-benzo [ D ] imidazol-2-yl) ethyl) piperazine-1-carboxamide

Synthetic method reference is made to example 1, step G.

¹H NMR(500MHz,CDCl₃):δ12.52(s,1H),11.87(s,1H),9.26(s,1H),7.84(m,2H),7.47(s,1H),7.10(d,J＝5.0Hz,1H),6.20(m,2H),5.15(m,1H),3.71(s,4H),3.46(s,4H),2.21(s,3H),2.14(s,3H),1.58(d,J＝5.0Hz,3H).

MS(ESI,[M+H]⁺)m/z:529.3。

EXAMPLE 41 preparation of 2- (4- ((6- (dimethylamino) pyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

The reaction flow is as follows:

Step A preparation of 2- (4- ((6-chloropyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

A single-port 100mL vial was charged with 1g (1.994 mmol) of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate, dichloromethane (25 mL), and 807mg (7.98 mmol) of triethylamine. The solution was clarified by stirring until the solids were completely dissolved. Subsequently 282mg (1.994 mmol) of 6-chloronicotinaldehyde, 1.268g (5.98 mmol) of sodium triacetoxyborohydride were added. The reaction was stirred at room temperature overnight. The reaction solution was distilled off under reduced pressure by means of a rotary evaporator, and purified by column chromatography to obtain 1.8g of a white solid product.

MS(ESI,[M+H]⁺)m/z:399.2。

Step B preparation of 2- (4- ((6- (dimethylamino) pyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

To a 30 mL-sealed tube was added, in order, 500mg (1.253 mmol) of 2- (4- ((6-chloropyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, 565mg (12.53 mmol) of dimethylamine, and N-methylpyrrolidone (10 mL), and the mixture was placed in a microwave reactor and heated to 180℃for 2 hours at 200 watts. The reaction solution was poured directly into 50mL of ice water, and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated and purified by column chromatography to give 60mg of an off-white powdery solid.

¹H NMR(500MHz,Chloroform-d)δ8.06(s,1H),7.49(d,J＝8.6Hz,1H),6.97(s,1H),6.52(d,J＝8.7Hz,1H),6.03(d,J＝15.4Hz,2H),3.79(s,4H),3.43(s,2H),3.09(s,6H),2.48(s,4H),2.26(d,J＝27.7Hz,6H).

MS(ESI,[M+H]⁺)m/z:408.4。

EXAMPLE 42 preparation of (S) -N- (benzo [ d ] [1,3] dioxin-5-ylmethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 19.

¹H NMR(500MHz,Chloroform-d)δ6.83(s,1H),6.75-6.79(m,2H),6.68(s,1H),6.14(s,1H),5.94(s,2H),5.92(s,1H),5.83(s,1H),4.76-4.78(m,1H),4.32-4.40(m,2H),4.17(s,1H),4.02(d,J＝12.2Hz,1H),3.92(d,J＝12.7Hz,1H),3.79-3.81(m,1H),3.28-3.33(m,1H),3.21-3.24(m,1H),3.00-3.05(m,1H),2.27(s,3H),2.20(s,3H),1.24(d,J＝6.8Hz,3H).

MS(ESI,[M+H]⁺)m/z:464.3.

EXAMPLE 43 preparation of (S) -N- ((2, 2-difluorobenzo [ d ] [1,3] dioxin-5-yl) methyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

Step A preparation of 2, 2-difluorobenzo [ d ] [1,3] dioxin-5-formaldoxime

To a 50mL eggplant-shaped flask, 1g (5.37 mmol) of 2, 2-difluoro-1, 3-benzodioxole-5-carbaldehyde, 373mg (5.37 mmol) of hydroxylamine hydrochloride and methanol (10 mL) were successively added, followed by 1.06g (13.43 mmol) of pyridine and then reacted at room temperature under N ₂ protection for 2 hours. The reaction solution was distilled off under reduced pressure by means of a rotary evaporator, and purified by column chromatography to obtain 0.6g of a white solid product.

Step B preparation of (2, 2-difluorobenzo [ d ] [1,3] dioxin-5-yl) methylamine

In a 25mL three-necked flask, 189mg (4.97 mmol) of lithium aluminum hydride, tetrahydrofuran (5 mL) was added under the protection of N ₂, the system was cooled to 0℃and then a solution of 1g (4.97 mmol) of 2, 2-difluoro-1, 3-benzodioxolane-5-formaldoxime in tetrahydrofuran (5 mL) was added dropwise, followed by transferring the mixture to room temperature for reaction for 2 hours. 5mL of saturated ammonium chloride aqueous solution is added into the reaction system, 30mL of ethyl acetate is added for extraction, the organic phase is separated, anhydrous sodium sulfate is dried, the filtrate is filtered, the solvent is distilled off under reduced pressure through a rotary evaporator, and the filtrate is purified through column chromatography, so that 0.25g of white solid product is obtained.

MS(ESI,[M+H]⁺)m/z:188.3.

Step C preparation of (S) -N- ((2, 2-difluoro-1, 3-benzodioxol-5-yl) methyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxamide

The synthesis is described in step D, example 19.

¹H NMR(500MHz,Chloroform-d)δ8.61(s,1H),7.34(d,J＝8.3Hz,1H),7.28(s,1H),7.16(t,J＝5.7Hz,1H),7.10(d,J＝8.3Hz,1H),6.33(s,1H),6.01(s,1H),5.96(s,1H),4.21-4.30(m,3H),4.10(d,J＝12.1Hz,1H),4.01(s,1H),3.82(d,J＝12.9Hz,1H),3.06-3.11(m,1H),2.96-2.99(m,1H),2.74-2.78(m,1H),2.18(s,3H),2.12(s,3H),1.10(d,J＝6.5Hz,3H).

MS(ESI,[M+H]⁺)m/z:500.3.

EXAMPLE 44 preparation of (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) (4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazin-1-yl) methanone

The reaction flow is as follows:

step A preparation of methyl 6- (4-fluoro-1H-pyrazol-1-yl) nicotinate

The synthesis method is described in example 1A.

MS(ESI,[M+H]⁺)m/z:222.1.

Step B preparation of 6- (4-fluoro-1H-pyrazol-1-yl) nicotinic acid

To a 50mL reaction flask was added 300mg (1.356 mmol) of methyl 6- (4-fluoro-1H-pyrazol-1-yl) nicotinate, ethanol (25 mL). The reaction system was suspended in white, and 2mL of a 20% aqueous sodium hydroxide solution was added to the reaction system and stirred at room temperature for 1 hour. The reaction system was distilled under reduced pressure to remove the solvent, concentrated hydrochloric acid was added dropwise to adjust the pH to 2, dichloromethane 20ml x 5 was extracted multiple times, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent to obtain 250mg of white solid.

MS(ESI,[M-H]^-)m/z:206.1.

Step C preparation of (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) (4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazin-1-yl) methanone

In a 50mL reaction flask, 746mg (0.965 mmol) of 6- (4-fluoro-1H-pyrazol-1-yl) nicotinic acid, N, N-dimethylformamide (10 mL) and methylene chloride (10 mL) were added, followed by 441mg (1.159 mmol) of 2- (1H-benzotrisazo L-1-yl) -1, 3-tetramethylurea tetrafluoroborate (1.159 mmol), and stirred at room temperature for 5 minutes, followed by 196mg (1.93 mmol) of N-methylmorpholine. N ₂ is protected, and stirred for 1h at room temperature. The above reaction system was slowly added dropwise to a solution of 746mg (1.931 mmol) of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate and 196mg (1.93 mmol) of N, N-dimethylformamide. N ₂ was protected and stirred overnight at room temperature. The reaction solution was distilled off under reduced pressure by rotary evaporator, 50ml of dichloromethane and 20ml of 3 x saturated brine were added and washed multiple times, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to obtain 150mg of yellow solid product.

¹H NMR(500MHz,Chloroform-d)δ8.50(s,1H),8.43(d,J＝4.4Hz,1H),8.02(d,J＝8.4Hz,1H),7.92(d,J＝6.3Hz,1H),7.63(d,J＝4.2Hz,1H),7.06(s,1H),6.16(s,1H),6.04(s,1H),3.85(s,6H),3.56(s,2H),2.30(s,3H),2.25(s,3H).

MS(ESI,[M+H]⁺)m/z:463.3.

EXAMPLE 45 preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

Step A preparation of 6, 7-dihydro-5H-cyclopenta [ d ] pyrimidine-2, 4-diol

In a 50mL three-necked flask, 5g (35.2 mmol) of 2-methoxycarbonyl cyclopentanone, 4.22g (70.3 mmol) of urea, and N, N-dimethylformamide (5 mL) were sequentially added, the temperature was lowered to 0℃under the protection of N ₂, 4.59g (42.2 mmol) of trimethylchlorosilane was injected with a syringe, and then the reaction system was warmed to room temperature to react overnight. 10ml of water was added to the reaction system to give a large amount of white solid, which was filtered, and the cake was washed with 5ml of water and 5ml of petroleum ether, and the cake was transferred to a eggplant-shaped bottle to remove the solvent by distillation under reduced pressure. To the above white solid was added 10mL of water, the solid was insoluble, followed by 4.22g (106 mmol) of sodium hydroxide, and the system was heated to 70℃with stirring for 1h. The reaction system was cooled to 0 ℃, concentrated hydrochloric acid was added dropwise, the pH of the system was adjusted to 2, a large amount of white solid was precipitated, filtration was performed, the cake was washed with 10mL of water, and the cake was distilled under reduced pressure to remove water, yielding 4.6g of white solid.

MS(ESI,[M-H]^-)m/z:151.0.

Step B preparation of 2, 4-dichloro-6, 7-dihydro-5H-cyclopenta [ d ] pyrimidine

In a 50mL three-necked flask, 3g (19.72 mmol) of 6, 7-dihydro-5H-cyclopenta [ d ] pyrimidine-2, 4-diol and phosphorus oxychloride (15 mL) were sequentially added, and the mixture was heated to 110℃under N ₂ for reflux reaction for 5 hours. The reaction system was distilled off under reduced pressure to remove the solvent, cooled to 0 ℃,50 mL of water was added, vigorously stirred, a large amount of yellow solid was precipitated, filtered, the cake was washed with 10mL of water, and the cake was dried under reduced pressure to remove the water, to obtain 2.5g of yellow solid.

MS(ESI,[M+Na]⁺)m/z:212.0.

Step C-F preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-2-yl) piperazine-1-carboxamide

The synthesis method is described in example 1.

¹H NMR(500MHz,DMSO-d₆)δ11.91(s,1H),8.74(s,1H),8.66(d,J＝4.3Hz,1H),8.40(s,1H),7.95(d,J＝8.4Hz,1H),7.90(d,J＝4.0Hz,1H),7.86(d,J＝8.4Hz,1H),6.88(d,J＝7.5Hz,1H),6.36(s,1H),4.92-4.98(m,1H),4.46(d,J＝12.2Hz,1H),4.39(d,J＝12.6Hz,1H),4.31(s,1H),3.83(d,J＝12.9Hz,1H),2.99-3.04(m,2H),2.81-2.84(m,1H),2.61-2.67(m,4H),2.22(s,3H),1.91-1.94(m,2H),1.44(d,J＝7.0Hz,3H),1.03(d,J＝6.4Hz,3H).

MS(ESI,[M+H]⁺)m/z:546.4.

EXAMPLE 46 preparation of N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -9- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3-oxa-7, 9-diazabicyclo [3.3.1] nonane-7-carboxamide

The reaction flow is as follows:

step A preparation of tert-butyl 9- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3-oxa-7, 9-diazabicyclo [3.3.1] nonane-7-carboxylate

To a 30mL microwave tube was added successively 70mg (0.313 mmol) of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, 121mg (0.939 mmol) of N, N-dimethylformamide (5 mL), 79mg (0.344 mmol) of 3-oxa-7, 9-diazabicyclo [3.3.1] nonane-7-carboxylic acid tert-butyl ester, and N, N-diisopropylethylamine. Heating to 140 ℃ under the protection of N ₂ for reaction 40h. The reaction solution was distilled off under reduced pressure by rotary evaporator, 50ml of dichloromethane and 20ml of 3 x saturated brine were added and washed several times, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to give 100mg of yellow oily product.

MS(ESI,[M+H]⁺)m/z:416.3.

Step B preparation of 2- (3-oxo-7, 9-diazabicyclo [3.3.1] non-9-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine trifluoroacetate

The synthesis method is described in example 1, step F.

Step C preparation of N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -9- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3-oxa-7, 9-diazabicyclo [3.3.1] nonane-7-carboxamide

The synthesis method is described in example 1, step G.

MS(ESI,[M+H]⁺)m/z:548.3.

EXAMPLE 47 preparation of 2- (4- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

The reaction flow is as follows:

step A preparation of 2- (4- ((6-bromopyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

To a100 mL single vial was added 0.5g (0.997 mmol) of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate, 25mL of dichloromethane, 0.404g (3.99 mmol) of triethylamine, and 0.185g (0.997 mmol) of 2-bromo-5-aldehyde pyridine. The reaction was carried out at room temperature. After the reaction is finished, the solid and the liquid are separated by suction filtration, a filter cake is washed by methylene dichloride, and the organic phases are combined, concentrated and purified by column chromatography to obtain white semisolid 535mg.

MS(ESI,[M+H]⁺)m/z:443.1.

Step B preparation of 2- (4- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

To a 30mL microwave tube was successively added 0.661g (2.030 mmol) of cesium carbonate, 0.193g (1.015 mmol) of cuprous iodide, 10mL of DMF, 0.175g (2.030 mmol) of 4-fluoro-1H-pyrazole, 0.144g (1.015 mmol) of 2- (4- ((6-bromopyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, and 0.3g (0.677 mmol) of trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine. After nitrogen protection, the reaction is carried out under 150 ℃ per 200W microwave condition by capping and sealing. After the completion of the reaction, the reaction mixture was poured into 150mL of purified water, extracted with DCM, and washed with saturated brine. The combined organic phases were dried over anhydrous sodium sulfate. Followed by filtration, concentration and purification by column chromatography gave 130mg of yellow solid.

¹H NMR(500MHz,DMSO-d₆)δ11.83(s,1H),9.20(s,1H),8.69(d,J＝4.5Hz,1H),8.40(s,1H),8.02–7.84(m,3H),6.21(s,1H),6.10(s,1H),3.70(t,4H),3.58(s,2H),3.33(s,3H),2.44(t,J＝5.0Hz,4H),2.18(s,3H).

MS(ESI,[M+H]⁺)m/z:449.2.

EXAMPLE 48 preparation of 2- (4- ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

The reaction flow is as follows:

The synthesis is described in example 47.

¹H NMR(500MHz,DMSO-d₆)δ11.88(s,1H),9.29(s,1H),8.12(s,1H),7.70(d,J＝7.7Hz,1H),6.83(d,J＝8.4Hz,1H),6.24(s,1H),6.11(s,1H),3.85(s,3H),3.43–3.32(m,4H),3.14–3.04(m,2H),2.54(s,2H),2.19(s,3H),2.12(s,3H),1.18(t,J＝7.3Hz,2H).

MS(ESI,[M+H]⁺)m/z:395.3.

EXAMPLE 49 preparation of 2- ((1R, 5S) -8- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

The reaction flow is as follows:

The synthesis is described in example 47.

¹H NMR(500MHz,DMSO-d₆)δ11.83(s,1H),9.19(s,1H),8.68(d,J＝4.2Hz,1H),8.45(s,1H),8.03(d,J＝8.4Hz,1H),7.91(s,2H),6.17(s,2H),4.21(d,J＝11.7Hz,2H),3.60(s,2H),3.23(s,2H),3.00(d,J＝11.9Hz,2H),2.18(s,3H),2.10(s,3H),1.99–1.94(m,2H),1.54(d,J＝7.5Hz,2H).

MS(ESI,[M+H]⁺)m/z:475.3.

EXAMPLE 50 preparation of 2- (6- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

The reaction flow is as follows:

The synthesis is described in example 47.

¹H NMR(500MHz,DMSO-d₆)δ11.88(s,1H),9.33(s,1H),8.66(s,1H),8.41(s,1H),7.97(d,J＝7.4Hz,1H),7.91(s,1H),7.88(s,1H),6.38(s,1H),6.23(s,1H),3.77(s,2H),3.73(s,2H),3.51(s,2H),2.27(s,3H),2.18(s,2H),2.16(s,3H),1.23(s,2H).

MS(ESI,[M+H]⁺)m/z:461.3.

EXAMPLE 51 preparation of 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- ((S) -1- (6- (((S) -pentan-2-yl) oxy) pyridin-3-yl) ethyl) piperazine-1-amide

The reaction flow is as follows:

Synthetic method reference is made to example 36.

¹H NMR(500MHz,DMSO-d₆)δ11.87(s,1H),9.26(s,1H),8.06(d,J＝2.4Hz,1H),7.65(s,1H),6.82(d,J＝7.8Hz,1H),6.69(d,J＝8.5Hz,1H),6.14(s,2H),5.18–5.10(m,1H),4.83(p,J＝7.0Hz,1H),3.67(t,J＝5.0Hz,4H),3.39(t,J＝5.0Hz,4H),2.21(s,3H),2.13(s,3H),1.68–1.47(m,2H),1.38(d,J＝7.1Hz,3H),1.37–1.28(m,2H),1.23(d,J＝6.1Hz,3H),0.88(t,J＝7.4Hz,3H).

MS(ESI,[M+H]⁺)m/z:508.3.

Example 52 preparation of (S) -N- (chroman-6-ylmethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-amide

The reaction flow is as follows:

the synthesis method is described in example 19.

¹H NMR(500MHz,DMSO-d₆)δ11.62(s,1H),8.55(s,1H),6.94(s,3H),6.65(s,1H),6.35(s,1H),6.01(s,1H),5.95(s,1H),4.26(s,2H),4.08(s,4H),3.81(s,1H),3.02(d,J＝46.5Hz,2H),2.69(s,2H),2.17(s,3H),2.11(s,3H),1.89(s,2H),1.29(d,J＝59.9Hz,2H),1.09(s,3H).

MS(ESI,[M+H]⁺)m/z:476.3.

Example 53 preparation of (1R, 5S) -N- ((R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-amide

The reaction flow is as follows:

step A preparation of 6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-ethanone

To a 250mL single vial was added 3g (15 mmol) of 5-acetyl-2-bromopyridine, 1.549g (18 mmol) of 4-fluoro-1H-pyrazole, 4.15g (30 mmol) of potassium carbonate, and 25mL of DMF. The reaction was heated at 100 ℃ for about 5 hours under nitrogen atmosphere. After the reaction was completed, 100mL of purified water was added to the reaction mixture, and a large amount of solid was precipitated. The filter cake was washed multiple times with purified water and the solid was collected and dried and then slurried with an appropriate amount of PE. After filtration and drying, 2.45g of a brown solid product was obtained.

MS(ESI,[M+H]⁺)m/z:206.1.

Step B (S, E) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylene) -2-methylpropan-2-sulfinamide preparation

To a 250mL single vial was added 2.45g (11.94 mmol) of 6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-ethanone, 50mL of THF, 3.20g (23.88 mmol) of diethylene glycol dimethyl ether, 5.45g (23.88 mmol) of ethyl titanate, and 2.89g (23.88 mmol) of S-tert-butylsulfinamide. The reaction was heated at 80 ℃ for about 3 hours under nitrogen atmosphere. And after the reaction is finished, the reaction liquid is not treated, and the next reaction is directly carried out.

Step C preparation of (S) -N- ((R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide

And (3) placing the reaction system in the last step under the nitrogen atmosphere, and cooling to-80 ℃. 5.45g (1 mol/L;28.7mL;28.7 mmol) of lithium tri-sec-butylborohydride was slowly added dropwise to the system via syringe. After the completion of the dropwise addition, the reaction was maintained at-80 ℃. After the reaction was completed, the reaction mixture was poured into 150mL of purified water, and a large amount of solid was precipitated. After suction filtration, the filter cake was washed with EA, the organic phases were combined and concentrated under reduced pressure to give 9.7g of crude product as a yellow oil. The crude product was directly subjected to the next reaction without further purification.

Step D preparation of (R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine hydrochloride

In a 250mL single vial was added 3.54g (11.40 mmol) of (S) -N- ((R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide, 50mL of methanol, 4.2g (4 mol/L;28.8mL;115 mmol) of hydrochloric acid. The reaction was carried out at room temperature under nitrogen atmosphere. After the reaction is finished, the solvent is removed under reduced pressure, 50mL of EA was added and the mixture was slurried. And washing by EA after suction filtration. The filter cake was dried under vacuum to give 3.19g of a yellowish white solid product.

MS(ESI,[M+H]⁺)m/z:207.14.

Step E preparation of (1R, 5S) -3- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

A50 mL single vial was charged with 0.6g (2.78 mmol) of 2, 6-dichloro-4-trifluoromethylpyridine, 5mL of DMF, 0.637g (3.00 mmol) of 8-BOC-3, 8-diazabicyclo [3.2.1] octane, and 0.718g (0.970 mL;5.56 mmol) of DIPEA. The mixture was heated to 110 ℃ and reacted for about 5h. After the reaction was completed, 50mLEA parts of the reaction mixture was added to dilute the mixture, and the organic phase was washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 0.4g of a white solid product.

Step F preparation of (1R, 5S) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a 35mL microwave tube was added 660mg (1.684 mmol) of tert-butyl (1R, 5S) -3- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, 15mL of THF, 180mg (1.853 mmol) of 3-amino-5-methylpyrazole, 154mg (0.168 mmol) of tris (dibenzylideneacetone) dipalladium, 133mg (0.337 mmol) of 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl, 730mg (4.36 mmol) of lithium bis trimethylsilylamide. Placing the mixture into a CEM microwave reactor under the nitrogen atmosphere, setting 130 ℃ and 100W power, and heating and reacting for 30min. After the completion of the reaction, 50mL of EA was added to the reaction mixture to dilute the mixture, and the organic phase was washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 480mg of a brown solid product.

MS(ESI,[M+H]⁺)m/z:453.2.

Step G preparation of 6- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (5-methyl-1H-pyrazol-3-yl) -4- (trifluoromethyl) pyridin-2-amine trifluoroacetate

To a 250mL single vial was added 0.48g (1.061 mmol) of tert-butyl (1R, 5S) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, 20mL DCM, 0.605g (5.30 mmol) of trifluoroacetic acid. The reaction was carried out at room temperature for about 5 hours. After the reaction was completed, the reaction solvent and excess trifluoroacetic acid were directly removed under reduced pressure, and slurried with DCM, filtered and dried to give 0.4g of an off-white solid.

MS(ESI,[M+H]⁺)m/z:353.2.

Step H preparation of (1R, 5S) -N- ((R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-amide

To a 25mL three-necked flask was added 0.073g (0.246 mmol) of solid triphosgene and 5mL of DCM. The ice salt bath is cooled to 0 ℃ under the protection of nitrogen. A15 mL tube was added with (R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine hydrochloride 0.063g (0.224 mmol), triethylamine 0.136g (1.344 mmol), DCM 5mL, and the solution was slowly added to the reaction. After about 30min of low temperature reaction, 5mL of DCM solution containing 0.13g (0.224 mmol) of 6- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (5-methyl-1H-pyrazol-3-yl) -4- (trifluoromethyl) pyridin-2-amine trifluoroacetate, and 0.136g (1.344 mmol) of triethylamine was added to the reaction system. After the addition, the reaction was carried out for about 30 minutes at 0℃in an ice bath. After the reaction was completed, the reaction solution was poured into 100mL of purified water and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate. Followed by filtration, concentration and purification by column chromatography gave 67mg of the product as an off-white solid.

¹H NMR(500MHz,DMSO-d₆)δ11.81(s,1H),9.18(s,1H),8.66(d,J＝4.3Hz,1H),8.41(s,1H),7.95(d,J＝8.3Hz,1H),7.90(s,1H),7.86(s,1H),7.14(d,J＝7.6Hz,1H),6.82(s,1H),6.21(s,1H),6.03(s,1H),4.95(p,J＝6.7Hz,1H),4.45(d,J＝13.9Hz,2H),3.95(d,J＝6.1Hz,2H),3.51(s,1H),2.98(d,J＝11.6Hz,2H),2.20(s,3H),1.79(s,1H),1.66(d,J＝7.8Hz,2H),1.45(d,J＝6.9Hz,3H).

MS(ESI,[M+H]⁺)m/z:585.3.

EXAMPLE 54 preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -8- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-3-amide

The reaction flow is as follows:

The synthesis method is described in example 53.

¹H NMR(500MHz,DMSO-d₆)δ11.85(s,1H),9.28(s,1H),8.68(s,1H),8.39(s,1H),7.93(d,J＝9.1Hz,1H),7.91(s,1H),7.86(d,J＝8.2Hz,1H),6.90–6.69(m,2H),6.34(s,1H),6.05(s,1H),4.90(p,J＝7.7Hz,1H),4.62(s,2H),3.72(s,1H),3.70(s,1H),3.03(d,J＝11.9Hz,2H),2.21(s,3H),1.90(s,2H),1.72(s,2H),1.41(d,J＝6.1Hz,3H).

MS(ESI,[M+H]⁺)m/z:585.3.

EXAMPLE 55 preparation of (R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) piperazine-1-amide

The reaction flow is as follows:

The synthesis method is described in example 53.

¹H NMR(500MHz,DMSO-d₆)δ11.83(s,1H),9.21(s,1H),8.68(d,J＝4.4Hz,1H),8.42(s,1H),8.00–7.84(m,3H),6.96(d,J＝7.4Hz,1H),6.85(s,1H),6.32(s,1H),6.03(s,1H),4.95(p,J＝6.9Hz,1H),4.31(s,1H),4.21(d,J＝12.2Hz,1H),4.13(d,J＝12.7Hz,1H),3.88(d,J＝13.0Hz,1H),3.17–3.01(m,2H),2.97–2.85(m,1H),2.21(s,3H),1.45(d,J＝7.1Hz,3H),1.09(d,J＝6.5Hz,3H).

MS(ESI,[M+H]⁺)m/z:573.3.

EXAMPLE 56 preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) piperazine-1-amide

The reaction flow is as follows:

The synthesis method is described in example 53.

¹H NMR(500MHz,DMSO-d₆)δ11.83(s,1H),9.22(s,1H),8.67(d,J＝4.5Hz,1H),8.42(d,J＝1.8Hz,1H),7.99–7.94(m,1H),7.93–7.85(m,2H),7.03(d,J＝7.5Hz,1H),6.88(s,1H),6.33(s,1H),6.03(s,1H),4.94(p,J＝7.0Hz,1H),3.54(d,J＝5.2Hz,4H),3.47(d,J＝5.1Hz,4H),2.21(s,3H),1.45(d,J＝7.1Hz,3H).

MS(ESI,[M+H]⁺)m/z:559.4.

Example 57 preparation of (S) -N- (1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

Step A preparation of (S) -N- (1- (4-bromophenyl) ethyl) -2, 2-trifluoroacetamide

(R) -1- (4-bromophenyl) ethyl-1-amine (1 g,5.00 mmol) was dissolved in 10mL of methylene chloride in a 50mL three-necked flask, the reaction system was cooled to 0℃in an ice-salt bath, and trifluoroacetic anhydride (1.260 g,0.847mL,6.00 mmol) was slowly added dropwise to the above reaction system via syringe over 3 min. The mixture was stirred at 0 ℃ for 1h, warmed naturally, and stirred at room temperature overnight. After the reaction was completed, 40mL of methylene chloride and 10mL of water were added to the reaction system, the organic phase was collected by extraction, and washed with 1M aqueous sodium hydrogen sulfate (20 mL) followed by saturated sodium hydrogen carbonate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1.45g of a white powdery solid.

MS(ESI,[M-H]^-)m/z:294.1.

Step B preparation of (S) -2, 2-trifluoro-N- (1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) acetamide

In a 35mL microwave tube, (R) -N- (1- (4-bromophenyl) ethyl) -2, 2-trifluoroacetamide (1.2 g,4.05 mmol), N, N-dimethylacetamide (15 mL), 4-fluoro-1H-pyrazole (0.319 g,4.86 mmol), copper iodide (0.154 g, 0.81mmol), 1, 10-phenanthroline (0.292 g, 1.6271 mmol) and Cs ₂CO₃ (2.64 g,8.11 mmol) were sequentially added, and the reaction was transferred to a microwave reactor under microwave conditions of 160℃for 3H. After the reaction was completed, 40mL of ethyl acetate and celite were added to the reaction system, and the filtrate was washed three times with 30mL of saturated brine. Dried over anhydrous sodium sulfate, concentrated by filtration, and purified by column chromatography to give 200mg of a brown oil.

MS(ESI,[M+H]⁺)m/z:302.1.

Step C preparation of (S) -1- (4- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethan-1-amine

In a 25mL single vial, (R) -2, 2-trifluoro-N- (1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) acetamide (0.03 g,0.100 mmol), methanol (5 mL), 1M aqueous LiOH (5 mL) were added sequentially and the mixture was stirred overnight at room temperature. After the reaction was completed, 40mL of ethyl acetate and 10mL of water were added to the reaction system. The organic phase was extracted and washed twice with 10mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated to give 10mg of a pale yellow oil.

Step D preparation of (S) -N- (1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide

Step D refer to step D of example 19.

¹H NMR(500MHz,CDCl₃):δ12.37(s,1H),12.35(s,1H),8.64(d,J＝4.5Hz,1H),7.80(d,J＝4.0Hz,1H),7.71(d,J＝8.5Hz,2H),7.46(d,J＝8.5Hz,2H),7.01(d,J＝7.5Hz,1H),6.30(m,2H),4.90(m,1H),3.82(s,4H),3.53(s,4H),2.36(s,3H),2.25(s,3H),1.42(d,J＝7.0Hz,3H).MS(ESI,[M+H]⁺)m/z:505.2.

EXAMPLE 58 preparation of 1- (6- (2-cyanopropan-2-yl) pyridin-3-yl) -3- (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-yl urea

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,DMSO-d₆):δ11.85(s,1H),9.19(s,1H),8.65(s,1H),8.55(d,J＝2.5Hz,1H),7.61(m,1H),7.56(d,J＝9.0Hz,1H),6.78(d,J＝8Hz,1H),6.22(s,1H),6.10(s,1H),3.76(m,1H),3.07(m,2H),2.51(m,2H),2.20(s,3H),2.12(s,3H),1.89(m,2H),1.67(s,6H),1.37(m,2H).

MS(ESI,[M+H]⁺)m/z:475.3。

Example 59 preparation of (1R, 5S) -3- (5-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- ((S) -1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,DMSO-d₆):δ12.07(s,1H),8.62(d,J＝4.5Hz,2H),8.00(s,1H),7.79(d,J＝4.0Hz,1H),7.71(d,J＝8.5Hz,2H),7.44(d,J＝8.5Hz,2H),7.01(d,J＝8.0Hz,1H),6.29(s,1H),4.91(t,J＝7.0Hz,1H),4.42(m,2H),4.18(s,2H),3.02(d,J＝12Hz,2H),2.24(s,3H),1.76(t,J＝4.5Hz,2H),1.57(d,J＝8.5Hz,2H),1.41(d,J＝7.0Hz,3H).

MS(ESI,[M+H]⁺)m/z:551.3。

Example 60 preparation of (1R, 5S) -N- ((S) -1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) -3- (5-fluoro-4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide

The reaction flow is as follows:

the synthesis method is described in example 1.

¹H NMR(500MHz,DMSO-d₆):δ12.03(s,1H),9.44(s,1H),8.62(d,J＝4.5Hz,1H),7.92(d,J＝3.5Hz,1H),7.79(d,J＝4.0Hz,1H),7.71(d,J＝8.5Hz,2H),7.44(d,J＝8.5Hz,2H),7.02(d,J＝8.0Hz,1H),6.33(s,1H),4.91(t,J＝7.0Hz,1H),4.42(m,2H),4.14(m,2H),3.01(d,J＝12.5Hz,2H),2.24(s,3H),1.76(t,J＝4.0Hz,2H),1.59(d,J＝8.0Hz,2H),1.41(d,J＝7.0Hz,3H).

MS(ESI,[M+H]⁺)m/z:535.3.

Example 61 preparation of (1R, 5S) -N- ((S) -1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide

The reaction flow is as follows:

The synthesis method is described in example 27.

¹H NMR(500MHz,DMSO-d₆):δ11.80(s,1H),9.16(s,1H),8.62(d,J＝4.5Hz,1H),7.79(d,J＝4.0Hz,1H),7.71(d,J＝8.5Hz,2H),7.45(d,J＝8.5Hz,2H),7.06(d,J＝8.0Hz,1H),6.83(s,1H),6.21(s,1H),6.03(s,1H),4.92(m,1H),4.46(m,2H),3.94(m,2H),3.00(m,2H),2.21(s,3H),1.79(d,J＝4.5Hz,2H),1.67(d,J＝8.0Hz,2H),1.41(d,J＝7.0Hz,3H).

MS(ESI,[M+H]⁺)m/z:584.4。

EXAMPLE 62 preparation of 2- (1- (4-methyl-6- (((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-yl) -N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) acetamide

The reaction flow is as follows:

The synthesis method is described in example 15.

¹H NMR(500MHz,DMSO-d₆):δ11.85(d,J＝5.0Hz,1H),9.88(s,1H),9.21(s,1H),7.54(d,J＝5.0Hz,2H),7.19(d,J＝8.5Hz,2H),6.11(s,2H),4.64(m,2H),2.80(m,2H),2.31(m,5H),2.24(d,J＝7.5Hz,3H),2.18(s,3H),2.15(s,3H),2.10(s,3H),2.02(m,2H),1.70(d,J＝11.0Hz,2H),1.35(s,1H),1.14(m,4H).

MS(ESI,[M+H]⁺)m/z:518.5.

EXAMPLE 63 preparation of N- (6- (2-cyanopropan-2-yl) pyridin-3-yl) -2- (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-ylpiperidin-4-ylacetamide

The reaction flow is as follows:

The synthesis method is described in example 15.

¹H NMR(500MHz,DMSO-d₆):δ11.85(s,1H),10.25(s,1H),9.21(s,1H),8.72(d,J＝2.0Hz,1H),8.14(m,1H),7.55(d,J＝8.5Hz,1H),6.11(m,2H),4.65(m,2H),2.80(m,2H),2.30(d,J＝7.0Hz,2H),2.19(s,3H),2.11(s,3H),1.99(s,1H),1.72(m,2H),1.68(s,6H),1.17(m,2H).

MS(ESI,[M+H]⁺)m/z:474.4。

EXAMPLE 64 preparation of (S) -N- ((S) -1- (6- ((R) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-ylpiperazine-1-carboxamide

The reaction flow is as follows:

Step A preparation of (S) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide

To a 250mL three-necked round bottom flask, 80mL anhydrous tetrahydrofuran, 1- (6-bromopyridin-3-yl) ethan-1-one (6 g,66.7 mmol), R-t-butylsulfinamide (7.27 g,60.0 mmol), diethylene glycol dimethyl ether (4.02 g,30.0 mmol) and tetraethyltitanate (13.68 g,60.0 mmol) were successively added, and the reaction system was heated under nitrogen atmosphere and refluxed for 5 hours. The reaction solution was cooled to-78 ℃, 1M solution of lithium tri-sec-butylborohydride in tetrahydrofuran (90 ml,90 mmol) was slowly added dropwise under nitrogen protection, the temperature was controlled to be not higher than-70 ℃, and the reaction was continued under stirring at-78 ℃ for 40min after the addition was completed. The reaction was quenched by dropwise addition of 40mL of methanol, and the reaction mixture was naturally warmed to 0℃and poured into 500mL of water with stirring. The mixture was filtered, and the filter cake was washed with ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to a yellow solid. 50mL of a mixed solution of petroleum ether and ethyl acetate=5:1 was added to the crude product, and the mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with petroleum ether to obtain 5.6g of a white powdery solid.

Step B preparation of (S) -N- ((S) -1- (6- ((R) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide

In a 35mL microwave tube, (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide (300 mg,0.983 mmol), THF (10 mL), (R) -3-fluoropyrrolidine hydrochloride (123 mg,0.983 mmol), davephos (26 mg,0.066 mmol), pd2 (dba) 3 (30 mg,0.033 mmol), 1M LiHMDS (0.8235 mL, 0.8235 mmol) were added sequentially, and the mixture was placed in a microwave reactor under nitrogen and microwave conditions were 130℃for 30min. After the reaction was completed, 50mL of a diluted solution of methylene chloride was added to the reaction system, and the reaction solution was washed three times with 20mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography purification gave 0.14g of brown oil.

MS(ESI,[M+H]⁺)m/z:314.2。

Step C preparation of (S) -1- (6- ((R) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethan-1-amine dihydrochloride

In a 50mL single flask, (S) -N- ((S) -1- (6- ((R) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethyl) -2-methylpropan-2-sulfinamide (0.14 g,0.447 mmol), methanol (10 mL), 1M dilute hydrochloric acid (4 mL,4.02 mmol) were added sequentially and the mixture stirred at room temperature for 3h. The reaction solution was concentrated under reduced pressure to give a brown solid, which was slurried with 20mL of ethyl acetate for 2 hours, filtered, and the cake was collected to give 0.07g of a gray solid.

Step D preparation of (S) -N- ((S) -1- (6- ((R) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-ylpiperazine-1-carboxamide

The synthesis method is described in example 1, step G.

¹H NMR(500MHz,DMSO-d₆):δ11.77(s,1H),8.67(s,1H),8.01(d,J＝2.0Hz,1H),7.55(d,J＝7.5Hz,1H),6.71(d,J＝8.0Hz,1H),6.50(d,J＝9.0Hz,1H),6.32(s,1H),6.01(m,2H),4.79(m,1H),4.28(t,J＝3.0Hz,1H),4.05(m,2H),3.82(m,1H),3.60(m,3H),3.03(m,2H),2.72(m,1H),2.24(m,2H),2.18(s,3H),2.12(s,3H),1.36(m,3H),1.22(m,2H),1.07(d,J＝6.0Hz,3H).

MS(ESI,[M+H]⁺)m/z:522.3.

Example 65 preparation of (2S) -N- (((1S) -1- (6- (3-azabicyclo [3.1.0] ] hex-3-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-ylpiperazine-1-carboxamide

The reaction flow is as follows:

synthetic method reference is made to example 64.

¹H NMR(500MHz,DMSO-d₆):δ11.71(s,1H),8.62(s,1H),7.97(d,J＝2.0Hz,1H),7.46(m,1H),6.66(d,J＝8.0Hz,1H),6.40(m,2H),6.01(m,2H),4.76(m,1H),4.27(t,J＝3.0Hz,1H),4.06(m,2H),3.81(m,1H),3.61(m,2H),3.28(d,J＝9.0Hz,2H),3.01(m,2H),2.71(m,1H),2.18(s,3H),2.11(s,3H),1.65(m,2H),1.34(d,J＝7.5Hz,3H),1.06(d,J＝8.0Hz,3H),0.85(m,1H),0.70(m,1H).

MS(ESI,[M+H]⁺)m/z:516.4.

Example 66 preparation of (S) -N- ((S) -1- (6- (azetidin-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

synthetic method reference is made to example 64.

¹H NMR(500MHz,DMSO-d₆):δ11.77(d,J＝5.0Hz,1H),8.66(s,1H),7.97(d,J＝3.0Hz,1H),7.55(d,J＝3.5Hz,1H),6.71(d,J＝7.5Hz,1H),6.36(m,2H),6.01(m,2H),4.76(m,1H),4.28(d,J＝3.0Hz,1H),4.05(m,2H),3.91(m,4H),3.81(m,1H),2.96(m,2H),2.72(m,1H),2.30(d,J＝7.5Hz,2H),2.17(s,3H),2.11(s,3H),1.34(m,3H),1.06(d,J＝6.5Hz,3H).

MS(ESI,[M+H]⁺)m/z:490.4.

EXAMPLE 67 preparation of (S) -N- ((S) -1- (6- ((S) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-ylpiperazine-1-carboxamide

The reaction flow is as follows:

synthetic method reference is made to example 64.

¹H NMR(500MHz,DMSO-d₆):δ11.73(s,1H),8.65(s,1H),8.01(s,1H),7.53(d,J＝7.5Hz,1H),6.70(d,J＝8.0Hz,1H),6.48(d,J＝8.5Hz,1H),6.32(s,1H),6.00(m,2H),4.78(m,1H),4.29(s,1H),4.06(m,2H),3.81(m,1H),3.61(m,3H),3.03(m,2H),2.93(d,J＝9.5Hz,1H),2.72(m,2H),2.18(s,3H),2.12(s,3H),1.36(d,J＝7.0Hz,3H),1.23(s,2H),1.07(d,J＝6.0Hz,3H).

MS(ESI,[M+H]⁺)m/z:522.4.

EXAMPLE 68 preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4- (6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrazin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

The synthesis method is described in example 27.

¹H NMR(500MHz,DMSO-d₆):δ11.83(s,1H),9.19(s,1H),8.66(d,J＝4.0Hz,1H),8.41(s,1H),7.89(m,3H),7.78(s,1H),7.55(s,1H),7.01(d,J＝7.5Hz,1H),6.11(s,1H),4.93(m,1H),3.48(m,8H),2.51(s,3H),2.20(s,3H).

MS(ESI,[M+H]⁺)m/z:492.3.

Example 69 preparation of (S) -N- ((S) -1- (6- (3-fluoroazetidin-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxamide

The reaction flow is as follows:

synthetic method reference is made to example 64.

¹H NMR(500MHz,CDCl₃):δ11.66(s,1H),8.63(s,1H),8.04(s,1H),7.54(d,J＝8.0Hz,1H),6.72(d,J＝7.5Hz,1H),6.43(d,J＝8.5Hz,1H),6.32(s,1H),6.02(s,1H),5.95(s,1H),5.48(m,1H),4.79(m,1H),4.23(m,3H),3.75(m,4H),3.81(m,1H),3.08(t,J＝11Hz,1H),2.92(d,J＝10.5Hz,1H),2.71(t,J＝11Hz,1H),2.18(s,3H),2.12(s,3H),1.36(d,J＝6.0Hz,3H),1.07(m,3H).

MS(ESI,[M+H]⁺)m/z:508.3.

EXAMPLE 70 preparation of (S) -4- (4- (difluoromethyl) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylpiperazine-1-carboxamide

The reaction flow is as follows:

Step A preparation of 2, 6-dichloro-4- (difluoromethyl) pyridine

In a 50mL three-necked flask, cuprous chloride (1.301 g,13.14 mmol) and potassium tert-butoxide (2.95 g,26.3 mmol) were added, and the reaction system was stirred at room temperature for 15min under nitrogen protection by adding 20mL anhydrous DMF, and (difluoromethyl) trimethylsilane (2.041 g,16.43 mmol) was slowly added to the reaction system, after the completion of the 5min addition, the reaction system was stirred at room temperature for 5min. 1, 10-phenanthroline (2.369 g,13.14 mmol) was dissolved in 5mL of anhydrous DMF and added to the above reaction system at one time, the reaction system was stirred at room temperature for 20min, 2, 6-dichloro-4-iodopyridine (3 g,10.95 mmol) was dissolved in 15mL of anhydrous DMF and added to the above system at one time, and stirred at room temperature overnight. After the reaction was completed, 20mL of water and 50mL of ethyl acetate were added to the reaction system, and the organic phase was collected. The organic phase was washed three times with 20mL of saturated brine, dried over anhydrous sodium sulfate, concentrated by filtration, and purified by column chromatography to give 1.0g of a colorless oil.

Step B Synthesis of tert-butyl 4- (6-chloro-4- (difluoromethyl) pyridin-2-yl) piperazine-1-carboxylate

To a 50mL single flask was added 2, 6-dichloro-4- (difluoromethyl) pyridine (0.4 mg,2.02 mmol), N, N-dimethylformamide (10 mL), N-Boc-piperazine (0.75 g,4.04 mmol), diisopropylethylamine (0.78 g,6.06 mmol) and the mixture was heated to 120℃for 4h. To the reaction solution, 30mL of ethyl acetate and 10mL of water were added, and the organic phase was collected by extraction. The organic phase was washed three times with 10mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 0.4g of a pale yellow oil.

MS(ESI,[M-Boc+H]⁺)m/z:248.1.

Step C Synthesis of tert-butyl 4- (4- (difluoromethyl) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate

In a 35mL microwave tube, tert-butyl 4- (6-chloro-4- (difluoromethyl) pyridin-2-yl) piperazine-1-carboxylate (0.4 g,1.150 mmol), tetrahydrofuran (10 mL), 5-methyl-1H-pyrazol-3-amine (0.117 g,1.208 mmol), 2'- (dicyclohexylphosphino) -N, N-dimethyl- [1,1' -biphenyl ] -2-amine (0.045 g,0.115 mmol), 1M lithium bis (trimethylsilyl) amide (5.2 mL,5.18 mmol), pd ₂(dba)₃ (0.053 g,0.058 mmol) were added sequentially. Nitrogen was purged of air and placed in a microwave reactor and 400W heated to 130 ℃ for 30 minutes of reaction. The reaction was quenched by dropwise addition of 5mL of 1M saturated ammonium chloride solution in ice bath and diluted with 20mL ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was concentrated and the crude product was purified by column chromatography to give 0.18g of a pale yellow oil.

MS(ESI,[M+H]⁺)m/z:409.2.

Step D Synthesis of trifluoroacetate salt of 4- (difluoromethyl) -N- (5-methyl-1H-pyrazol-3-yl) -6- (piperazin-1-yl) pyridin-2-amine (1:2)

In a 50mL round bottom flask, tert-butyl 4- (4- (difluoromethyl) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate (0.18 g,0.441 mmol), dichloromethane (10 mL) and trifluoroacetic acid (0.251 g,2.203 mmol) were added sequentially, stirred at room temperature overnight, the reaction mixture was concentrated after the reaction was completed to give 0.18g of a brown solid product, and the reaction was continued without purification.

MS(ESI,[M+H]⁺)m/z:309.1.

Step E synthesis of (S) -4- (4- (difluoromethyl) -6- (((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylpiperazine-1-carboxamide

Triphosgene (0.053 g,0.178 mmol) was dissolved in 5mL of dichloromethane and the ice salt bath was cooled to 0℃under nitrogen, and 5mL of a dichloromethane solution containing (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethanamine dihydrochloride (0.056 g,0.198 mmol) and triethylamine (0.17 g, 1.284 mmol) was added dropwise. After the reaction solution was stirred at 0℃for 5 minutes, 4- (difluoromethyl) -N- (5-methyl-1H-pyrazol-3-yl) -6- (piperazin-1-yl) pyridin-2-amine trifluoroacetate (0.1 g, 0.39 mmol) and triethylamine (0.09 g,0.792 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. After completion of the reaction, 50mL of methylene chloride was added to the reaction mixture to dilute it, and the mixture was washed with 20mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the obtained crude product was purified by column chromatography to obtain 47mg of the target product as a white powdery solid.

¹H NMR(500MHz,DMSO-d₆):δ11.76(s,1H),9.02(s,1H),8.67(d,J＝3.5Hz,1H),8.42(s,1H),7.88(m,3H),7.02(d,J＝6.5Hz,1H),6.88(m,1H),6.15(d,J＝6.5Hz,1H),6.23(s,1H),6.02(s,1H),4.94(m,1H),3.47(m,8H),2.20(s,3H),1.44(d,J＝6.5Hz,3H).

MS(ESI,[M+H]⁺)m/z:541.2。

Example 71 preparation of (1R, 5S) -8- (4- (difluoromethyl) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxamide

The reaction flow is as follows:

synthetic method reference is made to example 70.

¹H NMR(500MHz,DMSO-d₆):δ11.75(s,1H),9.04(s,1H),8.67(d,J＝5.0Hz,1H),8.38(s,1H),7.90(m,3H),6.85(m,3H),6.21(s,1H),6.04(s,1H),4.89(t,J＝5.0Hz,1H),4.54(s,2H),3.69(m,2H),3.03(m,2H),2.20(s,3H),1.8 9(s,2H),1.73(m,2H),1.41(d,J＝7.0Hz,3H).

EXAMPLE 72 preparation of 2- (4- ((6-isopropoxypyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine

The reaction flow is as follows:

To a 100mL single-necked flask, 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate (500 mg,1.065 mmol), DCM (20 mL), TEA (431 mg,0.594mL,4.26 mmol), 6- (1-methylethoxy) -3-pyridinecarboxaldehyde (194 mg,1.172 mmol), sodium triacetoxyborohydride (677 mg,3.20 mmol) were added sequentially and stirred overnight at room temperature. The filtrate was filtered, collected and concentrated, 20mL of DCM and 60mL of H ₂ O were added, the mixture was shaken to separate the solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give 427mg of white solid.

¹H NMR(500MHz,DMSO-d₆)δ9.57(s,1H),8.22(s,1H),7.84–7.70(m,1H),6.80(d,J＝8.5Hz,1H),6.21(d,J＝96.4Hz,2H),5.26(p,J＝6.2Hz,1H),4.18(s,2H),3.09(q,J＝7.0Hz,4H),2.18(d,J＝18.5Hz,6H),1.29(d,J＝6.2Hz,6H),1.19(s,1H),1.18(s,2H),1.16(s,1H).

MS(ESI,[M+H]⁺)m/z:423.3.

Example 73 preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide

The reaction flow is as follows:

The synthesis method is described in example 53.

¹H NMR(500MHz,DMSO-d₆)δ11.80(s,1H),9.16(s,1H),8.69–8.61(m,1H),8.40(d,J＝2.2Hz,1H),7.97–7.84(m,3H),7.13(d,J＝7.7Hz,1H),6.82(s,1H),6.20(s,1H),6.02(s,1H),4.94(p,J＝7.1Hz,1H),4.44(d,J＝15.3Hz,2H),3.94(d,J＝5.9Hz,2H),2.97(d,J＝12.2Hz,2H),2.19(s,3H),1.44(d,J＝7.1Hz,3H),1.23(s,4H).

MS(ESI,[M+H]⁺)m/z:585.3.

Experimental example 1 inhibition of in vitro Activity of kinases RET, RET (M918T), RET (Y791F), RET (V804L), RET (V804M), KDR

1.1 RET inhibitory Activity screening

50 Ng/. Mu.L of RET stock was diluted with kinase buffer (50 mM HEPES, 10mM MgCl ₂, 2mM DTT, 1mM EGTA, 0.01% Tween 20), 6. Mu.L of 1.67X 0.000334 ng/. Mu.L of working solution (final concentration of 0.0002 ng/. Mu.L) was added to each well, and DMSO-dissolved different compounds were added to the wells using a nanoliter-type-applicator to give final concentrations of 1000nM-0.24nM, 4-fold gradient for 7 total, and blank wells (without enzyme) and negative control wells (containing enzyme, vehicle DMSO) were simultaneously set, and 2 multiplex wells were set. After 30min of reaction of the enzyme with the compound or vehicle, 5. Mu.M ATP (final concentration of 10. Mu.M) prepared with kinase buffer was mixed with 5. Mu.M substrate (final concentration of 0.1. Mu.M, ULight-poly GT) at 1:1 and added to the wells at 4. Mu.L per well, after sealing the plate, 2h of reaction at room temperature, 5. Mu.L of 4X 40mM EDTA (final concentration of 10 mM) was added to each well, 5min at room temperature, and 5. Mu.L of 4X 8nM detection reagent (final concentration of 2nM, eu-anti-phospho-tyrosine antibody) was added to each well, and the plate read (excitation 320nM, emission 665 nM) was performed with a PE Envision multifunctional microplate reader at room temperature for 1h, using four-parameter fitting to calculate IC ₅₀.

1.2 RET (M918T) inhibitory Activity Screen

50 Ng/. Mu.L of RET (M918T) stock was diluted with kinase buffer (50 mM HEPES, 10mM MgCl ₂, 2mM DTT, 1mM EGTA, 0.01% Tween 20), 6. Mu.L of 1.67X 0.000835 ng/. Mu.L of working solution (final concentration 0.0005 ng/. Mu.L) was added to each well, and DMSO-dissolved compounds were added to the wells using a nanoliter-type-applicator to give a final concentration of 1000nM-0.24nM, 4-fold gradient, 7 total, and a blank well (without enzyme) and a negative control well (containing enzyme, plus vehicle DMSO) were simultaneously set. After 30min of reaction of the enzyme with the compound or vehicle, 5. Mu.M ATP (final concentration of 10. Mu.M) prepared with kinase buffer was mixed with 5. Mu.M substrate (final concentration of 0.1. Mu.M, ULight-poly GT) at 1:1 and added to the wells at 4. Mu.L per well, after sealing the plate, 2h of reaction at room temperature, 5. Mu.L of 4X 40mM EDTA (final concentration of 10 mM) was added to each well, 5min at room temperature, and 5. Mu.L of 4X 8nM detection reagent (final concentration of 2nM, eu-anti-phospho-tyrosine antibody) was added to each well, and the plate read (excitation 320nM, emission 665 nM) was performed with a PE Envision multifunctional microplate reader at room temperature for 1h, using four-parameter fitting to calculate IC ₅₀.

1.3 RET (Y791F) inhibitory Activity screening

50 Ng/. Mu.L of RET (Y791F) stock was diluted with kinase buffer (50 mM HEPES, 10mM MgCl ₂, 2mM DTT, 1mM EGTA, 0.01% Tween 20), 6. Mu.L of 1.67X 0.000835 ng/. Mu.L of working solution (final concentration 0.0005 ng/. Mu.L) was added to each well, and DMSO-dissolved different compounds were added to the wells using a nanoliter-type-applicator to give a final concentration of 1000nM-0.24nM, 4-fold gradient for 7 concentrations, and a blank control well (without enzyme) and a negative control well (containing enzyme, vehicle DMSO) were simultaneously set, and 2 multiplex wells were set. After 30min of reaction of the enzyme with the compound or vehicle, 5. Mu.M ATP (final concentration of 10. Mu.M) prepared with kinase buffer was mixed with 5. Mu.M substrate (final concentration of 0.1. Mu.M, ULight-poly GT) at 1:1 and added to the wells at 4. Mu.L per well, after sealing the plate, 2h of reaction at room temperature, 5. Mu.L of 4X 40mM EDTA (final concentration of 10 mM) was added to each well, 5min at room temperature, and 5. Mu.L of 4X 8nM detection reagent (final concentration of 2nM, eu-anti-phospho-tyrosine antibody) was added to each well, and the plate read (excitation 320nM, emission 665 nM) was performed with a PE Envision multifunctional microplate reader at room temperature for 1h, using four-parameter fitting to calculate IC ₅₀.

1.4 RET (V804L) inhibitory Activity Screen

50 Ng/. Mu.L of RET (V804L) stock was diluted with kinase buffer (50 mM HEPES, 10mM MgCl ₂, 2mM DTT, 1mM EGTA, 0.01% Tween 20), 6. Mu.L of 1.67X 0.000334 ng/. Mu.L working solution (final concentration 0.0002 ng/. Mu.L) was added to each well, and DMSO-dissolved compounds were added to the wells using a nanoliter-type-applicator to give a final concentration of 1000nM-0.24nM, 4-fold gradient for 7 concentrations, with blank wells (without enzyme) and negative control wells (with enzyme, with vehicle DMSO) being provided. After 30min of reaction of the enzyme with the compound or vehicle, 5. Mu.M ATP (final concentration of 10. Mu.M) prepared with kinase buffer was mixed with 5. Mu.M substrate (final concentration of 0.1. Mu.M, ULight-poly GT) at 1:1 and added to the wells at 4. Mu.L per well, after sealing the plate, 2h of reaction at room temperature, 5. Mu.L of 4X 40mM EDTA (final concentration of 10 mM) was added to each well, 5min at room temperature, and 5. Mu.L of 4X 8nM detection reagent (final concentration of 2nM, eu-anti-phospho-tyrosine antibody) was added to each well, and the plate read (excitation 320nM, emission 665 nM) was performed with a PE Envision multifunctional microplate reader at room temperature for 1h, using four-parameter fitting to calculate IC ₅₀.

1.5 RET (V804M) inhibitory Activity Screen

50 Ng/. Mu.L of RET (V804M) stock was diluted with kinase buffer (50 mM HEPES, 10mM MgCl ₂, 2mM DTT, 1mM EGTA, 0.01% Tween 20), 6. Mu.L of 1.67X 0.0835 ng/. Mu.L of working solution (final concentration 0.05 ng/. Mu.L) was added to each well, and DMSO-dissolved compounds were added to the wells using a nanoliter-type-applicator to give a final concentration of 1000nM-0.24nM, 4-fold gradient, 7 total, and a blank (without enzyme) and a negative control (with enzyme, with vehicle DMSO) were placed. After 30min of reaction of the enzyme with the compound or vehicle, 5. Mu.M ATP (final concentration of 10. Mu.M) prepared with kinase buffer was mixed with 5. Mu.M substrate (final concentration of 0.1. Mu.M, ULight-poly GT) at 1:1 and added to the wells at 4. Mu.L per well, after sealing the plate, 2h of reaction at room temperature, 5. Mu.L of 4X 40mM EDTA (final concentration of 10 mM) was added to each well, 5min at room temperature, and 5. Mu.L of 4X 8nM detection reagent (final concentration of 2nM, eu-anti-phospho-tyrosine antibody) was added to each well, and the plate read (excitation 320nM, emission 665 nM) was performed with a PE Envision multifunctional microplate reader at room temperature for 1h, using four-parameter fitting to calculate IC ₅₀.

1.5 KDR inhibition Activity Screen

50 Ng/. Mu.L of KDR stock solution was diluted with kinase buffer (50 mM HEPES, 10mM MgCl ₂, 2mM DTT, 1mM EGTA, 0.01% Tween 20), 6. Mu.L of 1.67X 0.1336 ng/. Mu.L of working solution (final concentration of 0.08 ng/. Mu.L) was added to each well, and the DMSO-dissolved different compounds were added to the wells using a nanoliter-type-applicator to give final concentrations of 1000nM-0.24nM, 4-fold gradient for 7 total, and blank wells (without enzyme) and negative control wells (containing enzyme, plus vehicle DMSO) were simultaneously set, and 2 multiplex wells were set. After 30min of reaction of the enzyme with the compound or vehicle, 5. Mu.M ATP (final concentration of 5. Mu.M) prepared with kinase buffer was mixed with 5. Mu.M substrate (final concentration of 0.1. Mu.M, ULight-poly GT) at 1:1 and added to the wells at 4. Mu.L per well, after sealing the plate, 2h of reaction at room temperature, 5. Mu.L of 4X 40mM EDTA (final concentration of 10 mM) was added to each well, 5min at room temperature, and 5. Mu.L of 4X 8nM detection reagent (final concentration of 2nM, eu-anti-phospho-tyrosine antibody) was added to each well, and the plate read (excitation 320nM, emission 665 nM) was performed with a PE Envision multifunctional microplate reader at room temperature for 1h, using four-parameter fitting to calculate IC ₅₀.

1.6 In vitro kinase RET, RET (M918T), RET (Y791F), RET (V804L), RET (V804M), KDR activity results, see Table 1.

TABLE 1

"-" Means undetected.

Claims

1. A compound shown in a formula (I), a stereoisomer and a pharmaceutically acceptable salt thereof,

Wherein,

X is selected from NH;

u is CH, V is N, W is N, or U is CH, V is CH, W is N;

q is selected from C (R ²);

Selected from the group consisting of

Ring B is a pyridine ring;

-L ¹ -is selected from single bonds;

Ring A-L ² -ring B is selected from ring A-C (O) -NH-CH (CH ₃) -ring B or ring A-C (S) -NH-CH (CH ₃) -ring B;

R ² and R ⁵ are each independently selected from H or C _1-4 alkyl, which C _1-4 alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino;

r ³ is selected from C _1-4 alkyl, which C _1-4 alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino;

R ⁴ is selected from pyrazolyl, which is substituted by one, two or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro;

n is 0 or 1;

p is 1;

And formula (I) is other than:

2. A compound of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R ² is selected from H, methyl, ethyl, isopropyl or tert-butyl, which methyl, ethyl, isopropyl or tert-butyl may be optionally substituted by one, two or three substituents selected from halogen.

3. A compound of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R ² is selected from H, methyl, difluoromethyl or trifluoromethyl.

4. A compound of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R ³ is independently selected from methyl, ethyl, isopropyl or tert-butyl.

5. A compound of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R ³ is selected from methyl.

6. The compound of formula (I), stereoisomers thereof, and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein ring a-L ² -ring B is selected from ring a-C (O) -NH-CH (CH ₃) -ring B.

7. The compound of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein ring B is

8. The compound of formula (I) according to claim 1, wherein,Is that

9. The compound of formula (I), stereoisomers thereof, and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R ⁵ is selected from H.

10. The compound of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R ⁴ is selected from

11. The compound of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein n is 0.

12. The compound of formula (I) as claimed in claim 1 has a structure represented by formula (IV-a),

Wherein R ³、R⁴、R⁵, ring A, ring B, n, p are as defined in claim 1.

13. The following compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof:

14. A pharmaceutical composition comprising a compound according to any one of claims 1-13, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

15. Use of a compound according to any one of claims 1 to 13, stereoisomers thereof and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for the prevention or treatment of diseases mediated by aberrant RET activity.