阅读说明：本技术 嘧啶并五元氮杂环类衍生物、其制备方法及其在医药上的应用 (Pyrimido five-membered nitrogen heterocyclic derivative, preparation method and application thereof in medicine ) 是由 邹昊 李正涛 王元昊 余健 祝伟 于 2020-06-28 设计创作，主要内容包括：嘧啶并五元氮杂环类衍生物、其制备方法及其在医药上的应用。具体为通式(II)所示的嘧啶并五元氮杂环类衍生物、其制备方法、含有该衍生物的组合物,其作为SHP2抑制剂及其用于制备预防和/或治疗肿瘤或者癌症的药物中的用途。(A pyrimido five-membered nitrogen heterocyclic derivative, a preparation method and application thereof in medicine. In particular to a pyrimido five-membered nitrogen heterocyclic derivative shown in a general formula (II), a preparation method thereof, a composition containing the derivative, and application of the derivative as an SHP2 inhibitor and in preparation of drugs for preventing and/or treating tumors or cancers.)

A compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

R ¹Selected from hydrogen atoms, C_1-6Alkyl, halo C_1-6Alkyl or amino, said alkyl and haloalkyl being each independently optionally further substituted with one or more substituents of deuterium atoms;

Y ¹is-S-or a direct bond;

ring A is selected from aryl, heteroaryl, preferably phenyl or pyridyl;

R ³each independently selected from hydrogen atom, deuterium atom, halogen, cyano, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl, -OR^a、-CHR ^aR ^b、-NR ^aR ^b；

The R is^a、R ^bEach independently selected from hydrogen, deuterium atom, hydroxyl group, C_1-6Alkyl, 3-12 membered heterocyclic group or C_3-8Cycloalkyl, wherein said alkyl, heterocyclyl or cycloalkyl is further substituted by one or more substituents selected from the group consisting of halogen, deuterium atom, cyano, amino, hydroxy;

or R^a、R ^bForm a 3-to 12-membered heterocyclic group or C with the atoms to which they are commonly attached_3-8Cycloalkyl, said alkyl, heterocyclyl or cycloalkyl being optionally further substituted by one or more substituents selected from the group consisting of halogen, deuterium atoms, cyano, amino, hydroxy;

ring B is a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, preferably selected from a benzene ring or a pyridine ring;

R ⁸each independently selected from hydrogen atom, deuterium atom, halogen, cyano, C_1-6Alkyl radical, C_1-6An alkoxy group;

m is selected from 0, 1,2, 3, 4;

n is selected from 1,2, 3, 4.

The compound of formula (II) according to claim1, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof¹Is selected from C_1-6Alkyl or halo C_1-6Alkyl radical, said C_1-6Alkyl or halo C_1-6Alkyl groups are optionally substituted with one or more deuterium atoms.

A compound of formula (II) according to claim 2, or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is¹is-S-.

A compound of formula (II) according to claim 3, wherein ring a is selected from phenyl or pyridyl, or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

A compound of formula (II) according to claim 4, wherein R is selected from the group consisting of tautomers, mesomers, racemates, enantiomers, diastereomers, atropisomers, and mixtures thereof, or a pharmaceutically acceptable salt thereof³Each independently selected from hydrogen atom, deuterium atom, halogen, cyano, C_1-6Alkyl radical、C _1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl, -NR^aR ^b(ii) a The R is^a、R ^bEach independently selected from hydrogen, deuterium atom, hydroxyl group, C_1-6An alkyl group substituted with one or more deuterium atoms.

The compound of the general formula (II) according to claim 5, wherein ring B is a benzene ring or a pyridine ring, or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

The compound of formula (II) according to any one of claims 1 to 6, wherein the compound is in the form of a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof

R ¹Selected from methyl, said methyl being optionally substituted with one or more deuterium atoms;

Y ¹is-S-;

ring A is selected from phenyl or pyridyl;

R ³each independently selected from hydrogen atom, deuterium atom, halogen, -NR^aR ^b；

The R is^a、R ^bEach independently selected from hydrogen, deuterium atom, C_1-6An alkyl group substituted with one or more deuterium atoms;

ring B is a benzene ring or a pyridine ring;

m is selected from 0;

n is selected from 1,2, 3, 4.

The compound of formula (II) according to claim 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein R is¹Is selected from methyl;

Y ¹is-S-;

ring A is selected from pyridyl;

R ³each independently selected from hydrogen atom, deuterium atom, halogen, -NR^aR ^b；

The R is^a、R ^bEach independently selected from hydrogen, deuterium atom, C_1-6An alkyl group substituted with one or more deuterium atoms;

ring B is a pyridine ring;

m is selected from 0;

n is selected from 1,2, 3, 4.

The compound of formula (II) according to claim 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein R is¹Is selected from methyl;

Y ¹is-S-;

ring A is selected from pyridyl;

R ³each independently selected from hydrogen atom, deuterium atom, chlorine atom, -NH-CH₃Or N- (CH)₃) ₂(ii) a the-NH-CH₃Or N- (CH)₃) ₂Wherein the hydrogen atoms on the methyl group are substituted with one or more deuterium atoms;

ring B is a pyridine ring;

m is selected from 0;

n is selected from 1,2, 3, 4.

A compound of formula (II) according to any one of claims 1 to 9, in the form of its tautomers, mesomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is

The process for the preparation of a compound of the general formula (II) according to any one of claims 1 to 10, or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of deprotecting the PG of the compound of the formula (II-2) to give a compound of the formula (II-1),

PG is an amino protecting group selected from Boc, PMB, S (═ O)^tBu，Cbz；

P is selected from 1,2, 3;

q is selected from 1, 2;

wherein, ring A, ring B, R¹、R ⁸B, m are as defined in claims 1-10.

The production method according to claim 11, further comprising the step of,

and (3) carrying out C-S coupling on the compound shown in the formula (II-3) and the compound shown in the formula (II-4) under an alkaline condition to obtain the compound shown in the formula (II-2).

A pharmaceutical composition comprising 0.1-2000mg of a compound of general formula (II) according to any one of claims 1-10, or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

Use of a compound of general formula (II) according to any one of claims 1 to 10, or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the preparation of a medicament for the prophylaxis or treatment of a disease or condition mediated by the activity of SHP 2.

Use of a compound of general formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, as an inhibitor of SHP2 for the preparation of a medicament for the prevention and/or treatment of tumors or cancers.

Use of a compound of general formula (II) according to any one of claims 1 to 10, or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the preparation of a medicament for the prophylaxis or treatment of noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, anaplastic large-cell lymphoma and glioblastoma.