阅读说明：本技术 2-氨基嘧啶类化合物及其用途 (2-aminopyrimidine compounds and application thereof ) 是由 赵燕芳 李颖修 秦铭泽 侯云雷 刘亚婧 宫平 于 2020-07-01 设计创作，主要内容包括：本发明涉及通式I所示的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或前药、它们的制备方法以及含有所述化合物的药物组合物,其中取代基R-(1)、R-(2)、R-(3)、R-(4)、X、Y、Z、Q、m、n具有在说明书中给出的含义。本发明还涉及通式Ⅰ的化合物在制备治疗和/或预防恶性血液疾病和其它增生性疾病的药物中的用途。(The invention relates to 2-aminopyrimidine compounds shown in a general formula I, pharmaceutically acceptable salts, solvates or prodrugs thereof, a preparation method thereof and a pharmaceutical composition containing the compounds, wherein a substituent R 1 、R 2 、R 3 、R 4 X, Y, Z, Q, m, n have the meanings given in the description. The invention also relates to the use of compounds of general formula (I) for the preparation of medicaments for the treatment and/or prophylaxis of hematological malignancies and other proliferative disorders.)

2-aminopyrimidine compounds with a general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,

wherein the content of the first and second substances,

x and Y are the same or different and are each independently selected from N, CH and CHNH;

q is NH, CH₂；

Z is selected from NH and NCH₃O or a chemical bond;

m and n are the same or different and are integers between 1 and 3;

R ₁and R₂The same or different, are respectively and independently selected from hydrogen, halogen and (C)₁-C ₆) Alkyl, (C)₁-C ₆) Alkoxy, trifluoromethyl, cyano, amino, nitro, or R₁And R₂Together form (C)₆-C ₁₀) Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, said heterocyclyl optionally including 0-3 bisA key;

R ₃is (C)₁-C ₆) Alkyl acyl group, (C)₆-C ₁₀) Aryl, 5-10 membered heteroaryl, said aryl or heteroaryl optionally substituted with 1-3R which may be the same or different₈Substitution;

R ₈is hydrogen, hydroxy, halogen, cyano, (C)₁-C ₆) Alkyl, (C)₁-C ₆) Alkoxy group, (C)₁-C ₆) Alkyl acyl group, (C)₁-C ₆) Carbamoyl, -NR₅R ₆、-(CH ₂) _pNR ₅R ₆、-CONR ₅R ₆、-NHCONR ₅R ₆、-O(CH ₂) _pNR ₅R ₆、-SO ₂(CH ₂) _pNR ₅R ₆、-SO ₂(CH ₂) _pCONR ₅R ₆；

Wherein R is₅And R₆The same or different, are respectively and independently selected from hydrogen and (C)₁-C ₆) Alkyl, (C)₃-C ₇) Cycloalkyl group, (C)₂-C ₆) Alkenyl, (C)₂-C ₆) Alkynyl, (C)₁-C ₆) Alkyl acyl group, (C)₁-C ₆) An alkoxy group;

or R₅And R₆Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl group, other than R₅And R₆Optionally containing 0 to 4 heteroatoms selected from N, O and/or S in addition to the attached nitrogen atom, said heterocyclic group optionally including 0 to 3 double bonds, said heterocyclic or heteroleptic groupAryl is optionally substituted by 0 to 3R, which may be the same or different₇Substitution;

R ₇is (C)₁-C ₆) Alkyl, (C)₃-C ₇) A cycloalkyl group;

p is an integer of 0 to 4;

R ₄is (C)₁-C ₆) Alkyl, (C)₃-C ₇) Cycloalkyl group, (C)₆-C ₁₀) Aryl, 5-to 10-membered heteroaryl, (C)₆-C ₁₀) Arylmethyl, 5-to 10-membered heteroarylmethyl, said aryl or heteroaryl optionally substituted with 1 to 3R which may be the same or different₉Substitution;

R ₉is hydrogen, hydroxy, halogen, halo (C)₁-C ₆) Alkyl, halo (C)₁-C ₆) Alkoxy, nitro, amino, cyano, (C)₁-C ₆) Alkyl, (C)₂-C ₆) Alkenyl, (C)₂-C ₆) Alkynyl, (C)₁-C ₆) Alkoxy, optionally hydroxy, amino or halo (C)₁-C ₆) Alkyl or (C)₁-C ₆) Alkoxy radical, 1-2 (C)₁-C ₆) Alkyl-substituted amino group, (C)₁-C ₆) Alkylamido, free, salified, esterified and amidated carboxyl, (C)₁-C ₆) Alkylsulfinyl (C)₁-C ₆) Alkylsulfonyl group, (C)₁-C ₆) Alkoxy group, (C)₁-C ₆) Alkyl, (C)₁-C ₆) Alkyl acyl group, (C)₁-C ₆) Carbamoyl radical, substituted by 1-2 (C)₁-C ₆) Alkyl-substituted carbamoyl group, (C)₁-C ₃) Alkylenedioxy, allyl。

2-aminopyrimidines of the general formula I according to claim 1 and their pharmaceutically acceptable salts, solvates or prodrugs thereof,

wherein the content of the first and second substances,

x and Y are the same or different and are each independently selected from N and CH;

z is selected from NH and NCH₃Or a chemical bond;

R ₁and R₂The same or different, are respectively and independently selected from hydrogen, halogen and (C)₁-C ₆) Alkyl, (C)₁-C ₆) Alkoxy, trifluoromethyl, cyano, amino, nitro, or R₁And R₂Together form (C)₆-C ₁₀) Aryl, 5-10 membered heteroaryl;

R ₃is (C)₆-C ₁₀) Aryl, 5-10 membered heteroaryl, said aryl or heteroaryl optionally substituted with 1-3R which may be the same or different₈And (4) substitution.

2-aminopyrimidines of the general formula I according to claim 2 and their pharmaceutically acceptable salts, solvates or prodrugs thereof,

wherein the content of the first and second substances,

m and n are the same or different and are 1, 2;

R ₃is phenyl, 5-6 membered heteroaryl, said phenyl or heteroaryl being optionally substituted by 1-3 identical or different R₈Substitution;

R ₈is (C)₁-C ₆) Alkoxy group, (C)₁-C ₆) Alkyl acyl group, (C)₁-C ₆) Carbamoyl, -NR₅R ₆、-(CH ₂) _pNR ₅R ₆、-CONR ₅R ₆、-NHCONR ₅R ₆、-O(CH ₂) _pNR ₅R ₆、-SO ₂(CH ₂) _pNR ₅R ₆；

R ₅And R₆The same or different, are respectively and independently selected from hydrogen and (C)₁-C ₄) Alkyl, (C)₃-C ₆) Cycloalkyl group, (C)₁-C ₄) An alkyl acyl group;

or R₅And R₆Together with the nitrogen atom to which they are attached to form

R ₄Is phenyl, 5-6 membered heteroaryl, said phenyl or heteroaryl being optionally substituted by 1-3 identical or different R₉And (4) substitution.

2-aminopyrimidines of the general formula I according to claim 3 and their pharmaceutically acceptable salts, solvates or prodrugs thereof,

wherein the content of the first and second substances,

z is NH or a bond;

R ₁and R₂The same or different, are respectively and independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl, cyano, amino, nitro or R₁And R₂Together form a phenyl, 5-6 membered heteroaryl;

R ₈is (C)₁-C ₆) Alkoxy group, (C)₁-C ₆) Alkyl acyl group, (C)₁-C ₆) Carbamoyl, -NR ₅R ₆、-(CH ₂) _pNR ₅R ₆、-CONR ₅R ₆、-NHCONR ₅R ₆、-O(CH ₂) _pNR ₅R ₆；

Wherein R is₅And R₆The same or different, are respectively and independently selected from hydrogen and (C)₁-C ₄) Alkyl, (C)₃-C ₆) A cycloalkyl group;

or R₅And R₆Together with the nitrogen atom to which they are attached to form

The 2-aminopyrimidines of the general formula I according to claim 4 and the pharmaceutically acceptable salts, solvates or prodrugs thereof,

wherein the content of the first and second substances,

q is NH;

x and Y are N;

z is a chemical bond;

m and n are 2;

R ₁and R₂The same or different, are respectively and independently selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, amino and nitro;

R ₃is phenyl optionally substituted by 1 to 3 identical or different R₈Substitution;

R ₈is-NR₅R ₆、-(CH ₂) _pNR ₅R ₆、-CONR ₅R ₆、-O(CH ₂) _pNR ₅R ₆；

p is an integer of 1 to 4;

R ₄is phenyl, optionally substituted by 1 to 3 identical or different R₉And (4) substitution.

2-aminopyrimidines of the general formula I according to claim 5 and their pharmaceutically acceptable salts, solvates or prodrugs thereof,

wherein the content of the first and second substances,

R ₂is hydrogen;

R ₈is-NR₅R ₆、-O(CH ₂) _pNR ₅R ₆；

p is 2, 3;

2-aminopyrimidines of the general formula I according to claim 6 and their pharmaceutically acceptable salts, solvates or prodrugs thereof,

wherein the content of the first and second substances,

R ₁hydrogen, fluorine, chlorine, methyl and trifluoromethyl;

R ₅and R₆Together with the nitrogen atom to which they are attached to form

2-aminopyrimidines of the following general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof:

n- (4-methoxyphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-trifluoromethoxyphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-ethylphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n-phenyl-4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-methoxycarbonylphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-acetylphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-nitrophenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-cyano-3-fluorophenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-isopropoxyphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-carbamoylphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-methylcarbamoylphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-aminosulfonylphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-acetamidophenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-methanesulfonylphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-carbamoylphenyl) -4- (2- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-acetylphenyl) -4- [2- ({4- [2- (pyrrolidin-1-yl) ethoxy ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;

n- (4-acetylphenyl) -4- (2- { [4- (4-methylpiperidin-1-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-acetylphenyl) -4- [2- ({4- [2- (morpholin-4-yl) ethoxy ] phenyl } amino ] pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-acetylphenyl) -4- [2- ({4- [3- (morpholin-4-yl) propoxy ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide;

n- (4-cyanophenyl) -4- (5-methyl-2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-cyanophenyl) -4- (6-methyl 2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-acetylphenyl) -4- (5-methyl-2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-acetylphenyl) -4- (6-methyl 2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-acetylphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } thieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-acetylphenyl) -4- (2- { [4- (morpholin-4-yl) phenyl ] amino } quinazolin-4-yl) piperazine-1-carboxamide;

n- (4-acetylphenyl) -4- (5-trifluoromethyl-2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-acetylphenyl) -4- (5-amino-2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) piperazine-1-carboxamide;

n- (4-acetylphenyl) -3- [ (5-methyl-2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) amino ] pyrrolidine-1-carboxamide;

n- (4-acetylphenyl) -4- [ (5-methyl-2- { [4- (morpholin-4-yl) phenyl ] amino } pyrimidin-4-yl) amino ] piperidine-1-carboxamide;

n- (4-acetylphenyl) -4- [ 5-methyl-2- ({4- [3- (pyrrolidin-1-yl) propoxy ] phenyl } amino) pyrimidin-4-yl ] piperazine-1-carboxamide.

Compounds of general formula I according to claims 1 to 8, wherein the pharmaceutically acceptable salts are salts with acids selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, and aspartic acid.

Compounds of general formula I according to claim 9, wherein the salts with acids are hydrochloride and mesylate.

A pharmaceutical composition comprising a compound of general formula I according to any one of claims 1 to 10 and pharmaceutically acceptable salts, solvates or prodrugs thereof.

The use of a compound of any one of claims 1-10, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, for the manufacture of a medicament for the prevention or treatment of a disease associated with a JAK2 kinase inhibitor.

The use of a compound of any one of claims 1-10, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, for the manufacture of a medicament for the prevention or treatment of diseases in which an inhibitor of FLT3 kinase is involved.

The use of a compound of any one of claims 1-10, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, for the manufacture of a medicament for the prevention or treatment of a disease associated with a JAK2/FLT3 dual-target kinase inhibitor.

Use of a compound of general formula I according to any one of claims 1 to 10, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, or a composition according to claim 12, for the preparation of a medicament for the treatment of proliferative diseases and hematological malignancies.

The use of claim 15, wherein the proliferative disease comprises myelofibrosis, multiple myeloma, polycythemia vera, essential thrombocythemia.

The use of claim 15, wherein said hematological malignancy comprises acute myelogenous leukemia, acute lymphocytic leukemia.