New bicyclic pyrazole derivative

文档序号：1776366 发布日期：2019-12-03 浏览：21次中文

阅读说明：本技术 新的二环吡唑衍生物 (New bicyclic pyrazole derivative ) 是由 N.格里贝诺庄伟� D.库尔克 A.克勒 T.伊尔希 C.韦尔茨 H-G.施瓦茨 U 于 2018-04-23 设计创作，主要内容包括：本发明涵盖通式(I)的二环吡唑化合物：其中G、A、R1、R2、R3和Q如本文所定义；制备所述化合物的方法,可用于制备所述化合物的中间体化合物,包含所述化合物的药物组合物和组合,和所述化合物以单剂形式或与其他活性成分的组合形式用于制造药物组合物的用途,所述药物组合物用于治疗、控制和/或预防疾病,特别是蠕虫感染。<Image he="131" wi="207" file="100004_DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention covers the bicyclic pyrazole compounds of logical formula (I): wherein G, A, R 1 、R 2 、R 3 It is as defined herein with Q；The method for preparing the compound, it can be used for preparing the midbody compound of the compound, pharmaceutical composition and combination comprising the compound, it is used to manufacture the purposes of pharmaceutical composition with unit dose form or with the combining form of other active components with the compound, described pharmaceutical composition is for treating, controlling and/or preventing disease, especially invermination.)

1. the compound of logical formula (I):

Wherein:

A is A1 or A2,

O is 0,1,2,3 or 4,

R is selected from hydrogen, halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl,

X, Y is independently selected from CR⁶R⁷, O, S and N-R⁸, wherein at least one of X and Y are CR⁶R⁷, or

X, Y is formed together ring members selected from the group below :-C (O)-O- ,-C (O)-NR⁸-、-S(O)-NR⁸-、-SO₂-NR⁸And- SO₂- O-,

G is S, O, N-R⁸

R¹Selected from hydrogen, cyano ,-CHO ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄- Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base, with 1 to 5 halogen atom C₃-C₆Halogenated cycloalkyl, C₃-C₄Alkenyl, C₃-C₄Alkynyl, C₁-C₄Alkoxy -C₁-C₄Alkyl, C₃-C₆Naphthenic base-C₁-C₃- Alkyl, cyano-C₁-C₄Alkyl ,-NH-C₁-C₄Alkyl ,-N (C₁-C₄Alkyl)₂、NH₂-C₁-C₄Alkyl-, C₁-C₄Alkyl- NH-C₁-C₄Alkyl-, (C₁-C₄Alkyl)₂N-C₁-C₄Alkyl-, C₁-C₄Alkyl-C (O)-, with 1 to 5 halogen atom C₁-C₄Halogenated alkyl-C (O)-, C₁-C₄Alkoxy -C (O)-, benzyl oxygroup-C (O)-, C₁-C₄Alkoxy -C₁-C₄Alkyl-C (O)-、-SO₂-C₁-C₄Alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl-C₁-C₄Alkyl is optionally replaced by 1,2,3,4 or 5 substituent group, and the substituent group is independently selected from halogen Element ,-OH ,-NO₂, cyano, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy has 1 to 5 halogen The C of atom₁-C₄Halogenated alkoxy ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)- C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 to 5 halogen - S (O)-C of atom₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent is selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- Unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen ,-OH ,- NO₂, cyano, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄- Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 to 5 halogen atom - S (O)-C₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl,

R²It is selected from

Hydrogen, halogen, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)- N(C₁-C₄Alkyl)₂、-C(O)-NH(C₃-C₆Naphthenic base) ,-C (O)-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base)；

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

C₁-C₆Alkyl, C₃-C₆Naphthenic base, C₂-C₄Alkenyl, C₃-C₆Cycloalkenyl, C₂-C₄Alkynyl or phenyl-C₁-C₄Alkyl, Each is optionally replaced by 1,2,3,4 or 5 substituent group, and the substituent group is independently selected from halogen ,-OH ,-NO₂, cyanogen Base, C₁-C₄Alkyl-C (O)-, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy ,-NH₂、- NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base) ,-S- C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Alkyl halide Base ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogen Substituted alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent is selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- Unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen ,-OH ,- NO₂, cyano, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄- Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl is optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Cycloalkanes Base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl, - S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl With-the SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

Monocycle or bicyclic heterocycles, selected from 4- to 10- membered heterocycloalkyl, miscellaneous spiro cycloalkyl group, 5- unit's heteroaryl and 6- unit's heteroaryl, Each is optionally replaced by 1,2,3 or 4 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, Oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N (C₁- C₄Alkyl)₂、C₁-C₄Alkyl, C₁-C₄Alkyl-C (O) --, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄- Alkoxy, hydroxyl-C₁-C₄Alkyl, C₁-C₄Alkoxy -C₁-C₄Alkyl-, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Oxygroup, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁- C₄Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl and 4- to 10- membered heterocycloalkyl,

R³Selected from hydrogen, halogen ,-OH, cyano, C₁-C₄Alkyl, C₃-C₆Naphthenic base, the C with 1 to 5 halogen atom₁-C₄Halogen Substituted alkyl, C₁-C₄Alkoxy -C₁-C₄Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkyl-C (O)-,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl,

R⁴Selected from hydrogen ,-OH, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁵Selected from hydrogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Or R⁴And R⁵Carbon atom in connection is formed together selected from C₃-C₆Naphthenic base and 3- to 6- membered heterocycloalkyl 3- extremely 6- member ring,

R⁶Selected from hydrogen ,-OH, fluorine, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁷Selected from hydrogen ,-OH, fluorine, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Or R⁶And R⁷Carbon atom in connection is formed together selected from C₃-C₆Naphthenic base and 3- to 6- membered heterocycloalkyl 3- extremely 6- member ring,

R⁸Selected from hydrogen, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and C₁-C₄Alkoxy,

R⁹And R¹⁰Independently selected from

Hydrogen ,-OH ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(-C(O)-C₁-C₄Alkyl) ,-N (C₁-C₄Alkane Base) (- C (O)-C₁-C₄Alkyl), C₁-C₄Alkoxy, C₁-C₄Alkoxy -C (O)-；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、-NH-C(O)-C₁-C₄Alkyl ,-N (C₁-C₄Alkyl) (- C (O)-C₁-C₄- Alkyl), C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy has 1 to 5 halogen The C of atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁- C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, - S (O)-C with 1 to 5 halogen atom₁-C₄The halogenated alkyl ,-SO with 1 to 5 halogen atom₂-C₁-C₄Alkyl halide Base and (C₁-C₄Alkoxy)₂P(=O)-；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent is selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- Unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, and the substituent group is independently selected from halogen, cyano, nitre Base ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)- N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl- C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl, benzo-C₅-C₆Naphthenic base, each are optionally replaced by 1,2 or 3 substituent group, and the substituent group is independently Selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alcoxyl Base, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁- C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S- with 1 to 5 halogen atom C₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and with 1 to 5 halogen atom- SO₂-C₁-C₄Halogenated alkyl；

Monocycle or bicyclic heterocycles, selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each is appointed Selection of land is replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, oxo, it is thio ,- COOH、C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁- C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl-C₁-C₄Alkyl, have 1 to The C of 5 halogen atoms₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S- C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Alkyl halide Base ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogen Substituted alkyl,

R¹¹It is selected from

-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent is selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- Unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, and the substituent group is independently selected from halogen, cyano, nitre Base ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)- N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl- C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl is optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 To-S (O)-C of 5 halogen atoms₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

R¹²It is selected from

Hydrogen；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent is selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- Unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, and the substituent group is independently selected from halogen, cyano, nitre Base ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)- N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl- C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl is optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 To-S (O)-C of 5 halogen atoms₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

Q is selected from 6- or 10- member aryl and 5- to 10- unit's heteroaryl, and each is optionally taken by 1,2,3,4 or 5 substituent group Generation, the substituent group are selected from halogen, SF₅, cyano ,-CHO, nitro, oxo, C₁-C₄Alkyl, C₁-C₄Hydroxy alkyl, have 1 to The C of 5 halogen atoms₁-C₄Halogenated alkyl, hydroxyl, C₁-C₄Alkoxy, C₃-C₆Naphthenic base-C₁-C₄Alkoxy, cyano-C₁- C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-NH (C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、- NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base) ,-NH-SO₂-(C₁-C₄Alkyl) ,-N (SO₂-[C₁-C₄- Alkyl]) (C₁-C₄Alkyl), (C_1-C₄Alkoximino)-C₁-C₄Alkyl, optionally by 1 or 2 selected from fluorine, chlorine, bromine, The 4- that the substituent group of methyl and cyano replaces is to 6- circle heterocyclic ring base ,-CH₂-O-(C₁-C₄Alkyl) ,-CH₂-NH(C₁-C₄Alkane Base) ,-CH₂-N(C₁-C₄Alkyl)₂, by its own optionally by 1 or 2 selected from fluorine, chlorine, bromine, methyl and cyano substituent group The methyl ,-CH of substituted 4- to 6- circle heterocyclic ring base substitution₂-S-(C₁-C₄Alkyl) ,-CH₂-S(O)-(C₁-C₄Alkyl) ,-CH₂- SO₂-(C₁-C₄Alkyl) ,-S- (C₁-C₄Alkyl) ,-S (O)-(C₁-C₄Alkyl) ,-SO₂-(C₁-C₄Alkyl), have 1 to 5 - S- (the C of halogen atom₁-C₄Halogenated alkyl) ,-S (O)-(C with 1 to 5 halogen atom₁-C₄Halogenated alkyl), have 1 To-the SO of 5 halogen atoms₂-(C₁-C₄Halogenated alkyl) ,-CONH (C₁-C₄Alkyl) ,-CONH (C₃-C₆Naphthenic base) ,- NHCO(C₁-C₄Alkyl) ,-NHCO (C₃-C₆Naphthenic base) ,-NHCO (C with 1 to 5 halogen atom₁-C₄Halogenated alkyl),

Wherein when Y is O, S or N-R⁸When, R⁴、R⁵、R⁶And R⁷No one of be-OH, and wherein when X is O, S or N-R⁸When, R⁶And R⁷No one of be-OH,

Or its stereoisomer, tautomer, N- oxide, hydrate, solvate or salt or their mixture.

2. compound according to claim 1, in which:

A is A1 or A2,

O is 0,1,2,3 or 4,

X, Y is independently selected from CR⁶R⁷, O, S and N-R⁸, wherein at least one of X and Y are CR⁶R⁷, or

X, Y is formed together ring members selected from the group below :-C (O)-O- ,-C (O)-NR⁸-、-S(O)-NR⁸-、-SO₂-NR⁸And- SO₂- O-,

G is S, O, N-R⁸

R²It is selected from

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent is selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- Unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen ,-OH ,- NO₂, cyano, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄- Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Monocycle or bicyclic heterocycles, selected from 4- to 10- membered heterocycloalkyl, miscellaneous spiro cycloalkyl group, 5- unit's heteroaryl and 6- unit's heteroaryl, Each is optionally replaced by 1,2,3 or 4 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, Oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N (C₁- C₄Alkyl)₂、C₁-C₄Alkyl, C₁-C₄Alkyl-C (O)-, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄- Alkoxy, hydroxyl-C₁-C₄Alkyl, C₁-C₄Alkoxy -C₁-C₄Alkyl-, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Oxygroup, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁- C₄Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl and 4- to 10- membered heterocycloalkyl,

R⁴Selected from hydrogen ,-OH, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁵Selected from hydrogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁶Selected from hydrogen ,-OH, fluorine, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁷Selected from hydrogen ,-OH, fluorine, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁸Selected from hydrogen, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and C₁-C₄Alkoxy,

R⁹And R¹⁰Independently selected from

Hydrogen ,-OH ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(-C(O)-C₁-C₄Alkyl), C₁-C₄Alcoxyl Base；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、-NH-C(O)-C₁-C₄Alkyl ,-N (C₁-C₄Alkyl)-(- C (O)-C₁- C₄Alkyl), C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy has 1 to 5 The C of halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S- C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Alkyl halide Base ,-S (O)-C with 1 to 5 halogen atom₁-C₄The halogenated alkyl ,-SO with 1 to 5 halogen atom₂-C₁-C₄It is halogenated Alkyl and (C₁-C₄Alkoxy)₂P(=O)-；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent is selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- Unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, and the substituent group is independently selected from halogen, cyano, nitre Base ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)- N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl- C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

R¹¹It is selected from

-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent is selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- Unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, and the substituent group is independently selected from halogen, cyano, nitre Base ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)- N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl- C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl is optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 To-S (O)-C of 5 halogen atoms₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

R¹²It is selected from

Hydrogen；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent is selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- Unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, and the substituent group is independently selected from halogen, cyano, nitre Base ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)- N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl- C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl is optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 To-S (O)-C of 5 halogen atoms₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹、Z²、Z³、Z⁴And Z⁵Independently selected from hydrogen, halogen, SF₅, cyano ,-CHO, nitro, C₁-C₄Alkyl has 1 to 5 halogen The C of plain atom₁-C₄Halogenated alkyl, hydroxyl, C₁-C₄Alkoxy, C₃-C₆Naphthenic base-C₁-C₄Alkoxy, cyano-C₁-C₄Alkane Oxygroup, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-NH (C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH (C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base) ,-NH-SO₂-(C₁-C₄Alkyl) ,-N (SO₂-[C₁-C₄Alkane Base]) (C₁-C₄Alkyl), (C_1-C₄Alkoximino)-C₁-C₄Alkyl, optionally by 1 or 2 be selected from fluorine, chlorine, bromine, first The 4- that the substituent group of base and cyano replaces is to 6- circle heterocyclic ring base ,-CH₂-O-(C₁-C₄Alkyl) ,-CH₂-NH(C₁-C₄Alkyl) ,- CH₂-N(C₁-C₄Alkyl)₂, optionally replaced by 1 or 2 substituent group selected from fluorine, chlorine, bromine, methyl and cyano by its own Methyl that 4- replaces to 6- circle heterocyclic ring base ,-CH₂-S-(C₁-C₄Alkyl) ,-CH₂-S(O)-(C₁-C₄Alkyl) ,-CH₂-SO₂- (C₁-C₄Alkyl) ,-S- (C₁-C₄Alkyl) ,-S (O)-(C₁-C₄Alkyl) ,-SO₂-(C₁-C₄Alkyl), have 1 to 5 halogen - S- (the C of atom₁-C₄Halogenated alkyl) ,-S (O)-(C with 1 to 5 halogen atom₁-C₄Halogenated alkyl), have 1 to 5 - the SO of a halogen atom₂-(C₁-C₄Halogenated alkyl) ,-CONH (C₁-C₄Alkyl) ,-CONH (C₃-C₆Naphthenic base) ,-NHCO (C₁-C₄Alkyl) ,-NHCO (C₃-C₆Naphthenic base) ,-NHCO (C with 1 to 5 halogen atom₁-C₄Halogenated alkyl), or

Z¹And Z²Carbon atom in connection is formed together 5- or 6- member saturation or fractional saturation heterocycle, 5- unit's heteroaryl Or 6- unit's heteroaryl, each can optionally be replaced by one or two substituent group for being selected from methyl, fluorine and oxo, and

Z³、Z⁴And Z⁵Independently selected from hydrogen, halogen, SF₅, cyano, CHO, nitro, C₁-C₄Alkyl has 1 to 5 halogen atom C₁-C₄Halogenated alkyl, hydroxyl, C₁-C₄Alkoxy, C₃-C₆Naphthenic base-C₁-C₄Alkoxy, cyano-C₁-C₄Alkoxy, C₁-C₄Alkoxy -C (O)-, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-NH (C₁-C₄Alkyl) ,-N (C₁- C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base) ,-NH-SO₂-(C₁-C₄Alkyl) ,-N (SO₂-[C₁-C₄Alkyl]) (C₁-C₄Alkyl), (C_1-C₄Alkoximino)-C₁-C₄Alkyl, optionally by 1 or 2 select 4- to 6- membered heterocycloalkyl ,-CH from the substituent group substitution of fluorine, methyl or cyano₂-O-(C₁-C₄Alkyl) ,-CH₂-NH(C₁- C₄Alkyl) ,-CH₂-N(C₁-C₄Alkyl)₂, taken by itself substituent group optionally by 1 or 2 selected from fluorine, methyl or cyano The methyl ,-CH that 4- to the 6- membered heterocycloalkyl in generation replaces₂-S-(C₁-C₄Alkyl) ,-CH₂-S(O)-(C₁-C₄Alkyl) ,-CH₂- SO₂-(C₁-C₄Alkyl) ,-S- (C₁-C₄Alkyl) ,-S (O)-(C₁-C₄Alkyl) ,-SO₂-(C₁-C₄Alkyl), have 1 to 5 - S- (the C of halogen atom₁-C₄Halogenated alkyl) ,-S (O)-(C with 1 to 5 halogen atom₁-C₄Halogenated alkyl), have 1 To-the SO of 5 halogen atoms₂-(C₁-C₄Halogenated alkyl) ,-CONH (C₁-C₄Alkyl) ,-CONH (C₃-C₆Naphthenic base) ,- NHCO(C₁-C₄Alkyl) ,-NHCO (C₃-C₆Naphthenic base) ,-NHCO (C with 1 to 5 halogen atom₁-C₄Halogenated alkyl), Or

Z²And Z³Carbon atom in connection is formed together 5- or 6- member saturation or fractional saturation heterocycle, 5- unit's heteroaryl Or 6- unit's heteroaryl, each can optionally be replaced by one or two substituent group for being selected from methyl, fluorine and oxo, and

Z¹、Z⁴And Z⁵Independently selected from hydrogen, halogen, SF₅, cyano, CHO, nitro, C₁-C₄Alkyl has 1 to 5 halogen atom C₁-C₄Halogenated alkyl, hydroxyl, C₁-C₄Alkoxy, C₃-C₆Naphthenic base-C₁-C₄Alkoxy, cyano-C₁-C₄Alkoxy, C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-NH (C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆- Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base) ,-NH-SO₂-(C₁-C₄Alkyl) ,-N (SO₂-[C₁-C₄Alkyl]) (C₁-C₄Alkyl), (C_1-C₄Alkoximino)-C₁-C₄Alkyl, optionally by 1 or 2 selected from fluorine, methyl or cyano 4- to the 6- membered heterocycloalkyl of substituent group substitution ,-CH₂-O-(C₁-C₄Alkyl) ,-CH₂-NH(C₁-C₄Alkyl) ,-CH₂-N(C₁- C₄Alkyl)₂, 4- to the 6- circle heterocyclic ring alkane that is replaced by itself substituent group optionally by 1 or 2 selected from fluorine, methyl or cyano The methyl ,-CH of base substitution₂-S-(C₁-C₄Alkyl) ,-CH₂-S(O)-(C₁-C₄Alkyl) ,-CH₂-SO₂-(C₁-C₄Alkyl) ,- S-(C₁-C₄Alkyl) ,-S (O)-(C₁-C₄Alkyl) ,-SO₂-(C₁-C₄Alkyl) ,-S- (C with 1 to 5 halogen atom₁- C₄Halogenated alkyl) ,-S (O)-(C with 1 to 5 halogen atom₁-C₄Halogenated alkyl), with 1 to 5 halogen atom- SO₂-(C₁-C₄Halogenated alkyl) ,-CONH (C₁-C₄Alkyl) ,-CONH (C₃-C₆Naphthenic base) ,-NHCO (C₁-C₄Alkyl) ,- NHCO(C₃-C₆Naphthenic base) ,-NHCO (C with 1 to 5 halogen atom₁-C₄Halogenated alkyl), or

Q is the pyridine ring of formula (Q2)

Wherein:

Z⁶、Z⁷、Z⁸And Z⁹Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogen Substituted alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-NH (C₁-C₄Alkyl) ,-N (C₁- C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base), or

Q is the pyrimidine ring of formula (Q3)

Wherein:

Z¹⁰、Z¹¹And Z¹²Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄It is halogenated Alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-NH (C₁-C₄Alkyl) ,-N (C₁-C₄- Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base), or

Q is the pyridine ring of formula (Q4)

Wherein:

Z¹³、Z¹⁴、Z¹⁵And Z¹⁶Independently selected from hydrogen halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄- Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₁-C₄Hydroxy alkyl, NH₂、- NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base) ,- NH-CO-C₁-C₄Alkyl and monocyclic heterocycles, the monocyclic heterocycles are selected from 4- to 7- membered heterocycloalkyl or have at least one heteroaryl Basic ring is connected through to the 5- unit's heteroaryl of the nitrogen-atoms of pyridine ring, and each is optionally taken by 1,2 or 3 substituent group In generation, the substituent group is independently selected from halogen, cyano, nitro ,-OH, oxo, thio, C₁-C₄Alkyl has 1 to 5 halogen The C of atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Ring Alkyl ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁- C₄Alkyl, the-S- (C with 1 to 5 halogen atom₁-C₄Halogenated alkyl) ,-S (O)-(C with 1 to 5 halogen atom₁- C₄Halogenated alkyl) ,-SO with 1 to 5 halogen atom₂-(C₁-C₄Halogenated alkyl), or

Q is the pyridine ring of formula (Q5)

Wherein:

Z¹⁷、Z¹⁸、Z¹⁹And Z²⁰Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄- Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-NH (C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base), or

Q is the 5- member aromatic heterocycle of formula (Q6)

Wherein:

T¹ – T⁴Independently selected from N, O, S, C-Z²¹And N-Z²², wherein T¹ – T⁴In be no more than one be O, T¹ – T⁴In Be no more than one be S, T¹ – T⁴In be no more than one be N-Z²², and wherein

Each Z²¹Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy and

Each Z²²Independently selected from hydrogen, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkane Base-C₃-C₆Naphthenic base, C₁-C₄Alkoxy -C₁-C₄Alkyl, or

Q is the 5- member aromatic heterocycle of formula (Q7)

Wherein:

U¹ – U⁴Independently selected from N and C-Z²³, wherein U¹ – U⁴In to be no more than three be N, and wherein

Each Z²³Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy,

Wherein when Y is O, S or N-R⁸When, R⁴、R⁵、R⁶And R⁷No one of be-OH, and wherein when X is O, S or N-R⁸When, R⁶And R⁷No one of be-OH,

Or its stereoisomer, tautomer, N- oxide, hydrate, solvate or salt or their mixture.

3. compound according to claim 1 or 2, in which:

A is A1 or A2,

O is 0,1 or 2,

R is selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy, cyano, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base,

X, Y is independently selected from CR⁶R⁷, O, S and N-R⁸, wherein at least one of X and Y are CR⁶R⁷,

G is S, O, N-R⁸

R¹Selected from hydrogen, C₁-C₄Alkyl, C₃-C₆Naphthenic base, C₃-C₄Alkenyl, C₃-C₄Alkynyl, C₁-C₄Alkoxy -C₁-C₄Alkane Base, C₃-C₆Naphthenic base-C₁-C₃Alkyl, cyano-C₁-C₄Alkyl,

R²It is selected from

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, C₂-C₄Alkenyl, C₃-C₆Cycloalkenyl, C₂-C₄Alkynyl or phenyl-C₁-C₄Alkyl, Each is optionally replaced by 1,2,3,4 or 5 substituent group, and the substituent group is independently selected from halogen ,-OH, cyano, C₁- C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkane Base)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkane Base ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄The halogenated alkyl ,-S with 1 to 5 halogen atom (O)-C₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

Monocycle or bicyclic heterocycles, selected from 4- to 10- membered heterocycloalkyl, miscellaneous spiro cycloalkyl group, 5- unit's heteroaryl and 6- unit's heteroaryl, Each is optionally replaced by 1,2,3 or 4 substituent group, the substituent group independently selected from halogen, cyano ,-OH, oxo ,- COOH、C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁- C₄Alkyl, C₁-C₄Alkyl-C (O)-, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl- C₁-C₄Alkyl, C₁-C₄Alkoxy -C₁-C₄Alkyl-, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆- Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃- C₆Naphthenic base) and 4- to 10- membered heterocycloalkyl,

R⁴Selected from hydrogen ,-OH, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁵It is hydrogen,

R⁶Selected from hydrogen and C₁-C₄Alkyl,

R⁷Selected from hydrogen and C₁-C₄Alkyl,

R⁸Selected from hydrogen and C₁-C₄Alkyl,

R⁹And R¹⁰Independently selected from

Hydrogen ,-NH (- C (O)-C₁-C₄Alkyl), C₁-C₄Alkoxy；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、-NH-C(O)-C₁-C₄Alkyl ,-N (C₁-C₄Alkyl)-(- C (O)-C₁- C₄Alkyl), C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy has 1 to 5 The C of halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S- C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Alkyl halide Base ,-S (O)-C with 1 to 5 halogen atom₁-C₄The halogenated alkyl ,-SO with 1 to 5 halogen atom₂-C₁-C₄It is halogenated Alkyl and (C₁-C₄Alkoxy)₂P(=O)-；

Phenyl, benzo-C₅-C₆Naphthenic base, each are optionally replaced by 1,2 or 3 substituent group, and the substituent group is independently Selected from halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy has 1 To the C of 5 halogen atoms₁-C₄Halogenated alkoxy；With

R¹¹It is selected from

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base；With

R¹²It is selected from

Hydrogen；

C₁-C₄Alkyl, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, and the substituent group is only On the spot it is selected from halogen ,-OH, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alcoxyl Base, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy；

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹、Z²、Z³、Z⁴And Z⁵Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄- Halogenated alkyl, hydroxyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-NH (C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base), optionally by 1 or 2 4- to 6- circle heterocyclic ring base, the-S- (C that a substituent group selected from fluorine, chlorine, bromine, methyl and cyano replaces₁-C₄Alkyl) ,-S (O)- (C₁-C₄Alkyl) ,-SO₂-(C₁-C₄Alkyl), or

Z¹And Z²Carbon atom in connection is formed together 5- or 6- membered heterocycloalkyl, 5- unit's heteroaryl or 6- unit's heteroaryl, Each can optionally be replaced by one or two substituent group for being selected from methyl, fluorine and oxo, and

Z³、Z⁴And Z⁵Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base, C₁-C₄Alkoxy, C₁-C₄Alkoxy -C (O)-, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, or

Z¹、Z⁴And Z⁵Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy,

Wherein when Y is O, S or N-R⁸When, R⁴It is not-OH,

Or its stereoisomer, tautomer, N- oxide, hydrate, solvate or salt or their mixture.

4. according to claim 1,2 or 3 compound, in which:

A is A1 or A2,

O is 0 or 1,

R is selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

X is selected from CR⁶R⁷, O, S and N-R⁸,

Y is CR⁶R⁷,

G is S, O, N-R⁸

R¹It is hydrogen or C₁-C₄Alkyl,

R²It is selected from

Hydrogen, halogen,

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, C₂-C₄Alkenyl or C₃-C₆Cycloalkenyl, each is optionally by 1,2,3,4 or 5 A substituent group replaces, and the substituent group is independently selected from halogen, cyano, C₁-C₄Alkoxy -C (O)-and-C (O)-NH₂；With

R³Selected from hydrogen, halogen ,-OH, cyano, C₁-C₄Alkyl, C₃-C₆Naphthenic base, the C with 1 to 5 halogen atom₁-C₄Halogen Substituted alkyl, C₁-C₄Alkoxy -C₁-C₄Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkyl-C (O)-,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base)-S-C₁-C₄Alkyl ,- S(O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl,

R⁴Selected from hydrogen ,-OH and C₁-C₄Alkyl,

R⁵It is hydrogen,

R⁶Selected from hydrogen and C₁-C₄Alkyl,

R⁷Selected from hydrogen and C₁-C₄Alkyl,

R⁸Selected from hydrogen and C₁-C₄Alkyl,

R⁹And R¹⁰Independently selected from

Hydrogen ,-NH (- C (O)-C₁-C₄Alkyl), C₁-C₄Alkoxy；

Phenyl and benzo-C₅-C₆Naphthenic base, each are optionally replaced by 1,2 or 3 substituent group, and the substituent group is independent Ground is selected from halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy has The C of 1 to 5 halogen atom₁-C₄Halogenated alkoxy；With

R¹¹It is selected from

4- to 10- membered heterocycloalkyl,

R¹²It is selected from

Hydrogen；

C₁-C₄Alkyl is optionally replaced by 1,2 or 3 substituent group, and the substituent group is independently selected from-OH and-COOH；With

6- unit's heteroaryl,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z²Selected from hydrogen, halogen ,-OH, C₁-C₄Alkyl, C₁-C₄Alkoxy ,-NH (C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、- NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base), the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-S- (C₁-C₄Alkyl) and 4- to 6- membered heterocycloalkyl and

Z³Selected from hydrogen, halogen, C₁-C₄Alkyl, C₁-C₄Alkoxy ,-NH (C₁-C₄Alkyl) and-N (C₁-C₄Alkyl)₂,

Z⁴Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z⁵Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Or its stereoisomer, tautomer, N- oxide, hydrate, solvate or salt or their mixture.

5. according to claim 1,2,3 or 4 compound, in which:

A is selected from

G is S, O, N-R⁸

R¹It is hydrogen or methyl,

R²It is selected from

Hydrogen, chlorine, fluorine,

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclohexyl, acrylic, cyclopentenyl, cyclohexenyl group, each are optional Ground is by 1 or 2 independently selected from cyano, ethyoxyl-C (O)-and-C (O)-NH₂Substituent group replace；With

Monocycle or bicyclic heterocycles are selected from azetidine, pyrrolidines, pyrazolidine, imidazolidine, 1,2,4- triazolidines, piperidines, piperazine Piperazine, tetrahydropyridine, dihydro -2HPyrans, 1,2- oxazolidine, 1,2- oxazines, morpholine, thiomorpholine, 3,4- dihydro-isoquinoline, 2,3- Dihydro-indole, 1,3- dihydro-isoindole, 3,9- dioxa -7- azabicyclo [3.3.1] nonane, 6- oxa- -3- azabicyclo [3.1.1] heptane, 8- oxa- -3- azabicyclo [3.2.1] octane, imidazoles, pyrazoles, 1,2,4- triazole, 1,2,3- triazole, 4- oxygen Miscellaneous -7- azaspiro [2.5] octane, each are optionally replaced by 1,2,3 or 4 substituent group, and the substituent group independently selects From fluorine, chlorine, cyano ,-OH, oxo ,-COOH, methoxyl group-C (O)-, ethyoxyl-C (O)-, tert-butoxy-C (O)-,-C (O)- NH₂, methyl, methyl-C (O)-, trifluoromethyl, hydroxymethyl-, methoxy-,-NH₂、-NMe₂, pyrrolidines,

R³Selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxyl group and trifluoromethyl,

R⁸Selected from hydrogen and methyl,

R⁹And R¹⁰Independently selected from

Hydrogen ,-NH (- C (O)-methyl), methoxyl group；

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, cyclopropyl, cyclobutyl, benzyl, 1- phenylethyl, each Optionally replaced by 1,2 or 3 substituent group, the substituent group is independently selected from fluorine ,-OH ,-COOH, methoxyl group-C (O)-, ethoxy Base-C (O)-, tert-butoxy-C (O)-,-C (O)-NH₂、-C(O)-NMe₂,-NH-C (O)-methyl, methyl, methoxyl group, cyclopropyl Base ,-NH₂、NMe₂, S- methyl, S (O)-methyl, SO₂Methyl and (EtO)₂P(=O)-；

Heterocyclyl-methyl, heterocycle-ethyl, wherein the heterocyclyl substituent is selected from pyrrolidines, morpholine, pyrazoles, 1,2,4- Oxadiazoles, pyridine, each are optionally replaced by 1 substituent group independently selected from fluorine, chlorine ,-OH, oxo and methyl；

Phenyl；

2,3- dihydro -1H- indenes, and

Monocycle or bicyclic heterocycles are selected from propylene oxide, Thietane, pyrrolidines, morpholine, oxinane, pyridine and pyrazoles, Each is optionally replaced by 1 or 2 substituent group independently selected from fluorine, chlorine ,-OH, oxo, methyl；

R¹¹It is selected from

Methyl, ethyl, isopropyl, butyl, cyclopenta, benzyl, each optionally by 1 or 2 independently selected from fluorine ,-OH, The substituent group of methyl, methoxyl group and cyclopenta replaces；With

Monocycle or bicyclic heterocycles are selected from pyrrolidines and oxinane,

R¹²It is selected from

Methyl and ethyl, each are optionally replaced by 1 substituent group independently selected from-OH and-COOH；With

Pyridine,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, fluorine, chlorine, methyl and methoxyl group,

Z²Selected from hydrogen, fluorine, chlorine ,-OH, methyl, ethyl, methoxyl group, ethyoxyl ,-NH (CH₃)、-N(CH₃)₂, trifluoromethyl, trifluoro Methoxyl group,

Z³Selected from hydrogen, fluorine, chlorine, methyl, methoxyl group ,-NH (CH₃) and-N (CH₃)₂,

Z⁴Selected from hydrogen, fluorine, chlorine, methyl and methoxyl group,

Z⁵Selected from hydrogen, fluorine, chloromethyl and methoxyl group,

Or its stereoisomer, tautomer, N- oxide, hydrate, solvate or salt or their mixture.

6. according to claim 1,2,3,4 or 5 compound, in which:

A is selected from

G is S, O, NH or N-CH₃

R¹It is hydrogen or methyl,

R²It is selected from

Hydrogen, chlorine, fluorine,

-NH₂、-NH(CH₃)、-N(CH₃)₂,

Methoxyl group, ethyoxyl,

Methyl, ethyl, propyl, isopropyl, cyclopropyl,

Trifluoromethyl and trifluoromethoxy,

R³Selected from hydrogen, chlorine, fluorine, methyl, methoxyl group and trifluoromethyl,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, fluorine, chlorine, methyl and methoxyl group,

Z²Selected from hydrogen, fluorine, chlorine ,-OH, methyl, ethyl, methoxyl group, ethyoxyl ,-NH (CH₃)、-N(CH₃)₂, trifluoromethyl, trifluoro Methoxyl group,

Z³Selected from hydrogen, fluorine, chlorine, methyl, methoxyl group ,-NH (CH₃) and-N (CH₃)₂,

Z⁴Selected from hydrogen, fluorine, chlorine, methyl and methoxyl group,

Z⁵Selected from hydrogen, fluorine, chloromethyl and methoxyl group,

Or its stereoisomer, tautomer, N- oxide, hydrate, solvate or salt or their mixture.

7. according to claim 1,2,3,4,5 or 6 compound, wherein G is S.

8. the compound of logical formula (II):

Wherein:

A is selected from

R¹It is hydrogen or methyl,

R²It is selected from

Hydrogen, chlorine, fluorine,

Methoxyl group,

Methyl, ethyl, propyl, isopropyl,

Trifluoromethyl and trifluoromethoxy,

R³Selected from hydrogen, chlorine, fluorine, methyl, methoxyl group and trifluoromethyl,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen and halogen,

Z²Selected from hydrogen, halogen ,-N (C₁-C₄Alkyl)₂,-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to The C of 5 halogen atoms₁-C₄Halogenated alkoxy,

Z³Selected from hydrogen and halogen,

Z⁴Selected from hydrogen and halogen,

Z⁵Selected from hydrogen and halogen,

Or its stereoisomer, tautomer, N- oxide, hydrate, solvate or salt or their mixture.

9. compound according to claim 8, wherein

A is selected from

R¹It is hydrogen,

R²It is isopropyl,

R³It is methyl,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹、Z³、Z⁴And Z⁵Independently selected from hydrogen, fluorine and chlorine, and

Z²Selected from hydrogen, fluorine, chlorine ,-N (CH₃)₂, trifluoromethyl and trifluoromethoxy,

Or its stereoisomer, tautomer, N- oxide, hydrate, solvate or salt or their mixture.

10. a kind of method for the compound for preparing logical formula (I) according to any one of claim 1 to 9 or (II), described Method includes the following steps: the midbody compound for making general formula 1N:

Wherein G, A, R¹、R³Determine with the compound of Q logical formula (I) for example according to any one of claim 1 to 9 or (II) Justice,

It is reacted with the compound of general formula 1F:

Wherein R²Selected from-NR⁹R¹⁰、–OR¹¹With-SR¹², wherein R⁹、R¹⁰、R¹¹And R¹²As according to claim 1 to any one of 9 The compound of the logical formula (I) or (II) is defined,

Thus logical formula (I) or the compound of (II) are obtained:

Wherein G, A, R¹、R²、R³With the compound institute of Q logical formula (I) for example according to any one of claim 1 to 9 or (II) Definition,

Or following step: make the midbody compound of general formula 1T:

Wherein G, A, R¹、R²And R³As the compound of logical formula (I) according to any one of claim 1 to 9 or (II) is determined Justice, and wherein Hal is halogen, especially chlorine, bromine or iodine,

It is reacted with the compound of general formula 1H:

Wherein the compound of Q logical formula (I) for example according to any one of claim 1 to 7 or (II) are defined, and each It is pinacol ester that R, which can be respectively H or Me or two R,

Thus logical formula (I) or the compound of (II) are obtained:

Wherein G, A, R¹、R²、R³With the compound institute of Q logical formula (I) for example according to any one of claim 1 to 9 or (II) Definition,

Or following step: make the midbody compound of general formula 1W:

Wherein G, Q, R²And R³If the compound of logical formula (I) according to any one of claim 1 to 9 or (II) defines,

It is reacted with the compound of general formula 1M:

Wherein R¹It is defined with the compound of A logical formula (I) for example according to any one of claim 1 to 9,

Thus logical formula (I) or the compound of (II) are obtained:

Wherein G, A, R¹、R²、R³With the compound institute of Q logical formula (I) for example according to any one of claim 1 to 9 or (II) Definition,

Or following step: make the midbody compound of general formula 1X:

Wherein G, Q, A, R¹And R³As the compound of logical formula (I) according to any one of claim 1 to 9 or (II) is determined Justice,

It is reacted with the compound of general formula 1Y:

Wherein R²It is optional as defined in the compound of logical formula (I) according to any one of claim 1 to 9 or (II) The C that ground replaces₁-C₄Alkoxy,

Thus logical formula (I) or the compound of (II) are obtained:

Wherein G, A, R¹、R³Determine with the compound of Q logical formula (I) for example according to any one of claim 1 to 9 or (II) Justice and R²Be as defined in the compound of logical formula (I) according to any one of claim 1 to 9 or (II) optionally Substituted C₁-C₄Alkoxy,

Or following step: make the midbody compound of general formula 1N:

Wherein G, Q, A, R¹And R³As the compound of logical formula (I) according to any one of claim 1 to 9 or (II) is determined Justice,

It is reacted with the compound of general formula 2A:

Wherein R²It is C₁-C₄Alkyl, C₃-C₆Naphthenic base, C₂-C₄Alkenyl, C₃-C₆Cycloalkenyl, C₂-C₄Alkynyl or phenyl-C₁- C₄Alkyl, each are that the compound of logical formula (I) according to any one of claim 1 to 9 or (II) such as defines It is optionally substituted, Met is magnesium or zinc, and X is chlorine, bromine or iodine,

Thus logical formula (I) or the compound of (II) are obtained:

Wherein G, A, R¹、R³Determine with the compound of Q logical formula (I) for example according to any one of claim 1 to 9 or (II) Justice and R²It is C₁-C₄Alkyl, C₃-C₆Naphthenic base, C₂-C₄Alkenyl, C₃-C₆Cycloalkenyl, C₂-C₄Alkynyl or phenyl-C₁-C₄- Alkyl, each are as defined in the compound of logical formula (I) according to any one of claim 1 to 9 or (II) It is optionally substituted.

11. the compound of general formula (VI-INT-1), (VI-INT-2), (VI-INT-3) or (IV-INT-1):

Wherein

R^ASelected from methyl, ethyl and tert-butyl,

R²Selected from C₁-C₆Alkyl and C₃-C₆Naphthenic base,

R³Selected from hydrogen, halogen, C₁-C₄Alkyl and C₃-C₆Naphthenic base and

A and R¹As any one of preceding claims define.

12. general formula (VI-INT-1), (VI-INT-2), (VI-INT-3) and (IV-INT-1) according to claim 11 Compound is used to prepare the purposes of logical formula (I) according to any one of claim 1 to 9 and the compound of (II).

13. the compound of logical formula (I) according to any one of claim 1 to 9 or (II), be used to control, treat and/ Or prevention disease.

14. pharmaceutical composition, it includes the compound of logical formula (I) according to any one of claim 1 to 9 or (II) and One or more pharmaceutically acceptable excipient.

15. the compound of logical formula (I) according to any one of claim 1 to 9 or (II) for control, treat and/or The purposes for preventing disease.

16. the compound of logical formula (I) according to any one of claim 1 to 9 or (II) are used to prepare the purposes of drug, The drug is for controlling, treating and/or preventing disease.

17. purposes described in 1,13 or 14 according to claim 1, wherein the disease is invermination.

18. the method for controlling invermination in people and/or animal, by compacted to needing its human or animal's application to resist The compound of a effective amount of at least one of worm logical formula (I) according to any one of claim 1 to 9 or (II).

Invention description

According to first aspect, the present invention covers the compound of logical formula (I):

Wherein:

A is A1 or A2,

O is 0,1,2,3 or 4,

X, Y is independently selected from CR⁶R⁷, O, S and N-R⁸, wherein at least one of X and Y are CR⁶R⁷, or

X, Y is formed together ring members selected from the group below :-C (O)-O- ,-C (O)-NR⁸-、-S(O)-NR⁸-、-SO₂-NR⁸And- SO₂- O-,

G is S, O, N-R⁸

R¹Selected from hydrogen, cyano ,-CHO ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁- C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base has 1 to 5 halogen atom C₃-C₆Halogenated cycloalkyl, C₃-C₄Alkenyl, C₃-C₄Alkynyl, C₁-C₄Alkoxy -C₁-C₄Alkyl, C₃-C₆Naphthenic base-C₁- C₃Alkyl, cyano-C₁-C₄Alkyl ,-NH-C₁-C₄Alkyl ,-N (C₁-C₄Alkyl)₂、NH₂-C₁-C₄Alkyl-, C₁-C₄Alkane Base-NH-C₁-C₄Alkyl-, (C₁-C₄Alkyl)₂N-C₁-C₄Alkyl-, C₁-C₄Alkyl-C (O)-, there is 1 to 5 halogen atom C₁-C₄Halogenated alkyl-C (O)-, C₁-C₄Alkoxy -C (O)-, benzyl oxygroup-C (O)-, C₁-C₄Alkoxy -C₁-C₄Alkane Base-C (O)-,-SO₂-C₁-C₄Alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen ,-OH ,- NO₂, cyano, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄- Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 to 5 halogen atom - S (O)-C₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl,

R²It is selected from

Hydrogen, halogen, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、-C(O)-NH(C₃-C₆Naphthenic base) ,-C (O)-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base)；

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen ,-OH ,- NO₂, cyano, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄- Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

R³Selected from hydrogen, halogen ,-OH, cyano, C₁-C₄Alkyl, C₃-C₆Naphthenic base, the C with 1 to 5 halogen atom₁-C₄- Halogenated alkyl, C₁-C₄Alkoxy -C₁-C₄Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkyl-C (O)-,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl,

R⁴Selected from hydrogen ,-OH, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁵Selected from hydrogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Or R⁴And R⁵Carbon atom in connection is formed together selected from C₃-C₆Naphthenic base and 3- to 6- membered heterocycloalkyl 3- To 6- member ring,

R⁶Selected from hydrogen ,-OH, fluorine, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁷Selected from hydrogen ,-OH, fluorine, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Or R⁶And R⁷Carbon atom in connection is formed together selected from C₃-C₆Naphthenic base and 3- to 6- membered heterocycloalkyl 3- To 6- member ring,

R⁸Selected from hydrogen, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and C₁-C₄Alkoxy,

R⁹And R¹⁰Independently selected from

Hydrogen ,-OH ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(-C(O)-C₁-C₄Alkyl) ,-N (C₁-C₄- Alkyl) (- C (O)-C₁-C₄Alkyl), C₁-C₄Alkoxy, C₁-C₄Alkoxy -C (O)-；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, Nitro ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl Base-C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄- Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl, benzo-C₅-C₆Naphthenic base, each are optionally replaced by 1,2 or 3 substituent group, and the substituent group is independent Ground is selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkane Oxygroup, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen atom - S-C₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 halogen original - the SO of son₂-C₁-C₄Halogenated alkyl；

R¹¹It is selected from

-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, Nitro ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl Base-C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄- Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl is optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 To-S (O)-C of 5 halogen atoms₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

R¹²It is selected from

Hydrogen；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, Nitro ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl Base-C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄- Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl is optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 To-S (O)-C of 5 halogen atoms₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

Wherein when Y is O, S or N-R⁸When, R⁴、R⁵、R⁶And R⁷No one of be-OH, and wherein when X is O, S or N-R⁸When, R⁶And R⁷No one of be-OH,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

Definition

Term " substituted " refers to that one or more hydrogen atoms on specified atom or group are replaced by the selection from shown group Generation, premise are, are no more than the normal chemical valence of specified atom in case of presence.The combination of substituent group and/or variable is Allow.

Term " optionally replacing " refers to that the quantity of substituent group can be equal to or be different from zero.Unless otherwise indicated, appoint Choose generation group can by with can by any available carbon or nitrogen-atoms with non-hydrogen substituent substitute hydrogen atom come The optional substituent group adjusted as many replaces.In general, optionally substituent group quantity in the presence of can be 1,2,3,4 or 5, especially It is 1,2 or 3.

As used in this article, the substituent group of the compound such as in logical formula (I) of the invention define in term " one Or multiple " refer to " 1,2,3,4 or 5, especially 1,2,3 or 4, more particularly 1,2 or 3, or even more particularly 1 or 2 It is a ".

As used in this article, oxo substituent indicates the oxygen atom that carbon atom or sulphur atom are bonded to via double bond.

Term " ring substituents " refers to the substitution for being connected to aromatics or non-aromatic ring instead of the available hydrogen atom on ring Base.

If complex substituents should be made of more than one part, such as (C₁-C₄Alkoxy)-(C₁-C₄Alkyl)-, Then the position of the given part can be in any suitable position of the complex substituents, i.e. C₁-C₄Alkoxy portion can connect It is connected to (the C₁-C₄Alkoxy)-(C₁-C₄Alkyl)-group C₁-C₄Any carbon atom of moieties.It is such compound The hyphen of the start or end of substituent group indicates the tie point of the complex substituents Yu molecule remainder.If including carbon The heteroatomic ring of atom and optional one or more such as nitrogen, oxygen or sulphur atom should be for example substituted with a substituent, then institute Any suitable position that substituent group can be bonded to the ring is stated, as long as it is bonded to suitable carbon atom and/or suitable miscellaneous Atom.

As used in this article, each substituent group can be in drafting by its position connecting with the rest part of molecule In structure by the substituent group pound sign (#) or dotted line indicate.

When used in this manual, term "comprising" include " by ... form ".

If any project to be censured in this text times that refer to for " as described herein " can in this text Meaning position refers to.

As the term referred in this document has the meaning that

Term " halogen atom " refers to fluorine, chlorine, bromine or iodine atom, especially fluorine, chlorine or bromine atom.

Term " C₁-C₆Alkyl " refers to linear chain or branched chain, saturation the monovalence with 1,2,3,4,5 or 6 carbon atom Alkyl.Term " C₁-C₄Alkyl " refers to linear chain or branched chain, saturation the monovalent hydrocarbon with 1,2,3 or 4 carbon atom, example Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl or its isomers.Particularly, institute Group is stated with 1,2 or 3 carbon atom (" C₁-C₃Alkyl "), such as methyl, ethyl, n-propyl or isopropyl.

Term " C₁-C₄Hydroxy alkyl " refers to linear chain or branched chain, saturation monovalent hydrocarbon, wherein term " C₁-C₄Alkane As defined above, and wherein 1 or 2 hydrogen atoms are substituted base " by hydroxyl, such as hydroxymethyl, 1- hydroxyethyl, 2- hydroxyl Ethyl, 1,2- dihydroxy ethyl, 3- hydroxypropyl, 2- hydroxypropyl, 1- hydroxypropyl, 1- hydroxyl propyl- 2- base, 2- hydroxyl propyl- 2- base, 2,3- dihydroxypropyl, 1,3- dihydroxy propyl- 2- base, 3- hydroxy-2-methyl-propyl, 2- hydroxy-2-methyl-propyl, 1- hydroxy-2-methyl-propyl.

Term "-NH (C₁-C₄Alkyl) " or "-N (C₁-C₄Alkyl)₂" refer to linear chain or branched chain, saturation univalent perssad, Wherein term " C₁-C₄Alkyl " as defined above, such as methylamino, ethylamino, n-propyl amino, isopropylamino,N, NDimethylamino,NMethyl-NEthylamino orN,NDiethylamino.

Term "-S-C₁-C₄Alkyl ", "-S (O)-C₁-C₄Alkyl " or "-SO₂-C₁-C₄Alkyl " refers to linear chain or branched chain , the group of saturation, wherein term " C₁-C₄Alkyl " as defined above, such as methylsulfanyl, Ethylsulfanyl, n-propyl Sulfanyl, isopropyl sulfanyl, normal-butyl sulfanyl, sec-butyl sulfanyl, isobutyl group sulfanyl or tert-butylsulfanyl, methyl Sulfinyl, ethylsulfinyl, n-propyl sulfinyl, isopropylsulphinyl, n-butylsulfinyl, sec-butyl Asia sulphur It is acyl group, isobutyl group sulfinyl or terf-butylsulfinyl or methyl sulphonyl, ethylsulfonyl, n-propyl sulfonyl, different Sulfonyl propyl base, normal-butyl sulfonyl, sec-butylsulfonyl, iso-butylsulfonyl or tert. butylsulfonyl.

Term " C₁-C₄Halogenated alkyl " refers to linear chain or branched chain, saturation monovalent hydrocarbon, wherein term " C₁-C₄Alkane As defined above, and wherein one or more hydrogen atoms are substituted by halogen atom base " identical or differently.Particularly, described Halogen atom is fluorine atom.More particularly, all halogen atoms are fluorine atom (" C₁-C₄Fluoroalkyl ").The C₁-C₄- Halogenated alkyl be for example methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyl, 2,2- bis-fluoro ethyls, 2,2,2- trifluoroethyl, Pentafluoroethyl group, 3,3,3- trifluoro propyl or 1,3- difluoro propyl- 2- base.

Term " C₁-C₄Alkoxy " refers to formula (C₁-C₄Alkyl)-O- linear chain or branched chain, saturation univalent perssad, Wherein term " C₁-C₄Alkyl " is as defined above, such as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, secondary Butoxy, isobutoxy or tert-butoxy or their isomers.

Term " C₁-C₄Halogenated alkoxy " refers to linear chain or branched chain as defined above, saturation monovalence C₁-C₄Alkane Oxygroup, wherein one or more hydrogen atoms are substituted by halogen atom identical or differently.Particularly, the halogen atom is fluorine original Son.The C₁-C₄Halogenated alkoxy is for example, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 2,2,2- trifluoro ethoxies Or five fluorine ethyoxyl.

Term " C₂-C₄Alkenyl " refers to the monovalent hydrocarbon of linear chain or branched chain, contains a double bond, and have 2,3 or 4 Carbon atom.The C₂-C₄Alkenyl is such as vinyl (ethenyl or vinyl), propyl- 2- alkene -1- base (or " allyl "), propyl- 1- alkene -1- base, butyl- 3- alkenyl, but-2-ene base, but-1-ene base, propyl- 1- alkene -2- base (or " isopropenyl "), 2- methyl propyl- 2- alkenyl, 1- methyl propyl- 2- alkenyl, 2- methyl propyl- 1- alkenyl or 1- methyl propyl- 1- alkenyl.Particularly, the group is allyl Base.

Term " C₂-C₄Alkynyl " refers to the monovalent hydrocarbon of straight chain, contains three keys, and contain 2,3 or 4 carbon originals Son.The C₂-C₄Alkynyl is such as acetenyl, propyl- 1- alkynyl, Propargyl (or " propargyl "), butyl- 1- alkynyl, butyl- 2- Alkynyl, butyl- 3- alkynyl or 1- methyl Propargyl.Particularly, the alkynyl is propyl- 1- alkynyl or Propargyl.

Term " C₃-C₆Naphthenic base " refers to the monovalent monocyclic hydrocarbon ring of saturation, contains 3,4,5 or 6 carbon atom (" C₃- C₆Naphthenic base ").The C₃-C₆Naphthenic base is such as monocycle hydrocarbon ring, such as cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.

Term " C₃-C₆Halogenated cycloalkyl " refers to the monovalent monocyclic hydrocarbon ring of saturation, wherein term " C₃-C₆Naphthenic base " is such as It is upper to be defined, and wherein one or more hydrogen atoms are substituted by halogen atom identical or differently.Particularly, the halogen is former Son is fluorine or chlorine atom.The C₃-C₆Halogenated cycloalkyl is the monocycle hydrocarbon ring for example replaced by one or two fluorine or chlorine atom, Such as the fluoro- cyclopropyl of 1-, 2- fluorine cyclopropyl, 2,2- difluorocyclopropyl, 2,3- difluorocyclopropyl, 1- chlorine cyclopropyl, 2- chlorine cyclopropyl Base, 2,2- dichloro cyclopropyl, 2,3- dichloro cyclopropyl, the fluoro- 2- chlorine cyclopropyl of 2- and the fluoro- 3- chlorine cyclopropyl of 2-.

Term "-NH (C₃-C₆Naphthenic base) " or "-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base₎" refer to linear chain or branched chain , the univalent perssad of saturation, wherein term " C₁-C₄Alkyl " and term " C₃-C₆Naphthenic base " is respectively as defined above, example As cyclopropylamino, Cyclobutylamino, clopentylamino, Cyclohexylamino,N-Methyl-N- cyclopropylamino,NEthyl-NRing Propylcarbamic,N-Methyl-N- Cyclobutylamino,NEthyl-NCyclobutylamino,N-Methyl-N- clopentylamino,NEthyl-NClopentylamino,N-Methyl-N-cyclohexyl amino, orNEthyl-NCyclohexylamino group.

Term " benzo-C₅-C₆Naphthenic base " refers to saturation monovalent monocyclic the hydrocarbon ring (" C wherein containing 5 or 6 carbon atoms₅- C₆Naphthenic base ") with benzyl ring condense (annelated) monovalence bicyclic hydrocarbons ring.Benzo-the C₅-C₆Naphthenic base is, for example, two Cyclic hydrocarbon ring, such as indane (i.e. 2,3- dihydro -1HIndenes) or naphthane (i.e. 1,2,3,4- naphthane) group.

Term " spiro cycloalkyl group " refers to that the monovalence bicyclic hydrocarbons base of saturation, two of them ring share a common ring carbon atom, And wherein the bicyclic hydrocarbons base contains 5,6,7,8,9,10 or 11 carbon atoms, and the spiro cycloalkyl group may be by except spiral shell carbon original Any one carbon atom other than son is connected to the rest part of molecule.The spiro cycloalkyl group is, for example, spiral shell [2.2] amyl, spiral shell [2.3] hexyl, spiral shell [2.4] heptyl, spiral shell [2.5] octyl, spiral shell [2.6] nonyl, spiral shell [3.3] heptyl, spiral shell [3.4] octyl, spiral shell [3.5] Nonyl, spiral shell [3.6] decyl, spiral shell [4.4] nonyl, spiral shell [4.5] decyl, spiral shell [4.6] undecyl or spiral shell [5.5] undecyl.

Term " Heterocyclylalkyl " refers to has 4,5,6,7,8,9 or 10 annular atoms (" 4- to 10- membered heterocycloalkyl " in total Group), the monocycle or two rings, saturation or fractional saturation of especially 4,5 or 6 annular atoms (" 4- to 6- membered heterocycloalkyl " group) Heterocycle, contain one or two identical or different ring hetero atom from N, O and S series, the Heterocyclylalkyl can be with The rest part of molecule is connected to by any one carbon atom or (if present) nitrogen-atoms.

The Heterocyclylalkyl can be following but not limited to this: 4 member rings, such as azetidinyl, oxetanyl Or Thietane base；Or 5 member rings, such as tetrahydrofuran base, 1,3- dioxolane base, tiacyclopentane base, pyrrolidines Base, imidazolidinyl, pyrazolidinyl, 1,1- sulfur dioxide heterocycle pentyl, 1,2- oxazolidinyl, 1,3- oxazolidinyl, 1,3- thiophene Oxazolidinyl or 1,2,4- triazolidinyl；Or 6 member rings, such as THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, dithiane Base, thio-morpholinyl, piperazinyl, 1,3- dioxanes base, 1,4- dioxanes base or 1,2- oxazines alkyl；Or 7 member rings, such as azepine Cycloheptyl alkyl, 1,4- Diazesuberane base or 1,4- oxazepine cycloheptyl alkyl；Or two ring 7- member rings, such as 6- oxa- -3- Azabicyclo [3.1.1] heptane；Or two ring 8- member rings, such as 5,6- dihydro -4H- furans simultaneously [2,3-c] pyrroles or 8- oxa- -3- Azabicyclo [3.2.1] octane；Or two ring 9- member rings, such as octahydro -1H- pyrrolo- [3,4-b] pyridine, 1,3- dihydro-different Yin Diindyl, 2,3- Dihydro-indole or 3,9- dioxa -7- azabicyclo [3.3.1] nonane；Or two ring 10- member rings, such as decahydroquinoline Or 3,4- dihydro-isoquinoline.

Term " miscellaneous spiro cycloalkyl group " refers to two ring filling heterocycles in total with 6,7,8,9,10 or 11 annular atoms, wherein Two rings share a common ring carbon atom, and be somebody's turn to do " miscellaneous spiro cycloalkyl group " containing one or two from series: N, O, S's is identical Or different ring hetero atom；The miscellaneous spiro cycloalkyl group can by any one carbon atom (in addition to spiral shell carbon atom) or (if In the presence of) nitrogen-atoms is connected to the rest part of molecule.

The miscellaneous spiro cycloalkyl group is, for example, azaspiro [2.3] hexyl, azaspiro [3.3] heptyl, oxazepine spiral shell [3.3] heptan Base, thiazepine spiral shell [3.3] heptyl, oxaspiro [3.3] heptyl, oxygen azaspiro [5.3] nonyl, oxygen azaspiro [4.3] octyl, oxygen Miscellaneous azaspiro [2.5] octyl, azaspiro [4.5] decyl, oxygen azaspiro [5.5] undecyl, diaza spiro [3.3] heptyl, sulphur Azaspiro [3.3] heptyl, sulphur azaspiro [4.3] octyl, azaspiro [5.5] undecyl or other homologous skeleton such as spiral shells [3.4]-, spiral shell [4.4]-, spiral shell [2.4]-, spiral shell [2.5]-, spiral shell [2.6]-, spiral shell [3.5]-, spiral shell [3.6]-, spiral shell [4.5]-and spiral shell One of [4.6]-.

Term " 6 or 10 yuan of aryl " refers to the monocycle or bicyclic aromatic ring of monovalence, has 6 or 10 carboatomic ring atoms, example Such as phenyl or naphthyl.

Term " heteroaryl " refers to monovalence, monocyclic, bicyclic or tricyclic aromatic ring, has 5,6,9 or 10 annular atoms (" 5 to 10 unit's heteroaryl "), particularly 5 or 6 annular atoms (" 5 to 6 unit's heteroaryl ") containing at least one ring hetero atom and are appointed Choosing from series: the other ring hetero atom of the one, two or three of N, O and/or S, and its via ring carbon atom or optionally It is bonded via theheterocyclic nitrogen atom (if chemical valence permission).

The heteroaryl can be with are as follows: 5 unit's heteroaryls, such as thienyl, furyl, pyrrole radicals, oxazolyl, thiazolyl, miaow Oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazoles base, triazolyl, thiadiazolyl group or tetrazole radical；Or 6 unit's heteroaryls, it is all Such as pyridyl group, pyridazinyl, pyrimidine radicals, pyrazinyl or triazine radical.

Term " heterocycle " refers to the heterocycle selected from Heterocyclylalkyl and heteroaryl.Particularly, term " 4- to 6- circle heterocyclic ring Base " refers to the heterocycle selected from 4- to 6- membered heterocycloalkyl and 5- to 6- unit's heteroaryl.

Typically and unless otherwise noted, heteroaryl or inferior heteroaryl include its all possible isomeric forms, Such as: tautomer and the position isomer for the tie point of molecule remainder.Therefore, for some illustrative Non-limiting example, term pyridyl group includes pyridine -2- base, pyridin-3-yl and pyridin-4-yl；Alternatively, term thienyl packet Include thiophene -2- base and thiene-3-yl.

As in this document, such as " C₁-C₄Alkyl ", " C₁-C₄Halogenated alkyl ", " C₁-C₄Hydroxy alkyl ", " C₁-C₄Alkane Oxygroup " or " C₁-C₄Term " C used in the context of the definition of halogenated alkoxy "₁-C₄" refer to 1 to 4 Finite Number The carbon atom of amount, i.e. 1,2,3 or 4 carbon atoms alkyl.

Further, as used in this article, as in this document, such as " C₃-C₆Naphthenic base " or C₃-C₆Halogenated cycloalkyl Definition context used in term " C₃-C₆" refer to carbon atom, i.e. 3 with 3 to 6 limited quantities, 4,5 or 6 carbon The naphthenic base of atom.

In the range of given value, the range covers each value and subrange in the range.

Such as:

"C₁-C₄" cover C₁、C₂、C₃、C₄、C₁-C₄、C₁-C₃、C₁-C₂、C₂-C₄、C₂-C₃And C₃-C₄；

"C₂-C₆" cover C₂、C₃、C₄、C₅、C₆、C₂-C₆、C₂-C₅、C₂-C₄、C₂-C₃、C₃-C₆、C₃-C₅、C₃-C₄、C₄-C₆、C₄-C₅With C₅-C₆；

"C₃-C₄" cover C₃、C₄And C₃-C₄；

"C₃-C₁₀" cover C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₃-C₁₀、C₃-C₉、C₃-C₈、C₃-C₇、C₃-C₆、C₃-C₅、C₃-C₄、 C₄-C₁₀、C₄-C₉、C₄-C₈、C₄-C₇、C₄-C₆、C₄-C₅、C₅-C₁₀、C₅-C₉、C₅-C₈、C₅-C₇、C₅-C₆、C₆-C₁₀、C₆-C₉、C₆-C₈、 C₆-C₇、C₇-C₁₀、C₇-C₉、C₇-C₈、C₈-C₁₀、C₈-C₉And C₉-C₁₀；

"C₃-C₈" cover C₃、C₄、C₅、C₆、C₇、C₈、C₃-C₈、C₃-C₇、C₃-C₆、C₃-C₅、C₃-C₄、C₄-C₈、C₄-C₇、C₄-C₆、C₄- C₅、C₅-C₈、C₅-C₇、C₅-C₆、C₆-C₈、C₆-C₇And C₇-C₈；

"C₃-C₆" cover C₃、C₄、C₅、C₆、C₃-C₆、C₃-C₅、C₃-C₄、C₄-C₆、C₄-C₅And C₅-C₆；

"C₄-C₈" cover C₄、C₅、C₆、C₇、C₈、C₄-C₈、C₄-C₇、C₄-C₆、C₄-C₅、C₅-C₈、C₅-C₇、C₅-C₆、C₆-C₈、C₆-C₇With C₇-C₈；

"C₄-C₇" cover C₄、C₅、C₆、C₇、C₄-C₇、C₄-C₆、C₄-C₅、C₅-C₇、C₅-C₆And C₆-C₇；

"C₄-C₆" cover C₄、C₅、C₆、C₄-C₆、C₄-C₅And C₅-C₆；

"C₅-C₁₀" cover C₅、C₆、C₇、C₈、C₉、C₁₀、C₅-C₁₀、C₅-C₉、C₅-C₈、C₅-C₇、C₅-C₆、C₆-C₁₀、C₆-C₉、C₆-C₈、 C₆-C₇、C₇-C₁₀、C₇-C₉、C₇-C₈、C₈-C₁₀、C₈-C₉And C₉-C₁₀；

"C₆-C₁₀" cover C₆、C₇、C₈、C₉、C₁₀、C₆-C₁₀、C₆-C₉、C₆-C₈、C₆-C₇、C₇-C₁₀、C₇-C₉、C₇-C₈、C₈-C₁₀、C₈- C₉And C₉-C₁₀。

As used in this article, term " leaving group " refers to and is replaced by together with its bonding electrons in chemical reaction The atom of stable material or the group of atom.Particularly, such leaving group is selected from: halogen ion, especially fluorine ion, chlorine from Son, bromide ion or iodide ion；(methyl sulphonyl) oxygroup, [(trifluoromethyl) sulfonyl] oxygroup, [(nona-fluoro butyl group) sulfonyl] Oxygroup, (phenyl sulfonyl) oxygroup, [(4- aminomethyl phenyl) sulfonyl] oxygroup, [(4- bromophenyl) sulfonyl] oxygroup, [(4- nitre Base phenyl) sulfonyl] oxygroup, [(2- nitrobenzophenone) sulfonyl] oxygroup, [(4- isopropyl phenyl) sulfonyl] oxygroup, [(2,4, 6- triisopropyl phenyl) sulfonyl] oxygroup, [(2,4,6- trimethylphenyl) sulfonyl] oxygroup, [(4- tert-butyl-phenyl) sulphonyl Base] oxygroup and [(4- methoxyphenyl) sulfonyl] oxygroup.

Oxo substituent in context of the invention refers to the oxygen atom for via double bond and being bonded to carbon atom.

The compound of logical formula (I) can exist in the form of isotopic variations.Present invention accordingly comprises the compounds of logical formula (I) One or more isotopic variations, the especially compound of the logical formula (I) containing deuterium.

The term " isotopic variations " of compound or reaction reagent is defined as showing to constitute the non-of such compound The compound of one or more isotopes of natural ratio.

Term " isotopic variations of the compound of logical formula (I) " is defined as showing to constitute the non-day of such compound The compound of the logical formula (I) of one or more isotopes of right ratio.

Expression " unnatural proportions " refers to the ratio of such isotope higher than its natural abundance.Applied to the context In natural abundance of isotopes be described in " Isotopic Compositions of the Elements 1997 ", Pure Appl.Chem., 70 (1), 217-235,1998.

The example of such isotope include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine stabilization and radioactivity it is same Position element, respectively such as²H (deuterium),³H (tritium),¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁵I、¹²⁹I and¹³¹I。

For treating and/or preventing imbalance referred to herein, the one or more isotopes for leading to the compound of formula (I) become Body preferably comprises deuterium (" compound of the logical formula (I) containing deuterium ").Wherein be mixed with it is one or more such as³H or¹⁴The radioactivity of C The isotopic variations of the compound of the logical formula (I) of isotope for example can be used for drug and/or substance Tissue distribution research.These are same Position procatarxis its incorporation easiness and detectability and it is particularly preferred.It can be by Positron emitting isotopes such as¹⁸F or¹¹C mixes In the compound for entering logical formula (I).The isotopic variations of the compound of these logical formula (I)s can be used for in-vivo imaging application.Containing deuterium and Contain¹³The compound of the logical formula (I) of C can be used for the mass spectral analysis under preclinical or clinical research background.

The isotopic variations of the compound of logical formula (I) usually can by methods known to those skilled in the art, such as Described in scheme and/or embodiment herein those, by the same position that reaction reagent is replaced with to the reaction reagent It is prepared by plain variant, the preferably reaction reagent containing deuterium.Depending on desired deuterated site, in some cases, can will come from D₂The deuterium of O is directly incorporated into compound, or in reaction reagent useful for incorporation compound such for synthesis.Deuterium It is useful reaction reagent for mixing deuterium in molecule.The catalysis of olefinic bonds and acetylene series key is deuterated be for incorporation deuterium and The fast route of speech.Metallic catalyst (i.e. Pd, Pt and Rh) in the presence of deuterium can be used for directly in the hydrocarbon containing functional group Hydrogen is changed to deuterium.A variety of deuterated reaction reagents and segmental member can be commercially available with subsidiary company, such as C/D/N Isotopes, Quebec, Canada；Cambridge Isotope Laboratories Inc., Andover, MA, USA；And CombiPhos Catalysts, Inc., Princeton, NJ, USA.

Term " compound of the logical formula (I) containing deuterium " is defined as the compound of logical formula (I), wherein one or more hydrogen are former Son is substituted by one or more D-atoms, and the abundance of the deuterium at each deuterated position of the compound of its formula of (I) is higher than The natural abundance of deuterium, i.e., about 0.015%.Particularly, in the compound of the logical formula (I) containing deuterium, lead to each deuterium of the compound of formula (I) Subrogate the abundance for setting the deuterium at place higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably in one or more institute's rhemes It sets place and is higher than 90%, 95%, 96% or 97%, be even more preferably higher than 98% or 99% at one or more positions.It is appreciated that , the abundance of the abundance of the deuterium at each deuterated position independently of the deuterium at other one or more deuterated positions.

One or more D-atoms are selectively mixed to the compound of logical formula (I), and may to change physicochemical characteristics (all Such as acid [C. L. Perrin et al., J. Am. Chem. Soc., 2007,129,4490], alkalinity [C. L. Perrin etc. People, J. Am. Chem. Soc., 2005,127,9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19 (3), 271]) and/or the metabolic characteristics of molecule, and it may cause the change in terms of the ratio of parent compound and metabolin Or it is formed by the change in terms of the amount of metabolin.Such change may cause certain treatment advantages, and therefore some It may be preferred in situation.Have reported the metabolic rate and metabolism conversion (A. of the reduction for wherein changing metabolin ratio E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000,169,102).These be exposed to parent drug and Change when metabolin can have important knot for the pharmacodynamics of the compound of the logical formula (I) containing deuterium, tolerance and efficiency Fruit.In some cases, deuterium replaces the formation for reduce or eliminating undesirable or virose metabolin, and improves expectation Metabolin formation (such as nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013,26,410； Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000,169,102).In other feelings In condition, deuterated main effect is reduction system clearance rate.As a result, improving the biological half-life of compound.Potentially Clinical benefit will include the ability that similar system exposure is maintained with the Cmax of reduction and increased Grain volume.Depending on specific The pharmacokinetics of compound/pharmacodynamics relationship, this can lead to the efficiency of lower side effect and raising.ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013,56,5208) and Ao Dangka replaces (K. Kassahun et al., WO2012/ 112363) be the deuterium effect example.Also reported in addition other the case where, wherein reduced metabolic rate cause drug exposure Increase without changing system clearance rate (such as rofecoxib: F. Schneider et al., Arzneim. Forsch./Drug. Res., 2006,56,295；Tirrevir: F. Maltais et al., J. Med. Chem., 2009,52,7993).Show this The deuterated drug of effect can have reduced dose requirements, and (such as lower dosage number or lower dosage are to realize expectation effect Fruit) and/or can produce the load of lower metabolin.

The compound of logical formula (I) can have multiple potential metabolic attacks sites.In order to optimize to physicochemical characteristics With the said effect of metabolic characteristics, logical formula (I) of one or more deuteriums with a certain form-hydrogen exchange containing deuterium can choose Compound.Particularly, one or more D-atoms of the compound containing deuterium of one or more logical formula (I)s are connected to carbon original Son, and/or be located at and be used as metabolic enzyme (such as cytochrome P₄₅₀) attack site those of the compound of logical formula (I) position.

The case where plural form of word compound used herein, salt, polymorph, hydrate, solvate etc. Under, also refer to single compound, salt, polymorph, isomers, hydrate, solvate etc..

" stable compound " or " stable structure " refers to sufficiently steadily and surely to be subjected to separating from reaction mixture to useful Purity and the compound for being formulated as effective therapeutic agent.

The compound of the present invention optionally contains one or more asymmetric centers, this depends on the position of a variety of expectation substituent groups It sets and property.One or more asymmetric carbon atoms can exist with (R) or (S) configuration, can be in single asymmetric center In the case where lead to racemic mixture, and lead to diastereomeric mixtures in the case where multiple asymmetric centers.In , can also be due to the given key around appointed compound in certain situations, such as abut the center key that two replace aromatic ring It is limited and rotates and there are asymmetry.

Preferred compound is to generate more desirable those of bioactivity.It is the separation of the compounds of this invention, pure or Partially purified isomers and stereoisomer or racemic or diastereomeric mixtures are also included in model of the invention In enclosing.The purifying and separation of such material can be completed by standard technique known in the art.

Preferred isomers is to generate more desirable those of bioactivity.These separation of the compound of the present invention, Pure or partially purified isomers or racemic mixture are also included in the scope of the present invention.Such material it is pure Change and separation can be completed by standard technique known in the art.

Optical isomer can be by according to conventional methods come resolving racemic mixtures, such as by using optical activity Acid or alkali formed diastereomeric salt, or formed covalent diastereomeric, to obtain.The example of suitable acid is wine Stone acid, acetyl tartaric acid, ditoluoyltartaric and camphorsulfonic acid.The mixture of diastereoisomer can be based on its object The difference of reason and/or chemistry, by methods known in the art, such as by chromatography or fractional crystallization, to be separated into it Individual diastereoisomer.Then optically active alkali or acid are discharged from isolated diastereomeric salt.For separating light The distinct methods for learning isomers are related in the case where being with or without conventional derivation using chiral chromatogram (such as using chiral phase HPLC column), carry out optimal selection so that the separation of enantiomter maximizes.The suitable HPLC column using chiral phase is Those of available commercial, such as manufactured by Daicel, wherein for example there is Chiracel OD and Chiracel OJ, they are It can conventional selection.Enzyme separation with or without derivatization is also useful.Optically active compound of the invention It can be similarly by being obtained using the chiral synthesis of optically active starting material.

For distinguishing one another for different type isomers, referring to the part IUPAC rule E (Pure Appl Chem 45,11- 30,1976).

The present invention include single stereoisomers form or arbitrary proportion the stereoisomer (such as (R)-or (S)-isomers) any mixture form the compound of the present invention all possible stereoisomer.For example, separation is originally The single stereoisomers (such as single enantiomter or single diastereoisomer) of the compound of invention pass through any suitable The art methods of conjunction, such as chromatography, especially chiral chromatogram and realize.

Further, the compound of the present invention can exist with tautomeric forms.For example, increased containing causing to have Any compound of the invention of the substitute mode of the α-CH- group at bicyclic pyrazole of CH- acidity can be with tautomerism Body exists, or exists even in the form of the mixture of any amount of two kinds of tautomers.

The present invention includes any mixture of the tautomer of single tautomeric forms or arbitrary proportion The all possible tautomer of the compound of the present invention of form.

Further, the compound of the present invention can exist in the form of N- oxide, be defined as chemical combination of the invention At least one nitrogen of object is oxidized.The present invention includes all such possible N- oxides.

Present invention also contemplates that the useful form of the compound of the present invention, such as metabolin, hydrate, solvate, prodrug, Salt (especially pharmaceutically acceptable salt) and/or co-precipitate.

The compound of the present invention can exist in the form of hydrate or solvate, wherein the compound of the present invention contains Polarized solvent, the especially such as structural element of water, methanol or ethyl alcohol as compound lattice.Polar solvent, especially water Amount can exist with stoichiometry or non-stoichiometric ratio.In the case where the solvate of stoichiometry, such as water Closing object, half-(hemi- or semi-), mono-, sesquialter-, two, three-, four-, five-equal solvents conjunction object or hydrate is possible respectively 's.The present invention includes all such hydrates or solvate.

Further, the compound of the present invention can in a free form, such as in the form of free alkali or free acid exist, or Person exists in the form of zwitterionic, or exists in a salt form.The salt can be any salt, be organic or inorganic addition Salt usually uses especially in drug or for example for any pharmaceutically acceptable of isolated or purified the compound of the present invention Organic or inorganic addition salts.

Term " pharmaceutically acceptable salt " refers to the inorganic or organic acid addition salt of the compound of the present invention.For example, ginseng See S. M. Berge et al., " Pharmaceutical Salt, " J. Pharm. Sci.1977,66,1-19.

The suitable pharmaceutically acceptable salt of the compound of the present invention can be for example in chain or in ring with nitrogen Atom for example sufficiently alkalinity the compound of the present invention acid-addition salts, such as: with inorganic acid or " mineral acid ", as hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, the acid-addition salts for weighing sulfuric acid (bisulfuric acid), phosphoric acid or nitric acid；Or With organic acid, such as formic acid, acetic acid, acetoacetate, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, hendecanoic acid, the moon Cinnamic acid, benzoic acid, salicylic acid, 2- (4- hydroxy benzoyl)-benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, didextrose Acid, 3- hydroxy-2-naphthoic acid, niacin, pamoic acid, pectic acid, 3- phenylpropionic acid, pivalic acid, 2- ethylenehydrinsulfonic acid, clothing health Acid, trifluoromethanesulfonic acid, dodecyl sulphate, ethanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, 2- naphthalene sulfonic acids, naphthalenedisulfonic acid, Camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, Malaysia Acid, fumaric acid, D- gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, phosphoglycerol, aspartic acid, sulfosalicylic acid or sulphur The acid-addition salts of cyanic acid.

Further, the in addition suitable pharmaceutically acceptable salt of sufficiently acid the compound of the present invention is alkali metal Salt, such as sodium or sylvite；Alkali salt, such as calcium, magnesium or strontium salt；Or aluminium or zinc salt；Or ammonium salt, derived from ammonia or Organic primary, secondary or tertiary amine with 1 to 20 carbon atom, such as ethylamine, diethylamide, triethylamine, ethyl diisopropyl amine, Monoethanolamine, diethanol amine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, DEAE diethylaminoethanol, three (hydroxyl first Base) aminomethane, procaine, dibenzyl amine, N-methylmorpholine, arginine, lysine, 1,2- ethylenediamine, N- methyl piperidine, N- methyl-glucamine, N, N- dimethyl-aminoglucose, N- ethyl-aminoglucose, 1,6- hexamethylene diamine, Glucosamine, sarcosine, silk Ammonia alcohol, 2- amino -1,3- propylene glycol, 3- amido-1,2-propanediol, 4- amino -1,2,3- butantriol；Or with have 1 to 20 The quaternary ammonium ion of a carbon atom, such as tetramethyl-ammonium, tetraethyl ammonium, four (n-propyl) ammoniums, four (normal-butyl) ammoniums, N- benzyl-N, The salt that N, N- trimethyl ammonium, choline or zephiran are formed.

Those skilled in the art will be further appreciated that, it is desirable that the acid-addition salts of the compound of protection can via it is a variety of Any one of perception method by make compound with suitable inorganic or organic acid reaction and prepare.Alternatively, acid of the invention Property compound alkali and alkaline earth metal ions salt via a variety of known methods by keeping the compound of the present invention and suitable alkali anti- It answers and prepares.

The present invention includes the change of the invention of any mixture form of the salt of single salt form or arbitrary proportion Close all possible salt of object.

In this text, especially in experimental section, in order to synthesize intermediate and embodiment of the invention, work as compound When being mentioned as the salt form formed with corresponding alkali or acid, by each preparation and/or the obtained salt form of purification process Actual stoichiometry composition be unknown in most cases.

Unless otherwise indicated, the suffix of chemical name relevant to salt or structural formula, such as " hydrochloride ", " trifluoroacetic acid Salt ", " sodium salt ", or " x HCl ", " x CF₃COOH”、“x Na⁺" referring to salt form, the stoichiometry of the salt form does not refer to It is fixed.

This is applied similarly to following situations: wherein obtaining solvent by described preparation and/or purification process The synthetic intermediate or embodiment compound or its salt of object (such as hydrate) form of conjunction, the change for having (if definition) unknown Learn metering composition.

Further, the present invention includes the mixing of more than one polymorph of single polycrystalline type thing form or arbitrary proportion The all possible crystal form or polymorph of the compound of the present invention of object form.

In addition, the invention also includes the prodrugs of compound according to the present invention.Term " prodrug " herein means for following Compound: itself can be bioactivity or nonactive, but in vivo within its residence time (such as metabolism ground or hydrolysis Ground) it is converted into compound according to the present invention.

According to the second embodiment of first aspect, the present invention covers the compound of above-mentioned logical formula (I), in which:

A is A1 or A2,

O is 0,1,2,3 or 4,

X, Y is independently selected from CR⁶R⁷, O, S and N-R⁸, wherein at least one of X and Y are CR⁶R⁷, or

X, Y is formed together ring members selected from the group below :-C (O)-O- ,-C (O)-NR⁸-、-S(O)-NR⁸-、-SO₂-NR⁸And- SO₂- O-,

G is S, O, N-R⁸

R²It is selected from

Hydrogen, halogen, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、-C(O)-NH(C₃-C₆Naphthenic base) ,-C (O)-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base)；

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen ,-OH ,- NO₂, cyano, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄- Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Monocycle or bicyclic heterocycles, selected from 4- to 10- membered heterocycloalkyl, miscellaneous spiro cycloalkyl group, 5- unit's heteroaryl and 6- unit's heteroaryl, Each is optionally replaced by 1,2,3 or 4 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, Oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N (C₁- C₄Alkyl)₂、C₁-C₄Alkyl, C₁-C₄Alkyl-C (O)-, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄- Alkoxy, hydroxyl-C₁-C₄Alkyl, C₁-C₄Alkoxy -C₁-C₄Alkyl-, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Oxygroup, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁- C₄Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl and 4- to 10- membered heterocycloalkyl,

R⁴Selected from hydrogen ,-OH, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁵Selected from hydrogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁶Selected from hydrogen ,-OH, fluorine, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁷Selected from hydrogen ,-OH, fluorine, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁸Selected from hydrogen, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and C₁-C₄Alkoxy,

R⁹And R¹⁰Independently selected from

Hydrogen ,-OH ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(-C(O)-C₁-C₄Alkyl), C₁-C₄Alcoxyl Base；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、-NH-C(O)-C₁-C₄Alkyl ,-N (C₁-C₄Alkyl)-(- C (O)-C₁- C₄Alkyl), C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy has 1 to 5 The C of halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S- C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Alkyl halide Base ,-S (O)-C with 1 to 5 halogen atom₁-C₄The halogenated alkyl ,-SO with 1 to 5 halogen atom₂-C₁-C₄It is halogenated Alkyl and (C₁-C₄Alkoxy)₂P(=O)-；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, Nitro ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl Base-C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄- Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl；

R¹¹It is selected from

-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, Nitro ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl Base-C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄- Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl is optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 To-S (O)-C of 5 halogen atoms₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

R¹²It is selected from

Hydrogen；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, Nitro ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl Base-C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄- Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl is optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 To-S (O)-C of 5 halogen atoms₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹、Z²、Z³、Z⁴And Z⁵Independently selected from hydrogen, halogen, SF₅, cyano ,-CHO, nitro, C₁-C₄Alkyl has 1 to 5 The C of halogen atom₁-C₄Halogenated alkyl, hydroxyl, C₁-C₄Alkoxy, C₃-C₆Naphthenic base-C₁-C₄Alkoxy, cyano-C₁-C₄- Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-NH (C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH (C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base) ,-NH-SO₂-(C₁-C₄Alkyl) ,-N (SO₂-[C₁-C₄Alkane Base]) (C₁-C₄Alkyl), (C_1-C₄Alkoximino)-C₁-C₄Alkyl, optionally by 1 or 2 be selected from fluorine, chlorine, bromine, first The 4- that the substituent group of base and cyano replaces is to 6- circle heterocyclic ring base ,-CH₂-O-(C₁-C₄Alkyl) ,-CH₂-NH(C₁-C₄Alkyl) ,- CH₂-N(C₁-C₄Alkyl)₂, optionally replaced by 1 or 2 substituent group selected from fluorine, chlorine, bromine, methyl and cyano by its own Methyl that 4- replaces to 6- circle heterocyclic ring base ,-CH₂-S-(C₁-C₄Alkyl) ,-CH₂-S(O)-(C₁-C₄Alkyl) ,-CH₂-SO₂- (C₁-C₄Alkyl) ,-S- (C₁-C₄Alkyl) ,-S (O)-(C₁-C₄Alkyl) ,-SO₂-(C₁-C₄Alkyl), have 1 to 5 halogen - S- (the C of atom₁-C₄Halogenated alkyl) ,-S (O)-(C with 1 to 5 halogen atom₁-C₄Halogenated alkyl), have 1 to 5 - the SO of a halogen atom₂-(C₁-C₄Halogenated alkyl) ,-CONH (C₁-C₄Alkyl) ,-CONH (C₃-C₆Naphthenic base) ,-NHCO (C₁-C₄Alkyl) ,-NHCO (C₃-C₆Naphthenic base) ,-NHCO (C with 1 to 5 halogen atom₁-C₄Halogenated alkyl), or

Z¹And Z²Carbon atom in connection is formed together 5- or 6- member saturation or fractional saturation heterocycle, 5- member heteroaryl Base or 6- unit's heteroaryl, each can optionally be replaced by one or two substituent group for being selected from methyl, fluorine and oxo, and

Z²And Z³Carbon atom in connection is formed together 5- or 6- member saturation or fractional saturation heterocycle, 5- member heteroaryl Base or 6- unit's heteroaryl, each can optionally be replaced by one or two substituent group for being selected from methyl, fluorine and oxo, and

Q is the pyridine ring of formula (Q2)

Wherein:

Q is the pyrimidine ring of formula (Q3)

Wherein:

Z¹⁰、Z¹¹And Z¹²Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogen Substituted alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-NH (C₁-C₄Alkyl) ,-N (C₁- C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base), or

Q is the pyridine ring of formula (Q4)

Wherein:

Z¹³、Z¹⁴、Z¹⁵And Z¹⁶Independently selected from hydrogen halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁- C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₁-C₄Hydroxy alkyl, NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Cycloalkanes Base) ,-NH-CO-C₁-C₄Alkyl and monocyclic heterocycles, the monocyclic heterocycles are selected from 4- to 7- membered heterocycloalkyl or have at least one Heteroaryl ring is connected through to the 5- unit's heteroaryl of the nitrogen-atoms of pyridine ring, and each is optionally by 1,2 or 3 substituent group Replace, the substituent group is independently selected from halogen, cyano, nitro ,-OH, oxo, thio, C₁-C₄Alkyl has 1 to 5 halogen The C of plain atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆- Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂- C₁-C₄Alkyl, the-S- (C with 1 to 5 halogen atom₁-C₄Halogenated alkyl) ,-S (O)-with 1 to 5 halogen atom (C₁-C₄Halogenated alkyl) ,-SO with 1 to 5 halogen atom₂-(C₁-C₄Halogenated alkyl), or

Q is the pyridine ring of formula (Q5)

Wherein:

Q is the 5- member aromatic heterocycle of formula (Q6)

Wherein:

Q is the 5- member aromatic heterocycle of formula (Q7)

Wherein:

U¹ – U⁴Independently selected from N and C-Z²³, wherein U¹ – U⁴In to be no more than three be N, and wherein

Wherein when Y is O, S or N-R⁸When, R⁴、R⁵、R⁶And R⁷No one of be-OH, and wherein when X is O, S or N-R⁸When, R⁶And R⁷No one of be-OH,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

According to the third embodiment of first aspect, the present invention covers the compound of above-mentioned logical formula (I), in which:

A is A1 or A2,

O is 0,1,2,3 or 4,

X, Y is independently selected from CR⁶R⁷, O, S and N-R⁸, wherein at least one of X and Y are CR⁶R⁷, or

X, Y is formed together ring members selected from the group below :-C (O)-O- ,-C (O)-NR⁸-、-S(O)-NR⁸-、-SO₂-NR⁸And- SO₂- O-,

G is S, O, N-R⁸

R²It is selected from

Hydrogen, halogen, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、-C(O)-NH(C₃-C₆Naphthenic base) ,-C (O)-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base)；

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen ,-OH ,- NO₂, cyano, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄- Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Monocycle or bicyclic heterocycles, selected from 4- to 10- membered heterocycloalkyl, miscellaneous spiro cycloalkyl group, 5- unit's heteroaryl and 6- unit's heteroaryl, Each is optionally replaced by 1,2,3 or 4 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, Oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N (C₁- C₄Alkyl)₂、C₁-C₄Alkyl, C₁-C₄Alkyl-C (O)-, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄- Alkoxy, hydroxyl-C₁-C₄Alkyl, C₁-C₄Alkoxy -C₁-C₄Alkyl-, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Oxygroup, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁- C₄Alkyl) (C₃-C₆Naphthenic base) ,-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl and 4- to 10- membered heterocycloalkyl,

R⁴Selected from hydrogen ,-OH, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁵Selected from hydrogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁶Selected from hydrogen ,-OH, fluorine, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁷Selected from hydrogen ,-OH, fluorine, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁸Selected from hydrogen, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and C₁-C₄Alkoxy,

R⁹And R¹⁰Independently selected from

Hydrogen ,-OH ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(-C(O)-C₁-C₄Alkyl), C₁-C₄Alcoxyl Base；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、-NH-C(O)-C₁-C₄Alkyl ,-N (C₁-C₄Alkyl)-(- C (O)-C₁- C₄Alkyl), C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy has 1 to 5 The C of halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S- C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Alkyl halide Base ,-S (O)-C with 1 to 5 halogen atom₁-C₄The halogenated alkyl ,-SO with 1 to 5 halogen atom₂-C₁-C₄It is halogenated Alkyl and (C₁-C₄Alkoxy)₂P(=O)-；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, Nitro ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl Base-C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄- Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl；

R¹¹It is selected from

-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, Nitro ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl Base-C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄- Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl is optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 To-S (O)-C of 5 halogen atoms₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

R¹²It is selected from

Hydrogen；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 halogen - the S-C of plain atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of halogen atom₂-C₁-C₄Halogenated alkyl；

Heterocycle-C₁-C₄Alkyl, wherein the heterocyclyl substituent be selected from 4- to 10- membered heterocycloalkyl, 5- unit's heteroaryl and 6- unit's heteroaryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, Nitro ,-OH, oxo, thio ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl Base-C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄- Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl has 1 to 5 - the S-C of halogen atom₁-C₄Halogenated alkyl ,-S (O)-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to 5 - the SO of a halogen atom₂-C₁-C₄Halogenated alkyl；

Phenyl is optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,-OH, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, with 1 to 5 halogen atom C₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkane Base ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl has 1 To-S (O)-C of 5 halogen atoms₁-C₄Halogenated alkyl and-SO with 1 to 5 halogen atom₂-C₁-C₄Halogenated alkyl；With

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z³、Z⁴And Z⁵Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄It is halogenated Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkoxy -C (O)-, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, or

Z¹、Z⁴And Z⁵Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄It is halogenated Alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, or

Q is the pyridine ring of formula (Q2)

Wherein:

Z⁶、Z⁷、Z⁸And Z⁹Independently selected from hydrogen halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogen Substituted alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy ,-NH (C₁-C₄Alkyl) ,-N (C₁- C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base), or

Q is the pyrimidine ring of formula (Q3)

Wherein:

Q is the pyridine ring of formula (Q4)

Wherein:

Z¹³、Z¹⁴、Z¹⁵And Z¹⁶Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁- C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₁-C₄Hydroxy alkyl, NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Cycloalkanes Base) ,-NH-CO-C₁-C₄Alkyl and monocyclic heterocycles, the monocyclic heterocycles are selected from 4- to 7- membered heterocycloalkyl or have at least one Heteroaryl ring is connected through to the 5- unit's heteroaryl of the nitrogen-atoms of pyridine ring, and each is optionally by 1,2 or 3 substituent group Replace, the substituent group is independently selected from halogen, cyano, nitro ,-OH, oxo, thio, C₁-C₄Alkyl has 1 to 5 halogen The C of plain atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆- Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S-C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂- C₁-C₄Alkyl, the-S- (C with 1 to 5 halogen atom₁-C₄Halogenated alkyl) ,-S (O)-with 1 to 5 halogen atom (C₁-C₄Halogenated alkyl) ,-SO with 1 to 5 halogen atom₂-(C₁-C₄Halogenated alkyl), or

Q is the pyridine ring of formula (Q5)

Wherein:

Q is the 5- member aromatic heterocycle of formula (Q6)

Wherein:

T¹ – T⁴Independently selected from N, O, S, C-Z²¹And N-Z²², wherein T¹ – T⁴In be no more than one be O, T¹ – T⁴ In be no more than one be S, T¹ – T⁴In be no more than one be N-Z²², and wherein

Each Z²¹Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base, C₁-C₄Alkoxy and

Q is the 5- member aromatic heterocycle of formula (Q7)

Wherein:

U¹ – U⁴Independently selected from N and C-Z²³, wherein U¹ – U⁴In to be no more than three be N, and wherein

Each Z²³Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base, C₁-C₄Alkoxy,

Wherein when Y is O, S or N-R⁸When, R⁴It is not-OH,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

According to the 4th embodiment of first aspect, the present invention covers the compound of above-mentioned logical formula (I), in which:

A is A1 or A2,

O is 0,1 or 2,

R is selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy, cyano, the C with 1 to 5 halogen atom₁-C₄It is halogenated Alkyl,

X, Y is independently selected from CR⁶R⁷, O, S and N-R⁸, wherein at least one of X and Y are CR⁶R⁷,

G is S, O, N-R⁸

R²It is selected from

Hydrogen, halogen, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N(C₁-C₄Alkyl)₂、-C(O)-NH(C₃-C₆Naphthenic base) ,-C (O)-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base)；

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

Monocycle or bicyclic heterocycles, selected from 4- to 10- membered heterocycloalkyl, miscellaneous spiro cycloalkyl group, 5- unit's heteroaryl and 6- unit's heteroaryl, Each is optionally replaced by 1,2,3 or 4 substituent group, the substituent group independently selected from halogen, cyano ,-OH, oxo ,- COOH、C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH(C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、C₁- C₄Alkyl, C₁-C₄Alkyl-C (O)-, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, hydroxyl- C₁-C₄Alkyl, C₁-C₄Alkoxy -C₁-C₄Alkyl-, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆- Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃- C₆Naphthenic base) and 4- to 10- membered heterocycloalkyl,

R⁴Selected from hydrogen ,-OH, C₁-C₄Alkyl and C₁-C₄Alkoxy,

R⁵It is hydrogen,

R⁶Selected from hydrogen and C₁-C₄Alkyl,

R⁷Selected from hydrogen and C₁-C₄Alkyl,

R⁸Selected from hydrogen and C₁-C₄Alkyl,

R⁹And R¹⁰Independently selected from

Hydrogen ,-NH (- C (O)-C₁-C₄Alkyl), C₁-C₄Alkoxy；

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano ,-COOH, C₁-C₄Alkoxy -C (O)-,-C (O)-NH₂、-C(O)-NH (C₁-C₄Alkyl) ,-C (O)-N (C₁-C₄Alkyl)₂、-NH-C(O)-C₁-C₄Alkyl ,-N (C₁-C₄Alkyl)-(- C (O)-C₁- C₄Alkyl), C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy has 1 to 5 The C of halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S- C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄The alkyl ,-S-C with 1 to 5 halogen atom₁-C₄Alkyl halide Base ,-S (O)-C with 1 to 5 halogen atom₁-C₄The halogenated alkyl ,-SO with 1 to 5 halogen atom₂-C₁-C₄It is halogenated Alkyl and (C₁-C₄Alkoxy)₂P(=O)-；

R¹¹It is selected from

C₁-C₄Alkyl, C₃-C₆Naphthenic base, phenyl-C₁-C₄Alkyl, each are optionally replaced by 1,2 or 3 substituent group, The substituent group is independently selected from halogen ,-OH, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base, C₁-C₄Alkoxy, the C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base；With

R¹²It is selected from

Hydrogen；

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Wherein when Y is O, S or N-R⁸When, R⁴It is not-OH,

Or its stereoisomer, tautomer, N- oxide, hydrate, solvate or salt or their mixture.

According to the 5th embodiment of first aspect, the present invention covers the compound of above-mentioned logical formula (I), in which:

A is A1 or A2,

O is 0 or 1,

R is selected from halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

X is selected from CR⁶R⁷, O, S and N-R⁸,

Y is CR⁶R⁷,

G is S, O, N-R⁸

R¹It is hydrogen or C₁-C₄Alkyl,

R²It is selected from

Hydrogen, halogen,

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

R³Selected from hydrogen, halogen ,-OH, cyano, C₁-C₄Alkyl, C₃-C₆Naphthenic base, the C with 1 to 5 halogen atom₁-C₄- Halogenated alkyl, C₁-C₄Alkoxy -C₁-C₄Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkyl-C (O)-,-NH₂、-NH(C₁-C₄Alkane Base) ,-N (C₁-C₄Alkyl)₂、-NH(C₃-C₆Naphthenic base) ,-N (C₁-C₄Alkyl) (C₃-C₆Naphthenic base)-S-C₁-C₄Alkyl ,- S(O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl,

R⁴Selected from hydrogen ,-OH and C₁-C₄Alkyl,

R⁵It is hydrogen,

R⁶Selected from hydrogen and C₁-C₄Alkyl,

R⁷Selected from hydrogen and C₁-C₄Alkyl,

R⁸Selected from hydrogen and C₁-C₄Alkyl,

R⁹And R¹⁰Independently selected from

Hydrogen ,-NH (- C (O)-C₁-C₄Alkyl), C₁-C₄Alkoxy；

R¹¹It is selected from

4- to 10- membered heterocycloalkyl,

R¹²It is selected from

Hydrogen；

C₁-C₄Alkyl is optionally replaced by 1,2 or 3 substituent group, and the substituent group is independently selected from-OH and-COOH；With

6- unit's heteroaryl,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z³Selected from hydrogen, halogen, C₁-C₄Alkyl, C₁-C₄Alkoxy ,-NH (C₁-C₄Alkyl) and-N (C₁-C₄Alkyl)₂,

Z⁴Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z⁵Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Or its stereoisomer, tautomer, N- oxide, hydrate, solvate or salt or their mixture.

Another aspect of the present invention covers the compound of above-mentioned logical formula (I), wherein G, A, R¹、R²And R³On such as any State meaning defined in embodiment and

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z³Selected from hydrogen, halogen, C₁-C₄Alkyl, C₁-C₄Alkoxy ,-NH (C₁-C₄Alkyl) and-N (C₁-C₄Alkyl)₂,

Z⁴Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z⁵Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Q is the pyridine ring of formula (Q4)

Wherein:

Z¹³、Z¹⁴、Z¹⁵And Z¹⁶Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, C₁-C₄Alkoxy, C₁-C₄Hydroxyl alkane Base, NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-NH-CO-C₁-C₄Alkyl and monocyclic heterocycles, the monocyclic heterocycles It is miscellaneous that the 5- member to the nitrogen-atoms of pyridine ring is connected through selected from 4- to 7- membered heterocycloalkyl or at least one heteroaryl ring Aryl, each are optionally replaced by 1,2 or 3 substituent group, the substituent group independently selected from halogen, cyano, nitro ,- OH, oxo, thio, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, have 1 to The C of 5 halogen atoms₁-C₄Halogenated alkoxy, C₃-C₆Naphthenic base ,-NH₂、-NH(C₁-C₄Alkyl) ,-N (C₁-C₄Alkyl)₂、-S- C₁-C₄Alkyl ,-S (O)-C₁-C₄Alkyl ,-SO₂-C₁-C₄Alkyl, the-S- (C with 1 to 5 halogen atom₁-C₄Alkyl halide Base) ,-S (O)-(C with 1 to 5 halogen atom₁-C₄Halogenated alkyl) ,-SO with 1 to 5 halogen atom₂-(C₁-C₄- Halogenated alkyl), or

Q is the pyridine ring of formula (Q5)

Wherein:

Z¹⁷、Z¹⁸And Z¹⁹It is hydrogen, and

Z²⁰It is halogen, or

Q is the 5- member aromatic heterocycle of formula (Q6)

Wherein:

Each Z²¹Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base, C₁-C₄Alkoxy and

Q is the 5- member aromatic heterocycle of formula (Q7)

Wherein:

U¹ – U⁴Independently selected from N and C-Z²³, wherein U¹ – U⁴In to be no more than three be N, and wherein

Each Z²³Independently selected from hydrogen, halogen, cyano, C₁-C₄Alkyl, the C with 1 to 5 halogen atom₁-C₄Alkyl halide Base, C₁-C₄Alkoxy,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

According to the 6th embodiment of first aspect, the present invention covers the compound of above-mentioned logical formula (I), in which:

A is selected from

G is S, O, N-R⁸

R¹It is hydrogen or methyl,

R²It is selected from

Hydrogen, chlorine, fluorine,

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

R³Selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxyl group and trifluoromethyl,

R⁸Selected from hydrogen and methyl,

R⁹And R¹⁰Independently selected from

Hydrogen ,-NH (- C (O)-methyl), methoxyl group；

Phenyl；

2,3- dihydro -1H- indenes, and

R¹¹It is selected from

Monocycle or bicyclic heterocycles are selected from pyrrolidines and oxinane,

R¹²It is selected from

Methyl and ethyl, each are optionally replaced by 1 substituent group independently selected from-OH and-COOH；With

Pyridine,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z³Selected from hydrogen, halogen, C₁-C₄Alkyl, C₁-C₄Alkoxy ,-NH (C₁-C₄Alkyl) and-N (C₁-C₄Alkyl)₂,

Z⁴Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z⁵Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

According to the 7th embodiment of first aspect, the present invention covers the compound of above-mentioned logical formula (I), in which:

G、A、R¹、R²And R³With meaning defined in the 6th embodiment such as above-mentioned first aspect, and wherein

Q is the pyridine ring of formula (Q4)

Wherein:

Z¹³、Z¹⁴、Z¹⁵And Z¹⁶Independently selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxyl group, ethyoxyl, isopropoxy, hydroxyl first Base, NH₂、-NHMe -NMe₂,-NH-C (O)-Me, morpholinyl, or

Q is the pyridine ring of formula (Q5)

Wherein:

Z¹⁷、Z¹⁸And Z¹⁹It is hydrogen, and

Z²⁰It is fluorine, chlorine, or

Q is selected from

Wherein:

Each Z²¹Independently selected from hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxyl group and

Z²²It is hydrogen, methyl, or

Q is selected from

Wherein:

Each Z²³Independently selected from hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxyl group, or

Q is selected from

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

In an alternative embodiment of the 6th and the 7th embodiment of the first aspect of aforementioned present invention, A It is selected from:

。

In another alternative embodiment of the 6th and the 7th embodiment of the first aspect of aforementioned present invention, A is selected from:

。

According to the 8th embodiment of first aspect, the present invention covers the compound of above-mentioned logical formula (I), in which:

A is selected from

G is S, O, NH or N-CH₃

R¹It is hydrogen or methyl,

R²It is selected from

Hydrogen, chlorine, fluorine,

-NH₂、-NH(CH₃)、-N(CH₃)₂,

Methoxyl group, ethyoxyl,

Methyl, ethyl, propyl, isopropyl, cyclopropyl,

Trifluoromethyl and trifluoromethoxy,

R³Selected from hydrogen, chlorine, fluorine, methyl, methoxyl group and trifluoromethyl,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, fluorine, chlorine, methyl and methoxyl group,

Z²Selected from hydrogen, fluorine, chlorine ,-OH, methyl, ethyl, methoxyl group, ethyoxyl ,-NH (CH₃)、-N(CH₃)₂, trifluoromethyl, three Fluorine methoxyl group,

Z³Selected from hydrogen, fluorine, chlorine, methyl, methoxyl group ,-NH (CH₃) and-N (CH₃)₂,

Z⁴Selected from hydrogen, fluorine, chlorine, methyl and methoxyl group,

Z⁵Selected from hydrogen, fluorine, chloromethyl and methoxyl group,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

According to the 9th embodiment of first aspect, the present invention covers the compound of above-mentioned logical formula (I), in which:

G is S, forms the compound of logical formula (II)

Wherein

A is selected from

R¹It is hydrogen or methyl,

R²It is selected from

Hydrogen, chlorine, fluorine,

Methoxyl group,

Methyl, ethyl, propyl, isopropyl,

Trifluoromethyl and trifluoromethoxy,

R³Selected from hydrogen, chlorine, fluorine, methyl, methoxyl group and trifluoromethyl,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z³Selected from hydrogen, halogen, C₁-C₄Alkyl, C₁-C₄Alkoxy ,-NH (C₁-C₄Alkyl) and-N (C₁-C₄Alkyl)₂,

Z⁴Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z⁵Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

According to the tenth embodiment of first aspect, the present invention covers the compound of above-mentioned logical formula (II), in which:

A is selected from

R¹It is hydrogen or methyl,

R²It is selected from

Hydrogen, chlorine, fluorine,

Methoxyl group,

Methyl, ethyl, propyl, isopropyl,

Trifluoromethyl and trifluoromethoxy,

R³Selected from hydrogen, chlorine, fluorine, methyl, methoxyl group and trifluoromethyl,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen and halogen,

Z²Selected from hydrogen, halogen ,-N (C₁-C₄Alkyl)₂,-C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and have 1 to The C of 5 halogen atoms₁-C₄Halogenated alkoxy,

Z³Selected from hydrogen and halogen,

Z⁴Selected from hydrogen and halogen,

Z⁵Selected from hydrogen and halogen,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

In an alternative embodiment of the 9th and the tenth embodiment of the first aspect of aforementioned present invention,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z³Selected from hydrogen, halogen, C₁-C₄Alkyl, C₁-C₄Alkoxy ,-NH (C₁-C₄Alkyl) and-N (C₁-C₄Alkyl)₂,

Z⁴Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z⁵Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy.

According to the 11st embodiment of first aspect, the present invention covers the compound of above-mentioned logical formula (II), in which:

A is selected from

R¹It is hydrogen,

R²It is isopropyl,

R³It is methyl,

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹、Z³、Z⁴And Z⁵Independently selected from hydrogen, fluorine and chlorine, and

Z²Selected from hydrogen, fluorine, chlorine ,-N (CH₃)₂, trifluoromethyl and trifluoromethoxy,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

Other embodiments of the first aspect of the present invention:

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

A is selected from

R¹It is hydrogen or methyl,

R²It is selected from

Hydrogen, chlorine, fluorine,

-NH₂、-NH(CH₃)、-N(CH₃)₂,

Methoxyl group, ethyoxyl,

Methyl, ethyl, propyl, isopropyl, cyclopropyl,

Trifluoromethyl and trifluoromethoxy,

R³Selected from hydrogen, chlorine, fluorine, methyl, methoxyl group and trifluoromethyl,

Q is selected from phenyl, 2,3,4- trifluorophenyl, 2,3,4- trichlorophenyl, 2,3,5- trichlorophenyl, 2,3,5- trifluorophenyl, 2, 3,6- trifluorophenyl, 2,3,6- trichlorophenyl, 2,3- difluorophenyl, 2,3- dichlorophenyl, 2,4,5- trifluorophenyl, 2,4,5- tri- Chlorphenyl, 2,4,6- trifluorophenyl, 2,4,6- trichlorophenyl, the fluoro- 3- methoxyphenyl of 2,4,6- tri-, the chloro- 3- first of 2,4,6- tri- Phenyl, the fluoro- 3- hydroxy phenyl of 2,4- bis-, the chloro- 3- hydroxy phenyl of 2,4- bis-, the fluoro- 3- methoxyphenyl of 2,4- bis-, 2,4- bis- Chloro- 3- methoxyphenyl, 2,4- bis- fluoro- 3- (dimethylamino) phenyl, 2,4- bis- chloro- 3- (dimethylamino) phenyl, 2,5- Two fluoro- 4- methoxyphenyls, the chloro- 4- methoxyphenyl of 2,5- bis-, 2,6- difluorophenyl, 2,6- dichlorophenyl, the fluoro- 3- chlorobenzene of 2- The chloro- 3- fluorophenyl of base, 2-, 2- fluoro- 3- (dimethylamino) phenyl, 2- chloro- 3- (dimethylamino) phenyl, the chloro- 4- fluorobenzene of 2- The fluoro- 4- chlorphenyl of base, 2-, the chloro- 5- fluorophenyl of 2-, 2- fluoro- 4- (dimethylamino) phenyl, 2- chloro- 4- (dimethylamino) benzene The chloro- 6- fluorophenyl of base, 2-, 2- fluorophenyl, 2- chlorphenyl, 2- fluoro- 3- (trifluoromethoxy) phenyl, 2- chloro- 3- (trifluoro methoxy Base) phenyl, 2- fluoro- 3- (trifluoromethyl) phenyl, 2- chloro- 3- (trifluoromethyl) phenyl, 3- (dimethylamino) phenyl, 3- (first Base amino) phenyl, 3- (trifluoromethoxy) phenyl, 3,4,5- trifluorophenyl, 3,4,5- trichlorophenyl, the fluoro- 5- (diformazan of 3,4- bis- Base amino) phenyl, 3,4- bis- chloro- 5- (dimethylamino) phenyl, 3,4- difluorophenyl, 3,4- dichlorophenyl, the fluoro- 2- of 3,4- bis- Methoxyphenyl, the chloro- 2- methoxyphenyl of 3,4- bis-, 3,5- bis- fluoro- 4- (dimethylamino) phenyl, the chloro- 4- (diformazan of 3,5- bis- Base amino) phenyl, the fluoro- 4- chlorphenyl of 3,5- bis-, the chloro- 4- fluorophenyl of 3,5- bis-, 3,5- difluorophenyl, 3,5- dichlorophenyl, 3, The chloro- 5- aminomethyl phenyl of the fluoro- 2- of 5- 3,5-dimethylphenyl, 3-, the fluoro- 5- aminomethyl phenyl of the chloro- 2- of 3-, 3- chloro-2-methyl phenyl, 3- are fluoro- 4- (dimethylamino) -5- chlorphenyl, 3- fluoro- 4- (dimethylamino) phenyl, 3- chloro- 4- (dimethylamino) phenyl, 3- are chloro- The fluoro- 4- aminomethyl phenyl of 4- fluorophenyl, 3-, the chloro- 4- aminomethyl phenyl of 3-, 3- fluoro- 5- (dimethylamino) phenyl, the chloro- 5- (diformazan of 3- Base amino) phenyl, 3- fluoro- 5- (methylsulfanyl) phenyl, 3- chloro- 5- (methylsulfanyl) phenyl, the fluoro- 5- of 3- (morpholine -4- Base) phenyl, the chloro- 5- of 3- (morpholine -4- base) phenyl, 3- fluoro- 5- (trifluoromethyl) phenyl, 3- chloro- 5- (trifluoromethyl) phenyl, 3- The chloro- 5- ethylphenyl of fluoro- 5- ethylphenyl, 3-, the chloro- 5- fluorophenyl of 3-, the fluoro- 5- methoxyphenyl of 3-, 3- chloro-5-methoxyl benzene The fluoro- 5- aminomethyl phenyl of base, 3-, 3- fluorophenyl, 3- chlorphenyl, the fluoro- 4- methoxyphenyl of 3-, 3- chloro-4-methoxy phenyl, 3- The chloro- 5- aminomethyl phenyl of fluoro- 5- aminomethyl phenyl, 3-, 4- fluoro- 3- (dimethylamino) phenyl, 4- chloro- 3- (dimethylamino) benzene The fluoro- 3- methoxyphenyl of base, 4-, the chloro- 3- methoxyphenyl of 4-, the chloro- 2,4 difluorobenzene base of 5-, the fluoro- 2,4 dichloro benzene base of 5-, 5- The chloro- 3- aminomethyl phenyl of fluoro- 2-, the fluoro- 3- aminomethyl phenyl of the chloro- 2- of 5-, the chloro- 4- aminomethyl phenyl of the fluoro- 2- of 5-, the fluoro- 4- first of the chloro- 2- of 5- The chloro- 2- fluorophenyl of base phenyl, 5-, the chloro- 2- methoxyphenyl of 5- and the fluoro- 2- methoxyphenyl of 5-,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

A is selected from

R¹It is hydrogen or methyl,

R²It is hydrogen or isopropyl,

R³It is hydrogen or methyl,

Q is selected from phenyl, 2,3,4- trifluorophenyl, 2,3,5- trichlorophenyl, 2,3- dichlorophenyl, the fluoro- 3- (dimethyl of 2,4- bis- Amino) phenyl, 2,6- dichlorophenyl, 2- fluoro- 3- (dimethylamino) phenyl, 2- fluoro- 3- (trifluoromethoxy) phenyl, 2- be fluoro- 3- (trifluoromethyl) phenyl, 2- chloro- 3- (trifluoromethyl) phenyl, 3,4- difluorophenyl, 3,4- dichlorophenyl, the chloro- 4- of 3,5- bis- Fluorophenyl, 3,5- dichlorophenyl,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers the compound of above-mentioned logical formula (I) in other embodiments, and wherein G is S and its alloisomerism Body, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

A is selected from

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

A is selected from

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

A is selected from

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

R¹It is hydrogen or C₁-C₄Alkyl, such as preferred methyl,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

R²It is selected from

Hydrogen, halogen,

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

R²It is selected from

Hydrogen, chlorine, fluorine,

–NR⁹R¹⁰；

–OR¹¹；

-SR¹²、-S(O)R¹²、-SO₂R¹²；

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

R²It is selected from

Hydrogen, halogen,

–NR⁹R¹⁰,

C₁-C₄Alkoxy,

C₁-C₄Alkyl,

C with 1 to 5 halogen atom₁-C₄Halogenated alkyl and

C with 1 to 5 halogen atom₁-C₄Halogenated alkoxy,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

R²It is selected from

Hydrogen, chlorine, fluorine,

-NH₂、-NH(CH₃)、-N(CH₃)₂,

Methoxyl group, ethyoxyl,

Methyl, ethyl, propyl, isopropyl, cyclopropyl,

Trifluoromethyl and trifluoromethoxy,

Wherein R²It is preferably selected from hydrogen and isopropyl,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

R³Selected from hydrogen, chlorine, fluorine, methyl, methoxyl group and trifluoromethyl,

Wherein R³It is preferably selected from hydrogen and methyl,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z³Selected from hydrogen, halogen, C₁-C₄Alkyl, C₁-C₄Alkoxy ,-NH (C₁-C₄Alkyl) and-N (C₁-C₄Alkyl)₂,

Z⁴Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

Z⁵Selected from hydrogen, halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, fluorine, chlorine, methyl and methoxyl group,

Z²Selected from hydrogen, fluorine, chlorine ,-OH, methyl, ethyl, methoxyl group, ethyoxyl ,-NH (CH₃)、-N(CH₃)₂, trifluoromethyl, three Fluorine methoxyl group,

Z³Selected from hydrogen, fluorine, chlorine, methyl, methoxyl group ,-NH (CH₃) and-N (CH₃)₂,

Z⁴Selected from hydrogen, fluorine, chlorine, methyl and methoxyl group,

Z⁵Selected from hydrogen, fluorine, chloromethyl and methoxyl group,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹Selected from hydrogen, fluorine and chlorine,

Z²Selected from hydrogen, fluorine, chlorine ,-N (CH₃)₂, trifluoromethyl and trifluoromethoxy,

Z³Selected from hydrogen, fluorine and chlorine,

Z⁴Selected from hydrogen, fluorine and chlorine,

Z⁵Selected from hydrogen, fluorine and chlorine,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

Q is the substituted benzyl ring of formula (Q1)

Wherein:

Z¹、Z³、Z⁴And Z⁵Independently selected from hydrogen, fluorine and chlorine, and

Z²Selected from hydrogen, fluorine, chlorine ,-N (CH₃)₂, trifluoromethyl and trifluoromethoxy,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

Q is selected from phenyl, 2,3,4- trifluorophenyl, 2,3,4- trichlorophenyl, 2,3,5- trichlorophenyl, 2,3,5- trifluorophenyl, 2, 3,6- trifluorophenyl, 2,3,6- trichlorophenyl, 2,3- difluorophenyl, 2,3- dichlorophenyl, 2,4,5- trifluorophenyl, 2,4,5- tri- Chlorphenyl, 2,4,6- trifluorophenyl, 2,4,6- trichlorophenyl, the fluoro- 3- methoxyphenyl of 2,4,6- tri-, the chloro- 3- first of 2,4,6- tri- Phenyl, the fluoro- 3- hydroxy phenyl of 2,4- bis-, the chloro- 3- hydroxy phenyl of 2,4- bis-, the fluoro- 3- methoxyphenyl of 2,4- bis-, 2,4- bis- Chloro- 3- methoxyphenyl, 2,4- bis- fluoro- 3- (dimethylamino) phenyl, 2,4- bis- chloro- 3- (dimethylamino) phenyl, 2,5- Two fluoro- 4- methoxyphenyls, the chloro- 4- methoxyphenyl of 2,5- bis-, 2,6- difluorophenyl, 2,6- dichlorophenyl, the fluoro- 3- chlorobenzene of 2- The chloro- 3- fluorophenyl of base, 2-, 2- fluoro- 3- (dimethylamino) phenyl, 2- chloro- 3- (dimethylamino) phenyl, the chloro- 4- fluorobenzene of 2- The fluoro- 4- chlorphenyl of base, 2-, the chloro- 5- fluorophenyl of 2-, 2- fluoro- 4- (dimethylamino) phenyl, 2- chloro- 4- (dimethylamino) benzene The chloro- 6- fluorophenyl of base, 2-, 2- fluorophenyl, 2- chlorphenyl, 2- fluoro- 3- (trifluoromethoxy) phenyl, 2- chloro- 3- (trifluoro methoxy Base) phenyl, 2- fluoro- 3- (trifluoromethyl) phenyl, 2- chloro- 3- (trifluoromethyl) phenyl, 3- (dimethylamino) phenyl, 3- (first Base amino) phenyl, 3- (trifluoromethoxy) phenyl, 3,4,5- trifluorophenyl, 3,4,5- trichlorophenyl, the fluoro- 5- (diformazan of 3,4- bis- Base amino) phenyl, 3,4- bis- chloro- 5- (dimethylamino) phenyl, 3,4- difluorophenyl, 3,4- dichlorophenyl, the fluoro- 2- of 3,4- bis- Methoxyphenyl, the chloro- 2- methoxyphenyl of 3,4- bis-, 3,5- bis- fluoro- 4- (dimethylamino) phenyl, the chloro- 4- (diformazan of 3,5- bis- Base amino) phenyl, the fluoro- 4- chlorphenyl of 3,5- bis-, the chloro- 4- fluorophenyl of 3,5- bis-, 3,5- difluorophenyl, 3,5- dichlorophenyl, 3, The chloro- 5- aminomethyl phenyl of the fluoro- 2- of 5- 3,5-dimethylphenyl, 3-, the fluoro- 5- aminomethyl phenyl of the chloro- 2- of 3-, 3- chloro-2-methyl phenyl, 3- are fluoro- 4- (dimethylamino) -5- chlorphenyl, 3- fluoro- 4- (dimethylamino) phenyl, 3- chloro- 4- (dimethylamino) phenyl, 3- are chloro- The fluoro- 4- aminomethyl phenyl of 4- fluorophenyl, 3-, the chloro- 4- aminomethyl phenyl of 3-, 3- fluoro- 5- (dimethylamino) phenyl, the chloro- 5- (diformazan of 3- Base amino) phenyl, 3- fluoro- 5- (methylsulfanyl) phenyl, 3- chloro- 5- (methylsulfanyl) phenyl, the fluoro- 5- of 3- (morpholine -4- Base) phenyl, the chloro- 5- of 3- (morpholine -4- base) phenyl, 3- fluoro- 5- (trifluoromethyl) phenyl, 3- chloro- 5- (trifluoromethyl) phenyl, 3- The chloro- 5- ethylphenyl of fluoro- 5- ethylphenyl, 3-, the chloro- 5- fluorophenyl of 3-, the fluoro- 5- methoxyphenyl of 3-, 3- chloro-5-methoxyl benzene The fluoro- 5- aminomethyl phenyl of base, 3-, 3- fluorophenyl, 3- chlorphenyl, the fluoro- 4- methoxyphenyl of 3-, 3- chloro-4-methoxy phenyl, 3- The chloro- 5- aminomethyl phenyl of fluoro- 5- aminomethyl phenyl, 3-, 4- fluoro- 3- (dimethylamino) phenyl, 4- chloro- 3- (dimethylamino) benzene The fluoro- 3- methoxyphenyl of base, 4-, the chloro- 3- methoxyphenyl of 4-, the chloro- 2,4 difluorobenzene base of 5-, the fluoro- 2,4 dichloro benzene base of 5-, 5- The chloro- 3- aminomethyl phenyl of fluoro- 2-, the fluoro- 3- aminomethyl phenyl of the chloro- 2- of 5-, the chloro- 4- aminomethyl phenyl of the fluoro- 2- of 5-, the fluoro- 4- methyl of the chloro- 2- of 5- The chloro- 2- fluorophenyl of phenyl, 5-, the chloro- 2- methoxyphenyl of 5- and the fluoro- 2- methoxyphenyl of 5-,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

The present invention covers above-mentioned logical formula (I) or the compound of (II) in other embodiments, wherein

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

In other embodiments of first aspect, the present invention covers the compound of above-mentioned formula (I), in which:

A is A1 or A2,

O is 0,1 or 2,

R is selected from hydrogen halogen, C₁-C₄Alkyl and C₁-C₄Alkoxy,

G is S, O, NH or N-CH₃

X, Y is independently selected from CR⁶R⁷And O, wherein at least one of X and Y are CR⁶R⁷,

R⁴Selected from hydrogen ,-OH, C₁-C₄Alkyl and C₁-C₄Alkoxy and

R⁵It is hydrogen,

R⁶Selected from hydrogen and C₁-C₄Alkyl,

R⁷Selected from hydrogen and C₁-C₄Alkyl,

Wherein when Y is O, R⁴It is not-OH,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

In other embodiments of first aspect, the present invention covers the compound of above-mentioned formula (I), wherein

A is A3 or A4

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

In a special other embodiments of first aspect, the present invention covers in title " first party of the invention The combination of two or more embodiments being mentioned above under other embodiments in face ".

The present invention covers appointing in above-mentioned logical formula (I) and any embodiment or aspect of the invention of the compound of (II) Meaning sub-portfolio.

The present invention covers the compound for leading to formula (I) and (II) disclosed in the embodiment part of following texts.

The compound of logical formula (I) according to the present invention and (II) can be according to such as in experimental sections (one of the invention As program) shown in scheme 1 prepare.The scheme and process description are illustrated to the change of logical formula (I) He (II) of the invention The synthetic route of object is closed, and is not intended to limit.It is clear that, turn as illustrated in scheme 1 to those skilled in the art The sequence of change can be modified in many ways.Therefore the sequence of the conversion illustrated in these schemes is not intended to limit.In addition, Any substituent group Q, A, R¹、R²Or R³Mutual inversion of phases can be realized before or after the conversion of illustration.These modifications can To be such as introducing protecting group, cracking protecting group, reduction or oxygenated functional group, halogenation, metallization, substitution, or to this field Other known reactions for technical staff.These conversions include introducing the functionality for allowing the further mutual inversion of phases of substituent group Those of.Suitable protecting group and their introducing and cracking are well known to those skilled in the art (see, for example, T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, the 3rd edition, Wiley 1999). Specific example describes in following paragraphs.

Hereinafter, several routes for being used to prepare the compound of logical formula (I) are described in scheme 1.

According to second aspect, the present invention covers the method that formula (I) and the compound of (II) are led in preparation as defined above, institute The method of stating includes the following steps: the midbody compound for making general formula 1N:

Wherein G, A, R¹、R³The compound of logical formula (I) as defined above and (II) are defined with Q,

It is reacted with the compound of general formula 1F:

Wherein R²Selected from-NR⁹R¹⁰、–OR¹¹With-SR¹², wherein R⁹、R¹⁰、R¹¹And R¹²Logical formula (I) and (II) as defined above Compound is defined,

Thus the compound of logical formula (I) is obtained, or leads to the compound of formula (II) if G is S:

Wherein G, A, R¹、R²、R³It is as defined above with Q.

According to second aspect alternative embodiment, the present invention covers preparation logical formula (I) as defined above The method of the compound of (II), the method includes the following steps: make the midbody compound of general formula 1T:

Wherein G, A, R¹、R²And R³The compound of logical formula (I) and (II) as defined above is defined, and wherein Hal is halogen Element, especially chlorine, bromine or iodine,

It is reacted with the compound of general formula 1H:

Wherein the compound of logical formula (I) Q as defined above and (II) are defined, and each R can be respectively H or Me or two A R is pinacol ester,

Thus the compound of logical formula (I) is obtained, or leads to the compound of formula (II) if G is S:

Wherein G, A, R¹、R²、R³It is as defined above with Q.

Wherein G, Q, R²And R³The compound of logical formula (I) and (II) as defined above is defined,

It is reacted with the compound of general formula 1M:

Wherein R¹The compound of logical formula (I) as defined above and (II) are defined with A,

Thus the compound of logical formula (I) is obtained, or leads to the compound of formula (II) if G is S:

Wherein G, A, R¹、R²、R³It is as defined above with Q.

Wherein G, Q, A, R¹And R³The compound of logical formula (I) and (II) as defined above is defined,

It is reacted with the compound of general formula 1Y:

Wherein R²It is C¹-C⁴Alkoxy is optionally taken defined in the compound of logical formula (I) and (II) as defined above Generation,

Thus the compound of logical formula (I) is obtained, or leads to the compound of formula (II) if G is S:

Wherein G, A, R¹、R³The as defined above and R with Q²It is optionally substituted C as defined above¹-C⁴Alkoxy.

Wherein G, Q, A, R¹And R³The compound of logical formula (I) and (II) as defined above is defined,

It is reacted with the compound of general formula 2A:

Wherein R²It is C₁-C₄Alkyl, C₃-C₆Naphthenic base, C₂-C₄Alkenyl, C₃-C₆Cycloalkenyl, C₂-C₄Alkynyl or phenyl-C₁- C₄Alkyl, each are optionally substituted, Met defined in the compound of logical formula (I) and (II) as defined above It is magnesium or zinc, and X is chlorine, bromine or iodine,

Thus the compound of logical formula (I) is obtained, or leads to the compound of formula (II) if G is S:

Wherein G, A, R¹、R³The as defined above and R with Q²It is C₁-C₄Alkyl, C₃-C₆Naphthenic base, C₂-C₄Alkenyl, C₃-C₆- Cycloalkenyl, C₂-C₄Alkynyl or phenyl-C₁-C₄Alkyl, each are as defined above optionally substituted.

According to the third aspect, the present invention covers the method that formula (I) and the compound of (II) are led in preparation as defined above, institute The method of stating includes the following steps: the midbody compound for making general formula 1N:

Wherein G, Q, A, R¹And R³The compound of logical formula (I) and (II) as defined above is defined,

It is reacted with the compound of general formula 1F:

Wherein R²Selected from-NR⁹R¹⁰、–OR¹¹With-SR¹², wherein R⁹、R¹⁰、R¹¹And R¹²Logical formula (I) and (II) as defined above Compound is defined,

Thus the compound of logical formula (I) is obtained, or leads to the compound of formula (II) if G is S:

Wherein G, A, R¹、R²、R³It is as defined above with Q,

Then, corresponding (i) solvent and/or (ii) alkali or acid are optionally employed and converts solvate, salt for the compound And/or the solvate of such salt.

According to the third aspect alternative embodiment, the present invention covers preparation logical formula (I) as defined above The method of the compound of (II), the method includes the following steps: make the midbody compound of general formula 1T:

Wherein G, A, R¹、R²And R³The compound of logical formula (I) and (II) as defined above is defined, and wherein Hal is halogen Element, especially chlorine, bromine or iodine,

It is reacted with the compound of general formula 1H:

Wherein the compound of logical formula (I) Q as defined above is defined, and can be respectively H or Me or two R equal by each R For pinacol ester,

Thus the compound of logical formula (I) is obtained, or leads to the compound of formula (II) if G is S:

Wherein G, A, R¹、R²、R³It is as defined above with Q,

Then, corresponding (i) solvent and/or (ii) alkali or acid are optionally employed and converts solvate, salt for the compound And/or the solvate of such salt.

Wherein G, Q, R²And R³The compound of logical formula (I) and (II) as defined above is defined,

It is reacted with the compound of general formula 1M:

Wherein R¹The compound of logical formula (I) as defined above and (II) are defined with A,

Thus the compound of logical formula (I) is obtained, or leads to the compound of formula (II) if G is S:

Wherein G, A, R¹、R²、R³It is as defined above with Q,

Then, corresponding (i) solvent and/or (ii) alkali or acid are optionally employed and converts solvate, salt for the compound And/or the solvate of such salt.

Wherein G, Q, A, R¹And R³The compound of logical formula (I) and (II) as defined above is defined,

It is reacted with the compound of general formula 1Y:

Wherein R²It is C₁-C₄Alkoxy is optionally taken defined in the compound of logical formula (I) and (II) as defined above Generation,

Thus the compound of logical formula (I) is obtained, or leads to the compound of formula (II) if G is S:

Wherein G, A, R¹、R³The as defined above and R with Q²It is optionally substituted C as defined above₁-C₄Alkoxy,

Then, corresponding (i) solvent and/or (ii) alkali or acid are optionally employed and converts solvate, salt for the compound And/or the solvate of such salt.

Wherein G, Q, A, R¹And R³The compound of logical formula (I) and (II) as defined above is defined,

It is reacted with the compound of general formula 2A:

Thus the compound of logical formula (I) is obtained, or leads to the compound of formula (II) if G is S:

Wherein G, A, R¹、R³The as defined above and R with Q²It is C₁-C₄Alkyl, C₃-C₆Naphthenic base, C₂-C₄Alkenyl, C₃-C₆- Cycloalkenyl, C₂-C₄Alkynyl or phenyl-C₁-C₄Alkyl, each be it is as defined above optionally substituted,

Then, corresponding (i) solvent and/or (ii) alkali or acid are optionally employed and converts solvate, salt for the compound And/or the solvate of such salt.

The present invention covers the method for preparing the compound of logical formula (I) and (II) of the invention, and the method includes such as at this Step described in experimental section in text.

According to fourth aspect, the present invention covers the intermediate that can be used for preparing the compound of above-mentioned logical formula (I) and (II) Close object.

Particularly, the present invention covers the midbody compound of general formula (I-INT):

Wherein the compound of for example above-mentioned general formula (I) of G and (II) are defined,

Or as G=S general formula (II-INT) midbody compound:

Wherein in above-mentioned formula (I-INT) and (II-INT)

R²Selected from C₁-C₆Alkyl and C₃-C₆Naphthenic base or as the compound of above-mentioned general formula (I) and (II) defines,

R³Selected from hydrogen, halogen, C₁-C₄Alkyl and C₃-C₆Naphthenic base or as the compound of above-mentioned general formula (I) and (II) defines,

The compound of for example above-mentioned general formula (I) of Q and (II) are defined, and

R^AIt is H or C₁-C₄Alkyl,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

Particularly, the present invention is also covered by the midbody compound of above-mentioned general formula (II-INT), wherein

Q is hydrogen or halogen, and

R²Selected from C₁-C₆Alkyl and C₃-C₆Naphthenic base or as the compound of above-mentioned general formula (I) and (II) defines,

R³Selected from hydrogen, halogen, C₁-C₄Alkyl and C₃-C₆Naphthenic base or as the compound of above-mentioned general formula (I) and (II) defines, With

R^AIt is H or C₁-C₄Alkyl；

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

Particularly, the present invention is also covered by the midbody compound of general formula (III-INT):

Wherein the compound of for example above-mentioned general formula (I) of G and (II) are defined,

Or as G=S general formula (IV-INT) midbody compound:

Wherein

Hal is halogen as defined above, and

R²Selected from C₁-C₆Alkyl and C₃-C₆Naphthenic base or as the compound of above-mentioned general formula (I) and (II) defines,

R³Selected from hydrogen, halogen, C₁-C₄Alkyl and C₃-C₆Naphthenic base or as the compound of above-mentioned general formula (I) and (II) defines, With

R¹It is defined with the compound of for example above-mentioned general formula (I) of A and (II)；

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

More particularly, the present invention is also covered by above-mentioned general formula (III-INT) or the midbody compound of (IV-INT), wherein

Hal is halogen as defined above, and

R²Selected from C₁-C₆Alkyl and C₃-C₆Naphthenic base,

R³Selected from hydrogen, halogen, C₁-C₄Alkyl and C₃-C₆Naphthenic base and

R¹It is defined with the compound of for example above-mentioned general formula (I) of A and (II)；

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

In above-mentioned intermediate (III-INT) and (IV-INT) particularly preferably according to above-mentioned formula (IV-INT) that A bit.

Particularly, the present invention is also covered by the midbody compound of general formula (V-INT):

Wherein the compound of for example above-mentioned general formula (I) of G and (II) are defined,

Or as G=S general formula (VI-INT) midbody compound:

Wherein in above-mentioned formula (V-INT) and (VI-INT)

R²Selected from C₁-C₆Alkyl and C₃-C₆Naphthenic base or as the compound of above-mentioned general formula (I) and (II) defines,

R³Selected from hydrogen, halogen, C₁-C₄Alkyl and C₃-C₆Naphthenic base or as the compound of above-mentioned general formula (I) and (II) defines,

R^AIt is H or C₁-C₄Alkyl and

R^BIt is H or halogen,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

Particularly, the present invention is also covered by the midbody compound of above-mentioned general formula (VI-INT), wherein

R²Selected from C₁-C₆Alkyl and C₃-C₆Naphthenic base or as the compound of above-mentioned general formula (I) and (II) defines,

R³Selected from hydrogen, halogen, C₁-C₄Alkyl and C₃-C₆Naphthenic base or as the compound of above-mentioned general formula (I) and (II) defines,

R^AIt is H or C₁-C₄Alkyl and

R^BIt is H or halogen,

And its stereoisomer, tautomer, N- oxide, hydrate, solvate and salt and their mixture.

Very particularly, the present invention is also covered by following midbody compounds and its stereoisomer, tautomer, N- oxygen Compound, hydrate, solvate and salt and their mixture:

The intermediate of formula (VI-INT-1):

Wherein

R^ASelected from methyl, ethyl and tert-butyl,

R²Selected from C₁-C₆Alkyl and C₃-C₆Naphthenic base and

R³Selected from hydrogen, halogen, C₁-C₄Alkyl and C₃-C₆Naphthenic base.

The intermediate of formula (VI-INT-2):

Wherein

R^ASelected from methyl, ethyl and tert-butyl,

R²Selected from C₁-C₆Alkyl and C₃-C₆Naphthenic base and

R³Selected from hydrogen, halogen, C₁-C₄Alkyl and C₃-C₆Naphthenic base.

The intermediate of formula (VI-INT-3):

Wherein

R²Selected from C₁-C₆Alkyl and C₃-C₆Naphthenic base and

R³Selected from hydrogen, halogen, C₁-C₄Alkyl and C₃-C₆Naphthenic base.

The intermediate of formula (IV-INT-1):

Wherein

R²Selected from C₁-C₆Alkyl and C₃-C₆Naphthenic base,

R³Selected from hydrogen, halogen, C₁-C₄Alkyl and C₃-C₆Naphthenic base and

A and R¹As defined above.

According to the 5th aspect, the present invention cover the midbody compound be used to prepare logical formula (I) as defined above and (II) purposes of compound.

Particularly, the present invention covers above-mentioned general formula (II-INT), (IV-INT) and (VI-INT), more particularly above-mentioned general formula (VI-INT-1), the midbody compound of (VI-INT-2), (VI-INT-3) and (IV-INT-1) are used to prepare as defined above Logical formula (I) and (II) compound purposes.

The present invention covers midbody compound disclosed in the embodiment part of following texts.

The compound of logical formula (I) and (II) of the invention can be turned by any means well known by persons skilled in the art Turn to any salt as described in this article, preferably pharmaceutically acceptable salt.Similarly, logical formula (I) of the invention and (II) Any salt of compound can be converted into free compound by any means well known by persons skilled in the art.

The compound of logical formula (I) and (II) of the invention shows valuable pharmacotoxicological effect spectrum, unpredictable. It was unexpectedly found that the compound of the present invention effectively interacts with Slo-1, and therefore the compound can For treating or preventing disease in humans and animals, preferably helminthic infection, especially stomach and intestine and parenteral invermination, particularly It is stomach and intestine and parenteral nematode infections.

The compound of the present invention can be used to control, treatment and/or prevention invermination, especially stomach and intestine and parenteral compacted Insect infection.This method includes to the change of the invention for needing its mammal application effectively to measure for treating the imbalance Close object or its pharmaceutically acceptable salt, isomers, polymorph, metabolin, hydrate, solvate or ester.

In in terms of the substitution, this method includes to needing its bird, i.e. cage bird or especially poultry is applied The compound of the present invention or its pharmaceutically acceptable salt, isomers, polymorphic effectively measured for treating the imbalance Object, metabolin, hydrate, solvate or ester.

Specifically, in veterinary medicine field, the compound of the present invention is suitable in warm-blooded animal with advantageous toxicity Occur in animal breeding and animal feeding in livestock, breeding, zoo, laboratory, experiment and domestic animal to control Helminth, especially worm., to helminth, all or moment of especially worm development is active for they.

Agricultural animals include such as mammal, such as sheep, goat, horse, donkey, camel, buffalo, rabbit, reinder, fallow deer (fallow deer) and especially ox and pig；Or poultry, such as turkey, duck, goose and especially chicken；Or fish or shell-fish Animal, for example, in aquatic products industry, or optionally can be insect, such as honeybee.

Domestic animal include such as mammal, such as hamster, cavy, rat, mouse, chinchilla, ferret, or especially It is dog, cat；Cage bird；Reptile；Amphibian or ornamental fish.

The present invention also provides treatment invermination, especially stomach and intestine and parenteral invermination, more particularly stomach and intestine and parenteral The method of nematode infections.

These imbalances are well characterized in animal, and can be controlled by applying pharmaceutical composition of the invention It treats.

The term " treatment (treating or treatment) " such as used in this document is conventional use of, such as with right It is anti-, alleviate, reduce, mitigating, improve disease or lack of proper care (such as nematode infections) state for the purpose of and manage or look after object.It is special Not, and especially in animal health or veterinary applications, term " treatment " includes prevention, remedial prevention (metaphylactic) or treatment is handled.

The worm pathogen of human or animal includes such as Acanthocephala (acanthocephala), nematode, linguatula Door (pentastoma) and Platyhelminthes (platyhelminthes) (such as Helerocolylea (monogenea), tapeworm (cestode) and fluke (trematodes)).

Illustrative worm includes but is not limited to:

Helerocolylea: for example: Dactylogyrus (Dactylogyrus spp.), Gyrodactylus (Gyrodactylus spp.), Microbothrium spp., Polystoma (Polystoma spp.), Troglecephalus spp..

Tapeworm: coming from Pseudophyllidea (Pseudophyllidea), such as: phyllidium tapeworm category (Bothridium spp.) is split Head tapeworm category (Diphyllobothrium spp.), Diplogonoporus (Diplogonoporus spp.), Ichthyobothrium spp., Ligula (Ligula spp.), Schistocephalus spp., Spirometra (Spirometra spp.)；

From Cyclophyllidea (Cyclophyllidea), such as: Andyra spp., Anaplocephala (Anoplocephala Spp.), Avitellina (Avitellina spp.), Bertiella (Bertiella spp.), Cittotaenia (Cittotaenia spp.), Davainea spp., double testis tapeworm categories (Diorchis spp.), Diplopylidium (Diplopylidium spp.), diphlidium caninum category (Dipylidium spp.), Echinococcus (Echinococcus Spp.), spine leaf tapeworm category (Echinocotyle spp.), Echinolepis (Echinolepis spp.), Hydatigera (Hydatigera spp.), Hymenolepis (Hymenolepis spp.), Joyeuxiella (Joyeuxiella Spp.), Mesocestoides (Mesocestoides spp.), moniezia category (Moniezia spp.), secondary naked head tapeworm Belong to (Paranoplocehala spp.), Rayleigh tapeworm category (Raillietina spp.), Si Taile tapeworm category (Stilesia Spp.), Hydatigena (Taenia spp.), Thysaniezia (Thysaniezia spp.), Thysanosomsa spp..

Fluke: coming from Digenea (Digenea), such as: Austrobilharzia (Austrobilharzia spp.), short pharynx Fluke category (Brachylaima spp.), Calicophoron (Calicophoron spp.), Catatropis (Catatropis Spp.), Clon (Clonorchis spp.), anus Collyriculum (Collyriclum spp.), Cotylophoron (Cotylophoron spp.), ring cavity fluke category (Cyclocoelum spp.), Dicrocoelium (Dicrocoelium Spp.), Diplostomum (Diplostomum spp.), Echinochasmus (Echinochasmus spp.), Echinoparyphium (Echinoparyphium spp.), Echinostoma (Echinostoma spp.), Eurytrema (Eurytema Spp.), Fasciola (Fasciola spp.), Fascioloides (Fascioloides spp.), Fasciolopsis (Fasciolopsis spp.), luxuriant and rich with fragrance plan fluke (Fischoederius spp.), abdomen bag fluke category (Gastrothylacus Spp.), Gigantobilharzia (Gigantobilharzia spp.), Gigantoctyle spp., Heterophyes(Heterophyes) (Heterophyes spp.), Hypoderaerum (Hypoderaeum spp.), Leucochloridium (Leucochloridium Spp.), Metagonimus (Metagonimus spp.), Meotrchis (Metorchis spp.), Nanophyetus (Nanophyetus spp.), Notocotylus (Notocotylus spp.), Opisthorchis (Opisthorchis Spp.), Ornithobilharzia (Ornithobilharzia spp.), Paragonimus (Paragonimus spp.), with end plate inhale Eimeria (Paramphistomum spp.), Plagiorchis (Plagiorchis spp.), stem Diplostomum (Posthodiplostomum spp.), Prosthogonimus (Prosthogonimus spp.), Schistosoma (Schistosoma Spp.), Trichobilharzia (Trichobilharzia spp.), salmon fluke category (Troglotrema spp.), Typhlocoelum (Typhlocoelum spp.)。

Nematode: coming from hair shape suborder (Trichinellida), such as: Hepaticola (Capillaria spp.), sheath Belong to (Eucoleus spp.), Paracapillaria spp., Trichinella (Trichinella spp.), Trichomosoides spp., Trichocephalus (Trichuris spp.)；

From Tylenchida (Tylenchida), such as: filament Nian belongs to (Micronema spp.), Parastrangyloides Spp., Strongyloides (Strongyloides spp.)；

From rod suborder (Rhabditina), such as: Aelurostrongylus (Aelurostrongylus spp.), anseris Belong to (Amidostomum spp.), hookworm Turbatrix (Ancylostoma spp.), Angiostrongylus (Angiostrongylus spp.), Bronchonema spp., Bunostomum (Bunostomum spp.), Xia Baite line Eimeria (Chabertia spp.), Cooperia (Cooperia spp.), Cooperioides spp., Crenosoma (Crenosoma spp.), rim of a cup category (Cyathostomum spp.), Cyclococercus spp., Cyclodontostomum spp., cup ring category (Cylicocyclus spp.), cup hat belong to (Cylicostephanus spp.), Column pharynx belongs to (Cylindropharynx spp.), capsule buttock line Eimeria (Cystocaulus spp.), Dictyocaulus (Dictyocaulus spp.), deer Strongylus (Elaphostrongylus spp.), Filaroides (Filaroides Spp.), ball head category (Globocephalus spp.), Graphidium (Graphidium spp.), Gyalocephalus (Gyalocephalus spp.), Haemonchus (Haemonchus spp.), helix Eimeria (Heligmosomoides Spp.), Metastrongylus apri category (Hyostrongylus spp.), Marshallagla (Marshallagia spp.), rear strongylid Belong to (Metastrongylus spp.), Muellerius category (Muellerius spp.), Necator (Necator spp.), Nematodirus (Nematodirus spp.), Neostrongylus (Neostrongylus spp.), Nippostrongylus category (Nippostrongylus spp.), Obeliscoides (Obeliscoides spp.), esophagus tooth category (Oesophagodontus Spp.), Oesophagostomum category (Oesophagostomum spp.), Ollulanus (Ollulanus spp.), bird strongylid Belong to (Ornithostrongylus spp.), Oslerus spp., ostertagi category (Ostertagia spp.), Paracooperia spp., Paracrenosoma spp., Parafilaroides (Parafilaroides spp.), quasi- red deer circle Turbatrix (Parelaphostrongylus spp.), Pneumocaulus (Pneumocaulus spp.), Pneumostrongylus (Pneumostrongylus spp.), Poteriostomum (Poteriostomum spp.), Protostrongylus (Protostrongylus spp.), Spicocaulus spp., hat buttock line category (Stephanurus spp.), Strongylus Spp., Syngamus (Syngamus spp.), Teladorsagia (Teladorsagia spp.), Trichonema (Trichonema Spp.), Trichostrongylus (Trichostrongylus spp.), Triodontophorus (Triodontophorus spp.), hidden strongylid Belong to (Troglostrongylus spp.), curved mouth category (Uncinaria spp.)；

From Spirurata (Spirurida), such as: Acanthocheilonema (Acanthocheilonema spp.), anisakis (Anisakis spp.), Ascaridia (Ascaridia spp.), Ascaris (Ascaris spp.), Ascarops (Ascarops spp.), Aspiculuris (Aspiculuris spp.), Baylisascaris (Baylisascaris Spp.), cloth Shandong Turbatrix (Brugia spp.), Cercopithifilaria spp., Crassicauda spp., spine lip line Eimeria (Dipetalonema spp.), Dirofilaria (Dirofilaria spp.), Dracunculus (Dracunculus Spp.), Draschia (Draschia spp.), Enterobius (Enterobius spp.), Filaria (Filaria Spp.), jaw mouth line Eimeria (Gnathostoma spp.), Gongylonema (Gongylonema spp.), Habronema (Habronema spp.), Heterakis (Heterakis spp.)；Litomosoides (Litomosoides spp.), sieve Ah Filaria (Loa spp.), Onchocerca (Onchocerca spp.), Oxyuris (Oxyuris spp.), secondary flex Belong to (Parabronema spp.), Parafilaria (Parafilaria spp.), parascris (Parascaris spp.), bolt Buttock line Eimeria (Passalurus spp.), physaloptera (Physaloptera spp.), Probstmayria (Probstmayria spp.), Pseudofilaria spp., Setaria (Setaria spp.), Skjrabinema Spp., tailspin Turbatrix (Spirocerca spp.), Stephanofilaria (Stephanofilaria spp.), Strongyluris Spp., Syphacia (Syphacia spp.), Thelazia (Thelazia spp.), Toxascaris (Toxascaris spp.), Belascaris (Toxocara spp.), Wuchereria (Wuchereria spp.).

Acanthocephala (Acanthocephala): kissing mesh (Oligacanthorhynchida) from few spine, such as: it is huge Kiss Acanthocephalus (Macracanthorhynchus spp.), Prosthenorchis (Prosthenorchis spp.)；It comes from Moniliformida mesh, such as: Moniliformis (Moniliformis spp.)；

From multiform mesh (Polymorphida), such as Filicollis (Filicollis spp.)；Mesh is kissed from spine (Echinorhynchida), such as: Acanthocephalus (Acanthocephalus spp.), Echinorhynchus (Echinorhynchus spp.), Leptorhynchoides (Leptorhynchoides spp.).

Linguatula door (Pentastoma): tang shape worm mesh (Porocephalida), such as Glossobalanus are come from (Linguatula spp.)。

The compound of the present invention may be particularly useful in treatment and prevent, i.e. prevention invermination, especially stomach and intestine and parenteral Invermination, more particularly stomach and intestine and parenteral nematode infections.

Parazoon, especially worm are controlled by using the compound of the present invention, it is intended that reduce or prevent disease, Death and reduced performance (in meat, milk, hair, skin, egg, honey etc.), enable to carry out more economical and simpler Animal feeding, and better animal welfare may be implemented.

As the term " control (control or controlling) " used herein for animal health fields refers to The compound of the present invention is in terms of being reduced to harmless level for the incidence of this helminth in the animal for infecting each helminth It is effective.More specifically, " control " refers to that the compound of the present invention is killing each helminth, inhibiting it as used in this article Growth, or it is effective for inhibiting its proliferation aspect.

According to a further aspect, the present invention covers the compound of logical formula (I) as described above or standing for theirs Body isomers, tautomer, N- oxide, hydrate, solvate and salt, especially theirs is pharmaceutically acceptable Salt or its mixture, are used to treat or prevent disease, especially invermination, especially stomach and intestine and parenteral invermination, More particularly stomach and intestine and parenteral nematode infections.

The pharmaceutical activity of compound according to the present invention can pass through the interaction of itself and Slo-1 ion channel It is explained.

According to a further aspect, the present invention cover formula (I) as described above logical and (II) compound or it Stereoisomer, tautomer, N- oxide, hydrate, solvate and salt, especially they can pharmaceutically connect The salt received or its mixture are for treating or preventing disease, especially invermination, especially stomach and intestine and parenteral worm sense Dye, the more particularly purposes of stomach and intestine and parenteral nematode infections.

According to a further aspect, the present invention cover formula (I) as described above logical and (II) compound or it Stereoisomer, tautomer, N- oxide, hydrate, solvate and salt, especially they can pharmaceutically connect The salt received or its mixture are treating or preventing disease, especially invermination, especially stomach and intestine and parenteral invermination, Purposes more particularly in stomach and intestine and the method for parenteral nematode infections.

According to a further aspect, the present invention cover formula (I) as described above logical and (II) compound or it Stereoisomer, tautomer, N- oxide, hydrate, solvate and salt, especially they can pharmaceutically connect The salt received or its mixture are used to prepare the purposes of pharmaceutical composition (preferred agents), and described pharmaceutical composition is for preventing Or treat disease, especially invermination, especially stomach and intestine and parenteral invermination, more particularly stomach and intestine and parenteral nematode sense Dye.

According to a further aspect, the present invention covers treatment or prevention disease, especially invermination, especially stomach Intestines and parenteral invermination, the more particularly method of stomach and intestine and parenteral nematode infections, using a effective amount of as described above logical Compound or their stereoisomer, tautomer, the N- oxide, hydrate, solvate of formula (I) and (II) And salt, especially their pharmaceutically acceptable salt or its mixture.

According to a further aspect, the present invention covers pharmaceutical composition, especially veterinary formulation, and it includes institutes as above It is the compound or their stereoisomer of the logical formula (I) stated and (II), tautomer, N- oxide, hydrate, molten Object, salt, especially pharmaceutically acceptable salt or its mixture and one or more excipient are closed in agent, especially a kind of Or a variety of pharmaceutically acceptable excipient.It can use for be suitble to dosage form to prepare the normal flow of such pharmaceutical composition Journey.

According to a further aspect, the present invention, which covers, is used to prepare pharmaceutical composition, especially the side of veterinary formulation Method comprising the compound or their stereoisomer, tautomer, N- of formula (I) and (II) will be led to as described above Oxide, hydrate, solvate, salt, especially pharmaceutically acceptable salt or its mixture and one or more figurations The step of agent, especially one or more pharmaceutically acceptable excipient are mixed.

According to a further aspect, the present invention covers using pharmaceutical composition, especially veterinary formulation treatment or pre- Anti- disease, especially invermination, especially stomach and intestine and parenteral invermination, the more particularly side of stomach and intestine and parenteral nematode infections Method, described pharmaceutical composition include that a effective amount of logical formula (I) as described above and the compound of (II) or their solid are different Structure body, tautomer, N- oxide, hydrate, solvate and salt, especially their pharmaceutically acceptable salt, or Its mixture of person.

Present invention further contemplates that pharmaceutical composition, especially veterinary formulation, it includes it is according to the present invention at least A kind of compound, it is conventional there are also one or more pharmaceutically suitable excipient and their purposes for the above purpose.

Compound according to the present invention can have whole body and/or Topically active.It, can be to be suitble to for the purpose Mode apply, such as via oral, parenteral, lung, nose, sublingual, tongue, cheek, rectum, vagina, skin, transdermal, conjunctiva, ear way Diameter is applied as implantation material or bracket.Such application can it is preventative, remedy preventative or therapeutically implement.

For these administration method, compound according to the present invention can be applied with administration form appropriate.

For being administered orally, compound according to the present invention being formulated as rapidly and/or being passed with modification mode Send the dosage form known in the art of the compounds of this invention, such as tablet (uncoated or coated tablet, for example, with delayed dissolved or Undissolved enteric coating or controlled release coat), Orally disintegrating tablet, film/thin slice, film/lyophilized products, capsule it is (such as hard or soft bright Glue capsule), sugar coated tablet, granule, pilule, chewable tablets (such as soft chewable tablets), pulvis, emulsion, suspension, aerosol or Solution.Compound according to the present invention can be crystallized and/or amorphous and/or dissolved form mix in the dosage form.

Parenteral administration can avoid absorption step (such as in intravenous, intra-arterial, intracardiac, intraspinal or waist) or packet It is realized in the case where including absorption (such as in intramuscular, subcutaneous, intradermal, percutaneous or peritonaeum).It is suitable for the application shape of parenteral administration The formula especially injection of the form of solution, suspension, lotion, lyophilized products or aseptic powdery and infusion preparation.

The example for being suitable for other administration method is medicament forms [especially powder inhalator, spraying for sucking Device], nasal drop, nose solution, nose spray；For tongue, tablet/film/thin slice/capsule of sublingual or cheek application；Suppository；Eye drip Agent, eye ointment, eye syringe, eye insert, auristilla, ear be spraying, ear pulvis, ear lotion, earplug；Vaginal capsule, aqueous suspension (lotion, oscillation mixture), lipophilic suspension, emulsion, ointment, emulsifiable paste, transdermal therapeutic system (such as patch), cream, paste, bubble Foam agent, drops, conspergative, implantation material or bracket.

Compound according to the present invention can be impregnated in the administration form.This can be in a way known It is realized and being mixed with the excipient being pharmaceutically suitble to.Pharmaceutically suitable excipient especially includes:

Filler and carrier (such as cellulose, microcrystalline cellulose (such as Avicel^®), lactose, mannitol, starch, calcium phosphate (such as Di-Cafos^®))；

Ointment bases (such as vaseline, paraffin, triglycerides, wax, lanocerin, wool wax alcohol, lanolin, hydrophily are soft Cream, polyethylene glycol)；

Suppository base (such as polyethylene glycol, cocoa butter, hard fat)；

Solvent (such as water, ethyl alcohol, isopropanol, glycerol, propylene glycol, middle chain length fat of triglyceride oil, liquid macrogol, Paraffin)；

Surfactant, emulsifier, dispersing agent or wetting agent (such as lauryl sodium sulfate), lecithin, phosphatide, fat Alcohol (such as Lanette^®), sorbitan fatty acid esters (such as Span^®), polyoxyethylene sorbitan fatty acid esters (such as Tween^®), polyoxyethylene fatty glyceride ester (such as Cremophor^®), polyoxyethylene fatty acid ester, polyoxyethylene rouge Fat alcohol ether, fatty acid glyceride, poloxamer (such as Pluronic^®)；

Buffer, bronsted lowry acids and bases bronsted lowry (such as phosphate, carbonate, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, Tromethamine, triethanolamine)；

Isotonic agent (such as glucose, sodium chloride)；

Adsorbent (such as high dispersive silica)；

Tackifier, gel former, thickener and/or adhesive (such as polyvinylpyrrolidone, methylcellulose, hydroxypropyl Ylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (such as Carbopol^®)； Alginates, gelatin)；

Disintegrating agent (such as modified starch, sodium carboxymethylcellulose, primojel (such as Explotab^®), crosslinking it is poly- Vinylpyrrolidone, croscarmellose sodium (such as AcDiSol^®))；

Flowing regulator, lubricant, glidant and release agent (such as magnesium stearate, stearic acid, talcum, high dispersive titanium dioxide Silicon (such as Aerosil^®))；

Coating material (such as sugar, lacca) and the quickly film forming agent (example of dissolution or the film or diffusion barrier that are dissolved with modification mode Such as polyvinylpyrrolidone (such as Kollidon^®), polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl it is fine Tie up element, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylate, Polymethacrylates (such as Eudragit^®))；

Capsule material (such as gelatin, hydroxypropyl methyl cellulose)；

Synthetic polymer (such as polylactide, polyglycolide, polyacrylate, polymethacrylates are (such as Eudragit^®), polyvinylpyrrolidone (such as Kollidon^®), it is polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, poly- Ethylene glycol and their copolymer and block copolymer)；

Plasticizer (such as polyethylene glycol, propylene glycol, glycerol, glyceryl triacetate, triacetyl citrate, two fourth of phthalic acid Ester)；

Penetration enhancer；

Stabilizer (such as antioxidant, such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxy Methyl phenyl ethers anisole, butylated hydroxytoluene, propylgallate)；

Preservative (such as p-hydroxybenzoic acid esters, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate)；

Colorant (such as inorganic pigment, such as iron oxide, titanium dioxide)；

Corrigent, sweetener, taste and/or odor masking agent.

The invention further relates to pharmaceutical compositions, and it includes at least one compounds according to the present invention, routine Ground there are also one or more pharmaceutically suitable excipient and they in accordance with the purpose of the invention.

According on the other hand, the present invention covers pharmaceutical composition, especially drug, and it includes at least one of the invention to lead to The compound of formula (I) and at least one or more of other active constituent, be particularly useful for the treatment of and/or prevent in vivo and/or Ectoparasitic infection.

Term " endoparasite " in the present invention uses like that as known in the art, and refers in particular to compacted Worm.Term " vermin " in the present invention uses like that as known in the art, and refers in particular to arthropod, Especially insect or mite.

Particularly, the present invention covers pharmaceutical composition, especially animal doctor and combines, it includes:

One or more first active constituents especially lead to the compound of formula (I) as defined above, and

One or more other active constituents, it is especially one or more to kill internal and/or vermin agent.

Term " combination " in the present invention uses like that as known in the art, and the combination can be fixed group Conjunction, non-fixed combinations or kit of parts.

" fixed Combination " in the present invention uses like that as known in the art, and is defined as following groups Close, wherein such as the first active constituent, the compounds of such as one or more logical formula (I)s of the invention and another activity at Divide and is present in a unit dose together or is present in a single entities.One example of " fixed Combination " is following Pharmaceutical composition, wherein the first active constituent and other active constituent exist in the form of the blend for being administered simultaneously, example Such as exist with dosage form.Another example of " fixed Combination " is following pharmaceutical compositions, wherein the first active constituent and in addition Active constituent in the form of a unit exist without in the form of blend exist.

Non-fixed combinations or " kit of parts " of the invention use like that as known in the art, and are defined For following combinations, wherein the first active constituent and other active constituent exist in the form of more than one unit.On-fixed group It closes or an example of kit of parts is following combinations, wherein the first active constituent and other active constituent are separately present.It is non- The component of fixed Combination or kit of parts can respectively, connect, simultaneously, it is synchronous or intersect application in chronological order.

The compound of the present invention can with single medicine type or with one or more other pharmacy activity components Combination (wherein, combination does not cause unacceptable side effect) form application.Present invention also contemplates that such pharmaceutical composition.Example Such as, the compound of the present invention can be combined with known combatting ectoparasites agent and/or Endoparasiticidal agent.

It is herein known with the active constituent alternatively or additionally that its common name is pointed out, and is described in and for example kills Worm agent handbook (" The Pesticide Manual " the 16th edition, British Crop Protection Council 2012), Or (such as http://www.alanwood.net/pesticides) can be retrieved in internet.It is classified based on and is submitting Existing IRAC mechanism of action classification chart when present patent application.

The example of combatting ectoparasites agent and/or Endoparasiticidal agent is insecticide, acaricide and nematicide, and And particularly including:

(1) acetylcholinesterase (AChE) inhibitor, such as carbamate, such as alanycarb (alanycarb), Aldicarb (aldicarb), Ficam (bendiocarb), Benfuracard micro (benfuracarb), butocarboxim (butocarboxim), fourth Ketone sulfone prestige (butoxycarboxim), carbaryl (carbaryl), carbofuran (carbofuran), carbosulfan (carbosulfan), ethiofencarb (ethiofencarb), Bassa (fenobucarb), Carzol (formetanate), Furathiocarb (furathiocarb), Mobucin (isoprocarb), methiocarb (methiocarb), methomyl (methomyl), MTMC (metolcarb), oxamyl (oxamyl), Aphox (pirimicarb), arprocarb (propoxur), thiodicarb (thiodicarb), thiofanox (thiofanox), triaguron (triazamate), Landrin (trimethacarb), XMC and Meobal (xylylcarb)；Or organophosphorus ester, such as orthene (acephate), azamethiphos (azamethiphos), triazotion (azinphos-ethyl), methyl azinphos-methyl (azinphos-methyl), cadusafos (cadusafos), chlorethoxyfos (chlorethoxyfos), chlorfenviphos (chlorfenvinphos), chlormephos (chlormephos), chlorpyrifos-methyl (chlorpyrifos-methyl), Resistox (coumaphos), cynock (cyanophos), demeton-methyl (demeton-S-methyl), basudin (diazinon), DDVP/DDVP (dichlorvos/DDVP), Carbicron (dicrotophos), Rogor (dimethoate), dimethylvinphos (dimethylvinphos), disulfoton (disulfoton), EPN, Ethodan (ethion), phonamiphos (ethoprophos), Famphur (famphur), fenamiphos (fenamiphos), fenifrothion (fenitrothion), Entex (fenthion), thiophene Azoles phosphorus (fosthiazate), heptenophos (heptenophos), new cigarette phosphorus (imicyafos), isofenphos (isofenphos), O- (Methoxyamino thiophosphoryl) isopropyl salicylate (isopropyl O- (methoxyaminothiophosphoryl) Salicylate), isoxathion (isoxathion), malathion (malathion), Afos (mecarbam), acephatemet (methamidophos), methidathion (methidathion), Menite (mevinphos), Azodrin (monocrotophos), 2-dichloroethylk dimethyl phosphate (naled), omethoate (omethoate), oxydemeton_methyl (oxydemeton-methyl), parathion-methyl (parathion-methyl), phenthoate dimephenthoate cidial (phenthoate), thimet (phorate), zolone (phosalone), imines Sulphur phosphorus (phosmet), phosphamidon (phosphamidon), phoxim (phoxim), pirimiphos-methyl (pirimiphos- Methyl), Profenofos (profenofos), propetamphos (propetamphos), Toyodan (prothiofos), pyraclofos (pyraclofos), pyridaphethione (pyridaphenthion), quinalphos (quinalphos), sulfotep (sulfotep), fourth Yl pyrimidines phosphorus (tebupirimfos), Temefos (temephos), Terbufos (terbufos), stirofos (tetrachlorvinphos), thiometon (thiometon), Hostathion (triazophos), metrifonate (triclorfon) and vamidothion (vamidothion).

(2) GABA- gate chloride channel blockers, such as cyclic diolefine organochlorine class, for example, Niran (chlordane) and 5a,6,9,9a-hexahydro-6,9-methano-2,4 (endosulfan) or Phenylpyrazole (fiproles), such as ethiprole (ethiprole) and Fipronil (fipronil)。

(3) sodium channel modulators, such as pyrethroid (pyrethroid), such as acrinathrin (acrinathrin), allethrin (allethrin), d- cis-trans allethrin (d-cis-trans allethrin), Anti- the third pyrethroids of ethylenic (d-trans allethrin) of d-, Biphenthrin (bifenthrin), bioallethrin (bioallethrin), bioallethrin S- cyclopentenyl isomers, bioresmethrin (bioresmethrin), second cyanogen Pyrethroids (cycloprothrin), cyfloxylate (cyfluthrin), β-cyfloxylate, lambda-cyhalothrin (cyhalothrin), λ-lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin (cypermethrin), α-cypermethrin, β- Cypermethrin, θ-cypermethrin, ζ-cypermethrin, cyphenothrin [(1R)-transisomer] (cyphenothrin [(1R)- Trans-isomer]), decis (deltamethrin), empenthrin [(EZ)-(1R) isomers] (empenthrin [(EZ)-(1R)-isomer]), esfenvalerate (esfenvalerate), ethofenprox (etofenprox), Fenpropathrin (fenpropathrin), fenvalerate (fenvalerate), flucythrinate (flucythrinate), fluorine chlorine Benzene pyrethroids (flumethrin), τ-taufluvalinate (tau-fluvalinate), halfenprox (halfenprox), miaow alkynes pyrethroids (imiprothrin), kadethrin (kadethrin), momfluorothrin, Permethrin (permethrin), phenothrin [(1R)-transisomer] (phenothrin [(1R)-trans-isomer]), prallethrin (prallethrin), deinsectization Pyrethroids (pyrethrine) (Dalmatian chrysanthemum (pyrethrum)), resmethrin (resmethrin), silafluofene (silafluofen), Tefluthrin (tefluthrin), tetramethrin (tetramethrin), tetramethrin [(1R)-isomers] (tetramethrin [(1R)-isomer]), tralomethrin (tralomethrin) and transfluthrin (transfluthrin) or DDT or methoxychlor (methoxychlor).

(4) the competitive regulator of nicotinic acetylcholine receptor (nAChR), such as anabasine (neonicotinoids), Such as Acetamiprid (acetamiprid), clothianidin (clothianidin), dinotefuran (dinotefuran), imidacloprid (imidacloprid), Nitenpyram (nitenpyram), thiacloprid (thiacloprid) and Diacloden (thiamethoxam)；Or nicotine or sulfoxaflor (sulfoxaflor) or fluorine pyrrole furanone (flupyradifurone)。

(5) nicotinic acetylcholine receptor (nAChR) allosteric modulators, such as pleocidin class (spinosyns), such as second Quito bacteriocidin (spinetoram) and pleocidin (spinosad).

(6) glutamic acid gates chloride channel (GluCl) allosteric modulators, such as Avermectins/milbemycins Such as Abamectin (abamectin), emaricin (emamectin (avermectins/milbemycins), Benzoate), rayperidin (lepimectin) and milbemectin (milbemectin).

(7) juvenile hormone dummy, such as juvenoid, such as hydroprene (hydroprene), alkene worm alkynes Ester (kinoprene) and methoprene (methoprene) or fenoxycarb (fenoxycarb) or pyriproxyfen (pyriproxyfen)。

(9) regulator of scolopiddium, such as pymetrozine (pymetrozine) or flonicamid (flonicamid).

(10) mite growth inhibitor, such as clofentezine (clofentezine), Hexythiazox (hexythiazox) and flufenzine (diflovidazin) or etoxazole (etoxazole).

(12) inhibitor of mitochondrial ATP synthesis, such as ATP agent interfering, such as diafenthiuron (diafenthiuron) or Organo-tin compound, such as azacyclotin (azocyclotin), plictran (cyhexatin) and fenbutatin oxide (fenbutatin ) or propargite (propargite) or tetradifon (tetradifon) oxide.

(13) via destroy proton gradient oxidative phosphorylation uncoupler, such as capillary (chlorfenapyr), DNOC and sulfluramid (sulfluramid).

(14) nicotinic acetylcholine receptor channel blocker, such as bensultap (bensultap), cartap hydrochloride (cartap hydrochloride), thiocyclam (thiocyclam) and dimehypo (thiosultap-sodium).

(15) 0 type benzoylurea derivertives, such as bistrifluron (bistrifluron), UC 62644 (chlofluazuron), diflubenzuron (diflubenzuron), flucycloxuron (flucycloxuron), flufenoxuron (flufenoxuron), flubenzuron (hexaflumuron), Lufenuron (lufenuron), Rimon (novaluron), Noviflumuron (noviflumuron), fluorobenzene urea (teflubenzuron) and triflumuron (triflumuron).

(16) 1 type benzoylurea derivertives, such as Buprofezin (buprofezin).

(17) it casts off a skin agent interfering (particularly with Diptera, i.e. diptera), such as cyromazine (cyromazine).

(18) ecdysone receptor agonist, such as ring tebufenozide (chromafenozide), chlorine tebufenozide (halofenozide), methoxyfenozide (methoxyfenozide) and tebufenozide (tebufenozide).

(19) octopamine receptor agonist, such as Amitraz (amitraz).

(20) mitochondrial complex III electron transfer inhibitor, such as hydramethylnon (hydramethylnone), or mite of going out Quinone (acequinocyl) or fluacrypyrim (fluacrypyrim).

(21) mitochondrial complex I electron transfer inhibitor, such as from acaricidal group of METI, such as fenazaquin (fenazaquin), fenpyroximate (fenpyroximate), pyrimidifen (pyrimidifen), pyridaben (pyridaben), pyrrole mite Amine (tebufenpyrad) and Tolfenpyrad (tolfenpyrad)；Or rotenone (rotenone) (trifoliate jewelvine).

(22) sodium channel blockers that voltage relies on, such as indoxacarb (indoxacarb) or metaflumizone (metaflumizone)。

(23) inhibitor of acetyl-CoA carboxylase, such as tetronic acid (tetronic acid) and tetramic acid (tetramic acid) derivative, such as Envidor (spirodiclofen), Spiromesifen (spiromesifen) and spiral shell worm Ethyl ester (spirotetramat).

(25) mitochondrial complex II electron transfer inhibitor, such as ss-ketonitriles derivative, such as nitrile pyrrole mite ester (cyenopyrafen) and cyflumetofen (cyflumetofen)；And carboxanilide, such as pyflubumide.

(28) blue Buddhist nun alkali (Ryanodine) receptor modulators, such as diamide, such as Rynaxypyr (chlorantraniliprole), bromine cyanogen insect amide (cyantraniliprole) and fipronil bisamide (flubendiamide),

Other active constituent, such as Rana afidopyropen, A Fu (afoxolaner), nimbin (azadirachtin), benclothiaz, Citrazon (benzoximate), Bifenazate (bifenazate), Broflanilide, fenisobromolate (bromopropylate), chinomethionat (chinomethionat), d-trans propargyl chloride pyrethroids (chloroprallethrin), ice crystal (cryolite), ring bromine insect amide (cyclaniliprole), cycloxaprid (cycloxaprid), chlorine fluorine cyanogen insect amide (cyhalodiamide), dicloromezotiaz, dicofol (dicofol), ε-metofluthrin (epsilon-Metofluthrin), epsilon-Momfluthrin, Flometoquin, fluazaindolizine, fluensulfone, phonetic worm amine (flufenerim), fluorine bacterium mite ester (flufenoxystrobin), butene-fipronil (flufiprole), fluhexafon, fluopyram (fluopyram), fluorine thunder are drawn Receive (fluralaner), fluxametamide, furan tebufenozide (fufenozide), guadipyr (guadipyr), Heptafluthrin, imidaclothiz (imidaclothiz), iprodione (iprodione), κ-Biphenthrin (kappa- Bifenthrin), Rana (lotilaner), fluorine chlorine ether pyrethroids are replaced in κ-Tefluthrin (kappa-tefluthrin), Lip river (meperfluthrin), paichongding (paichongding), fluoroform pyrrole ether (pyridalyl), pyrifluquinazon, phonetic Mite amine (pyriminostrobin), spirobudiclofen, etrafluorine ethofenprox (tetramethylfluthrin), Tetraniliprole, four chlorantraniliproles (tetrachlorantraniliprole), tioxazafen, sufluoxime (thiofluoximate), triflumezopyrim and iodomethane (iodomethane)；And it is based on bacillus firmus The preparation (I-1582, bioneem, Votivo) of (Bacillus firmus)；And there are also following compounds: 1- { the fluoro- 4- of 2- Methyl -5- [(2,2,2- trifluoroethyl) sulfinyl] phenyl } -3- (trifluoromethyl) -1H-1,2,4- triazole -5- amine (know in WO2006/043635) (CAS 885026-50-6), { 1'- [(2E) -3- (4- chlorphenyl) propyl- 2- alkene -1- base] -5- fluorine spiral shell [indoles -3,4'- piperidines] -1 (2H)-yl } (2- chloropyridine -4- base) ketone (knows in WO2003/106457) (CAS 637360-23-7), the chloro- N- of 2- [2- { 1- [(2E) -3- (4- chlorphenyl) propyl- 2- alkene -1- base] piperidin-4-yl } -4- (fluoroform Base) phenyl] Pyrazinamide (knowing in WO2006/003494) (CAS 872999-66-1), 3- (the chloro- 2,6- dimethyl benzene of 4- Base) -4- hydroxyl -8- methoxyl group -1,8- diaza spiro [4.5] decyl- 3- alkene -2- ketone (knows in WO 2010052161) (CAS 1225292-17-0), carbonic acid 3- (the chloro- 2,6- 3,5-dimethylphenyl of 4-) -8- methoxyl group -2- oxo -1,8- diaza spiro [4.5] Decyl- 3- alkene -4- base ethyl ester (knowing in EP2647626) (CAS 1440516-42-6), 4- (butyl- 2- alkynes -1- base oxygroup) - 6- (3,5- lupetidine -1- base) -5-FU (knowing in WO2004/099160) (CAS 792914-58-0), PF1364 (knowing in JP2010/018586) (CAS 1204776-60-2), N- [(2E) -1- [(6- chloropyridine -3- base) first Base] pyridine -2 (1H)-subunit] -2,2,2- trifluoroacetamide (knowing in WO2012/029672) (CAS 1363400-41-2), (3E) -3- [1- [(6- chloro-3-pyridyl base) methyl] -2- sub-pyridyl group] -1,1,1- trifluoro -propyl- 2- ketone (is known in WO2013/ 144213) (CAS 1461743-15-6), N- [3- (carbamovl) -4- chlorphenyl] -1- methyl -3- (five fluorine second Base) -4- (trifluoromethyl) -1H- pyrazoles -5- formamide (knowing in WO2010/051926) (CAS 1226889-14-0), 5- The bromo- chloro- N- of 4- [4- chloro-2-methyl -6- (methylcarbamoyl) phenyl] -2- (3- chloro-2-pyridyl) pyrazole-3-formamide (knowing in CN103232431) (CAS 1449220-44-3), 4- [5- (3,5- dichlorophenyl) -4,5- dihydro -5- (fluoroform Base) -3- isoxazolyl] -2- methyl-N- (cis- -1- oxidation -3- Thietane base)-benzamide, 4- [5- (3,5- dichloro Phenyl)-4,5- dihydro-5- (trifluoromethyl)-3- isoxazolyl]-2- methyl-N- (anti-form-1-oxidation-3- Thietane Base)-benzamide and 4- [(5S) -5- (3,5- dichlorophenyl) -4,5- dihydro -5- (trifluoromethyl) -3- isoxazolyl] -2- first Base-N- (cis- -1- oxidation -3- Thietane base) benzamide (knows in 2013/050317 A1 of WO) (CAS 1332628-83-7), [(3,3,3- trifluoro propyl) is sub- by N- [the chloro- 1- of 3- (3- pyridyl group) -1H- pyrazoles -4- base]-N- ethyl -3- Sulfonyl]-propionamide, (+)-N- [the chloro- 1- of 3- (3- pyridyl group) -1H- pyrazoles -4- base]-N- ethyl -3- [(3,3,3- trifluoropropyl Base) sulfinyl]-propionamide and (-)-N- [the chloro- 1- of 3- (3- pyridyl group) -1H- pyrazoles -4- base]-N- ethyl -3- [(3,3,3- Trifluoro propyl) sulfinyl]-propionamide (knows in 20,13/,162,715 2013/162716 A2, US 2014/ of A2, WO of WO 0213448 A1) (CAS 1477923-37-7), 5- [[(2E) -3- chloro-2-propene -1- base] amino] -1- [chloro- 4- of 2,6- bis- (trifluoromethyl) phenyl] -4- [(trifluoromethyl) sulfinyl] -1H- pyrazoles -3- formonitrile HCN (knowing in 101337937 A of CN) (CAS 1105672-77-2), the bromo- N- of 3- [4- chloro-2-methyl -6- [(methylamino) sulphomethyl] phenyl] -1- (chloro- 2- of 3- Pyridyl group) -1H- pyrazoles -5- formamide, (thiobenzamide is known in 103109816 A of CN) (CAS 1232543-85- 9)；N- [the chloro- 2- of 4- [[(1,1- dimethyl ethyl) amino] carbonyl] -6- aminomethyl phenyl] -1- (3- chloro-2-pyridyl) -3- (fluorine Methoxyl group) -1H- pyrazoles -5- formamide (knows in 2012/034403 A1 of WO) (CAS 1268277-22-0), N- [2- (5- Amino -1,3,4- thiadiazoles -2- base) the chloro- 6- aminomethyl phenyl of -4-] the bromo- 1- of -3- (3- chloro-2-pyridyl) -1H- pyrazoles -5- first Amide (knows in 2011/085575 A1 of WO) (CAS 1233882-22-8), 4-, and [[[(3,3- bis- is chloro- by the chloro- 4- of 2,6- bis- by 3- 2- propylene -1- base) oxygroup] phenoxy group] propoxyl group] -2- methoxyl group -6- (trifluoromethyl)-pyrimidine (knows in CN 101337940 A) (CAS 1108184-52-6)；(2E)-and 2 (Z) -2- [Asia 2- (4- cyano-phenyl) -1- [3- (trifluoromethyl) phenyl] second Base]-N- [4- (difluoro-methoxy) phenyl]-Hydrazinecarboxamidederivatives (know in 101715774 A of CN) (CAS 1232543-85-9)； 3- (2,2- dichloroethylene) -2,2- dimethyl -4- (1H- benzimidazolyl-2 radicals-yl) phenyl-cyclopropane formic ether (is known in CN 103524422 A) (CAS 1542271-46-4)；(4aS) -7- chloro- 2,5- dihydro -2- [[(methoxycarbonyl) [4- [(trifluoro Methyl) sulfenyl] phenyl] amino] carbonyl]-indeno [1,2-e] [1,3,4] oxadiazines -4a (3H)-methyl formate (knows in CN 102391261 A) (CAS 1370358-69-2)；Two-O- methyl of 6- deoxidation -3-O- ethyl -2,4- -, 1- [N- [4- [1- [4- (five fluorine ethyoxyl of 1,1,2,2,2-) phenyl] -1H-1,2,4- triazole -3- base] phenyl] carbamate]-α-L- pyrans is sweet Reveal sugared (knowing in 2014/0275503 A1 of US) (CAS 1181213-14-8)；8- (2- cyclo propyl methoxy -4- fluoroform Base-phenoxy group) -3- (6- trifluoromethyl-pyridazine -3- base) -3- aza-bicyclo [3.2.1] octane (CAS 1253850-56- 4), (8- is trans-) -8- (2- cyclo propyl methoxy -4- tri fluoromethy I-phenoxy) -3- (6- trifluoromethyl-pyridazine -3- base) -3- Aza-bicyclo [3.2.1] octane (CAS 933798-27-7), (8- is cis-) -8- (2- cyclo propyl methoxy -4- trifluoromethyl - Phenoxy group) -3- (6- trifluoromethyl-pyridazine -3- base) -3- aza-bicyclo [3.2.1] octane (knows in WO 2007040280 2007040282 A1 of A1, WO) (CAS 934001-66-8) and N- [the chloro- 1- of 3- (3- pyridyl group) -1H- pyrazoles -4- base]-N- Ethyl -3- [(3,3,3- trifluoro propyl) sulfenyl]-propionamide (is known in 2015/058021 A1, WO 2015/058028 of WO A1) (CAS 1477919-27-9) and N- [4- (aminothio methyl) -2- methyl -6- [(methylamino) carbonyl] phenyl] -3- Bromo- 1- (3- chloro-2-pyridyl) -1H- pyrazoles -5- formamide (knows in 103265527 A of CN) (CAS 1452877-50- 7)。

Active constituent with unknown or nonspecific binding mode, such as fluorine nitre diphenylamines (fentrifanil), non-promise Crin (fenoxacrim), cycloprene, chlorobenzilate (chlorobenzilate), Spanon (chlordimeform), flumethiazide (flubenzimin), Dicyclanil (dicyclanil), sulfanilamide (SN) mite ester (amidoflumet), chinomethionat (quinomethionat), triarathene (triarathene), clothiazoben, Diphenylsulfide (tetrasul), potassium oleate (potassium oleate), petroleum (petroleum), metoxadiazone (metoxadiazone), Gossyplur, flufenzine (flutenzin), fenisobromolate (brompropylate), ice crystal (cryolite)；

The active constituent of other classifications, such as butacarb (butacarb), dimetilan (dimetilan), cloethocarb (cloethocarb), phosphorus worm prestige (phosphocarb), Diothyl (ethyl-pyrimidine phosphorus) (pirimiphos (- ethyl)), to sulphur Phosphorus (ethyl parathion) (parathion (- ethyl)), methacrifos (methacrifos), o- isopropyl salicylate (isopropyl o-salicylate), trichlorine phosphonate ester (trichlorfon), sulprofos (sulprofos), Kayaphos (propaphos), gram line pellet (sebufos), sulphur phosphorus (pyridathion) of rattling away, prothoate (prothoate), dichlofenthion (dichlofenthion), methyl sulfone demeton (demeton-S-methylsulfone), isazofos (isazofos), cyanophenyl Phosphine (cyanofenphos), dialifos (dialifos), carbophenothion (carbophenothion), autathiofos, Aromfenvinfos (- methyl), azinphos-methyl (triazotion) (azinphos (- ethyl)), chlopyrifos (poison with poison by ethyl Tick) (chlorpyrifos (- ethyl)), fosmethilan (fosmethilan), iodfenphos (iodofenphos), salithion (dioxabenzofos), pacify fruit (formothion), Dyfonate (fonofos), Flupyrazofos-containpesticide (flupyrazofos), rich rope Phosphorus (fensulfothion), etrimfos (etrimfos)；

Organochlorine class, such as toxaphene (camphechlor), lindane (lindane), heptachlor (heptachlor)；Or phenyl pyrazoline Azole, for example, acetyl worm nitrile (acetoprole), pyrazine Fipronil (pyrafluprole), pyridine Fipronil (pyriprole), Methylene Fipronil (vaniliprole), Virginiamycin (sisapronil)；Or isoxazoles, such as the Rana Sa Ou (sarolaner), Rana (lotilaner), fluorine thunder Rana (fluralaner) are replaced in the Rana A Fu (afoxolaner), Lip river；

Pyrethroid (pyrethroids), such as (cis-trans-) metofluthrin (metofluthrin), third Flumethrin (profluthrin), trifluoro ethofenprox (flufenprox), brofluthrinate (flubrocythrinate), Fubfenprox, Fenfluthrin (fenfluthrin), protrifenbute, anti-Chryson (pyresmethrin), RU15525, terallethrin (terallethrin), cis--resmethrin (cis-resmethrin), Heptafluthrin, penta ring resmethrin (bioethanomethrin), biopermethrin (biopermethrin), pyrrole chlorine cyanogen Pyrethroids (fenpyrithrin), cis--cypermethrin (cis-cypermethrin), cis--Permethrin (cis- Permethrin), cyhalothrin (clocythrin), (λ -) lambda-cyhalothrin (cyhalothrin (lambda-)), dichloro alkynes Valerate (chlovaporthrin) or halogenated hydrocarbon compound (HCH)；

Anabasine (neonicotinoids), such as nithiazide (nithiazine)；

Dicloromezotiaz, trifluoro-benzene pyrimidine (triflumezopyrim)；

Macrolides (macrocyclic lactones), such as nemadectin (nemadectin), ivermectin (ivermectin), draw for rhzomorph (latidectin), Moxidectin (moxidectin), selamectin (selamectin), Eprinomectin (eprinomectin), doramectin (doramectin), emaricin (emamectin benzoate)；Rice That shellfish oxime (milbemycin oxime)；

Triprene (triprene) protects young ether (epofenonane), difenolan (diofenolan)；

Biological agent, hormone or pheromones, such as natural products, such as thuringiensin (thuringiensin), 12 carbon diene Alcohol (codlemone) or print chinaberry (neem) ingredient；

Dinitrophenols, such as dinocap (dinocap), dinobuton (dinobuton), binapacryl (binapacryl)；

Benzoyl urea, such as Fluazuron (fluazuron), penfluron (penfluron)；

Amidine derivative, such as chlormebuform, Tifatol (cymiazole), demiditraz (demiditraz)；

Honeycomb Varroa acaricide (beehive varroa acaricides), such as organic acid, such as formic acid, oxalic acid.

Paying special attention to for the insecticide of animal health and acaricidal non-limiting example is and including especially [i.e. Mehlhorn et al., Encyclpaedic Reference of Parasitology fourth edition (ISBN 978-3-662- 43978-4)]:

The effector in arthropod ligand-gated chloride channel: Niran (chlordane), heptachlor (heptachlor), Endoculfan, dieldrite (Dieldrin), bromociclen (bromocyclen), toxaphene (Toxaphene), lindane (lindane), Fipronil (fipronil), pyridine Fipronil (pyriprole), Virginiamycin (sisapronil), A Fula Receive (afoxolaner), fluorine thunder Rana (fluralaner), the Rana Sa Ou (sarolaner), Lip river for Rana (lotilaner), Fluametamide, broflanilide, avermectin (avermectin), doramectin (doramectin), Yi Linuoke Fourth (eprinomectin), ivermectin (ivermectin), milbemycin (milbemycin), Moxidectin (moxidectin), selamectin (selamectin)；

Arthropod octopamine energy receptor modulators: Amitraz (amitraz), Tifatol (cymiazole), obtains BTS27271 Meter song (demiditraz)；

The effector of arthropod voltage-gated sodium channel: DDT, methoxychlor (methoxychlor), metaflumizone (metaflumizone), indoxacarb (indoxacarb), cinerin, cinerin I, jasmolin I, jasmolin ii, deinsectization Pyrethroids I, chrysanthemumdicarboxylic acid monomethyl ester pyrethrolone ester, allethrin (allethrin), α-cypermethrin (alphacypermethrin), biological allyl chrysanthemum Ester (bioallethrin), β-cyfloxylate (betacyfluthrin), cyfloxylate (cyfluthrin), chlorine fluorine cyanogen chrysanthemum Ester (cyhalothrin), cypermethrin (cypermethrin), decis (deltamethrin), ethofenprox (etofenprox), fenvalerate (fenvalerate), flucythrinate (flucythrinate), flumethrin (flumethrin), halfenprox (halfenprox), Permethrin (permethrin), phenothrin (phenothrin), benzyl furan Pyrethroids (resmethrin), τ-taufluvalinate (tau-fluvalinate), tetramethrin (tetramethrin)；

The effector of arthropod nicotine cholinergic synapse (acetylcholinesterase, acetylcholinergic receptor): fenisobromolate (bromoprypylate), Ficam (bendiocarb), carbaryl (carbaryl), methomyl (methomyl), promacyl (promacyl), arprocarb (propoxur), azamethiphos (azamethiphos), chlorfenviphos (chlorfenvinphos), Chlopyrifos (chlorpyrifos), Resistox (coumaphos), Cythioate (cythioate), basudin (diazinon), Diclorvos, Carbicron (dicrotophos), Rogor (dimethoate), Ethodan (ethion), famphur (famphur), fenifrothion (fenitrothion), Entex (fenthion), heptenophos (heptenophos), horse traction sulphur Phosphorus (malathion), 2-dichloroethylk dimethyl phosphate (naled), phosmet (phosmet), phoxim (phoxim), phthalein amine sulphur phosphorus (phtalofos), propetamphos (propetamphos), Temefos (temephos), stirofos (tetrachlorvinphos), metrifonate (triclorfon), imidacloprid (imidacloprid), Nitenpyram (nitenpyram), dinotefuran (dinotefuran), pleocidin (spinosad), ethyl pleocidin (spinetoram)；

The effector of arthropod development process: cyromazine (cyromazine), Dicyclanil (dicyclanil), diflubenzuron (diflubenzuron), Fluazuron (fluazuron), Lufenuron (lufenuron), triflumuron (triflumuron), benzene Oxygen prestige (fenoxycarb), hydroprene (hydroprene), methoprene (methoprene), pyriproxyfen (pyriproxyfen), fenoxycarb (fenoxycarb), hydroprene (hydroprene), S- methoprene (S- Methoprene), pyriproxyfen (pyriproxyfen).

In the present invention as in addition or other active components the group from Endoparasiticidal agent Exemplary active at Divide includes but is not limited to Anthelmintic Activity compound and Anti-protozoal activity compound.

Anthelmintic Activity compound includes but is not limited to following nematicidals, kills fluke and/or kill tapeworm reactive compound:

From macrolides, such as: Eprinomectin (eprinomectin), Abamectin (abamectin), nemadectin (nemadectin), Moxidectin (moxidectin), doramectin (doramectin), selamectin (selamectin), Rayperidin (lepimectin) draws and replaces rhzomorph (latidectin), milbemectin (milbemectin), ivermectin (ivermectin), emaricin (emamectin), milbemycin (milbemycin)；

From benzimidazole and probenzimidazoles class, such as: oxibendazole (oxibendazole), mebendazole (mebendazole), triclabendazole (triclabendazole), thiophanate (thiophanate), parbendazole (parbendazole), pheno difficult to understand reaches azoles (oxfendazole), Netobimin (netobimin), Fenbendazole (fenbendazole), febantel (febantel), thiabendazole (thiabendazole), ciclobendazole (cyclobendazole), cambendazole (cambendazole), albendazole-sulfoxide (albendazole-sulphoxide), Albendazole (albendazole), flubendazole (flubendazole)；

From yuan cyclic depsipeptide of depsipeptides, preferably cyclic depsipeptide, especially 24, such as: according to De Sai (emodepside), PF1022A；

From tetrahydropyrimidine class, such as: Morantel (morantel), Pyrantel (pyrantel), oxantel (oxantel)；

From Imidazothiazole class, such as: Butamisole (butamisole), levamisol (levamisole), tetramisole (tetramisole)；

From aminophenyl amidine class, such as: Amidantel (amidantel), the Amidantel (dAMD) of removal of acylation, triphen are double Amidine (tribendimidine)；

From aminoacetonitriles class, such as: Mo Naitaier (monepantel)；

From to Hao's quinoline amides (Paraherquamides), such as: to Hao's quinoline amide (paraherquamide), bent grace Special (derquantel)；

From Salicylanilide, such as: Tribromsalan (tribromsalan), Bromoxanide (bromoxanide), bromine replace Buddhist nun Spy (brotianide), Clioxanide (clioxanide), closantel (closantel), niclosamidum (niclosamide), oxyclozanide (oxyclozanide), rafoxanide (rafoxanide)；

From substituted phenols, such as: nitroxinil (nitroxynil), Bithionol (bithionol), Disophenol (disophenol), hexaclofen (hexachlorophene), Niclofolan (niclofolan), meniclopholan；

From organophosphorus compounds, such as: trichlorine phosphonate ester (trichlorfon), naphthalofos, DDVP/DDVP (dichlorvos/DDVP), crufomate (crufomate), Resistox (coumaphos), haloxon (haloxon)；

From piperazinones/quinolines, such as: praziquantel (praziquantel), epsiprantel (epsiprantel)；

From piperazines, such as: piperazine (piperazine), hydroxyzine (hydroxyzine)；

From Tetracyclines, such as: tetracycline (tetracycline), aureomycin (chlorotetracycline), Duo Xihuan Element (doxycycline), terramycin (oxytetracycline), rolitetracycline (rolitetracyclin)；

From other different classifications, such as Bunamidine (bunamidine), niridazole (niridazole), Resorantel (resorantel), omphalotin, Oltipraz (oltipraz), Nitroscanate (nitroscanate), nitroxinil (nitroxynil), Oxamniquine (oxamniquine), mirasan, miracil, sulphur bank ketone (lucanthon), azanol thiaxanthene Ketone (hycanthon), great waves woods (hetolin), emetine (emetine), diethylcarbamazine (diethylcarbamazine), double chlorine Phenol (dichlorophen), diamfenetide (diamfenetide), Clonazepam (clonazepam), bepheninum (bephenium), nithiocyamine (amoscanate), clorsulon (clorsulon).

Anti-protozoal activity ingredient of the invention includes but is not limited to following active constituents:

From triazines, such as: diclazuril (diclazuril), pa that pearl benefit (ponazuril), Letrazuril (letrazuril), Toltrazuril (toltrazuril)；

From polyether ionophore class, such as: coban (monensin), salinomycin (salinomycin), maduramicin (maduramicin), nasamycin (narasin)；

From macrolides, such as: milbemycin (milbemycin), erythromycin (erythromycin)；

From quinolones, such as: Enrofloxacin (enrofloxacin), Pradofloxacin (pradofloxacin)；

From quinine class, such as: chloroquine (chloroquine)；

From miazines, such as: pyrimethamine (pyrimethamine)；

From sulfamido, such as: sulfaquinoxaline (sulfaquinoxaline), methoxybenzyl aminopyrimidine (trimethoprim), sulfaclozin；

From thiamine class, such as: Amprolium (amprolium)；

From woods can amine (lincosamides) class, such as: clindamycin (clindamycin)；

From hexichol ureas, such as: imidocarb (imidocarb)；

From itrofurans, such as: nifurtimox (nifurtimox)；

From quinazolinone alkaloids, such as: Halofuginone (halofuginon)；

From other different classifications, such as: Oxamniquine (oxamniquin), paromomycin (paromomycin)；

From the vaccine or Antigens from microorganism, from for example: Roche Babesia subspecies (Babesia canis Rossi), Eimeria tenella (Eimeria tenella), precocious Eimeria (Eimeria praecox), murder by poisoning Chinese mugwort U.S. ear ball worm (Eimeria necatrix), slow Eimeria (Eimeria mitis), Eimeria maxima (Eimeria Maxima), E.brunetti (Eimeria brunetti), heap-type Eimeria (Eimeria acervulina), Webster Babesia subspecies (Babesia canis vogeli), leishmania infantum (Leishmania infantum), dog Babesia subspecies (Babesia canis canis), Dictyocaulus viviparus (Dictyocaulus viviparus).

If its functional group of the active constituent alternatively or additionally of all names of the invention allow, can optionally with Alkali appropriate or sour forming salt.

Based on the standard laboratory techniques for becoming known for evaluating useful compound for treating invermination, pass through Standard toxotest and by for determine the treatment of the above-mentioned specified patient's condition in animal Standard pharmacological measure, and pass through by These results and the result of known active constituent or drug for treating these patient's condition compare, it is possible to easily determine The effective dose for treating the compound of the present invention of each expectation indication.In treating one of these patient's condition activity to be administered at Point amount can be according to specific compound and dosage unit, administration mode, treatment time section, the treated object such as used The property and degree of age and gender and the treated patient's condition and occur to change in a wide range.

The total amount of active constituent to be administered will be usually daily about 0.001 mg/kg to about 200 mg/kg weight, and It is preferred that daily about 0.01 mg/kg to about 20 mg/kg weight.Clinical useful dosing schedule will be administered to every for daily 1 to 3 time Surrounding 1 time administration.In addition, " withdrawal time " is also possible, wherein drug is not given to object within the specific period, from And it is beneficial to the population equilibrium between pharmacological effect and tolerance.Further, it is able to carry out long-acting treatment, wherein object exists More than receiving seance in the time of surrounding.Unit dosage forms can contain the active constituent of about 0.5 mg to about 1500 mg, and And it can be to be carried out one or more times a day or less than applying once a day.By injection (including intravenous, intramuscular, it is subcutaneous and Parenteral injection) and will preferably 0.01 to 200 mg/kg total weight using the average daily dose that infusion techniques are applied.It is average Daily rectal dosage regimen will preferably 0.01 to 200 mg/kg total weight.Average daily vaginal dosage scheme will preferably 0.01 to 200 mg/kg total weight.Average daily topical dosage regimen will be preferably 0.1 to 200 mg of daily 1 to 4 application. Transdermal concentration will be preferably concentration needed for maintaining the daily dosage of 0.01 to 200 mg/kg.Average daily inhalation dose scheme By preferably 0.01 to 100 mg/kg total weight.

Certainly, for each object, specific initial and continuing dosage regimen will be true according to the diagnostician cured mainly When the property and severity of the fixed patient's condition, the activity of used particular compound, the age of object and overall situation, application Between, administration method, excretion of drug rate, pharmaceutical composition etc. and change.The compound of the present invention or its pharmaceutically acceptable salt Or the expectation treatment mode and dosage number of ester or composition can be true using conventional treatment test by those skilled in the art It is fixed.

Experimental section

Abbreviation:

The many aspects of invention described in this application illustrate that the embodiment is not meant that appoint by following embodiments What form limitation present invention.

Embodiment test experiments described herein are for illustrating the present invention, and the present invention is not limited to the implementations provided Example.

Experimental section-summation part

All reaction reagents that synthesis is not described in experimental section are commercially available or known compounds, or Person can be formed by those skilled in the art from known compound by known method.

The compound and intermediate generated according to the method for the present invention can require to purify.The purifying of organic compound is this Well known to the technical staff of field, and there may be the modes of a variety of purifying the same compounds.In some cases, it may not be necessary to Purifying.In some cases, compound can pass through crystallization purifying.In some cases, solvent appropriate can be used will be miscellaneous Matter, which stirs out, to be come.In some cases, compound can be by chromatography, especially flash column chromatography, and use is for example pre-filled Silica gel pillar (such as Biotage SNAP pillar KP-Sil^®Or KP-NH^®) and the automatic purification system (SP4 of Biotage^®Or Isolera Four^®) and the combination of eluant, eluent (hexane/ethyl acetate or methylene chloride/methanol of such as gradient) purify.In In some cases, compound can be by preparative HPLC, using being for example equipped with diode array detector and/or online electricity The automatic purifier of the mass spectrographic Waters of electrospray ionisation and suitable pre-filled reversed-phase column and the eluant, eluent (water and second of such as gradient The combination of nitrile (it may include additive, such as trifluoroacetic acid, formic acid or ammonium hydroxide)) Lai Chunhua.

In some cases, purification process as described above can provide in a salt form has sufficiently alkalinity or acid official Those of the present invention of energy degree compound, such as, in the case where the compound of the present invention of abundant alkalinity, such as with trifluoro second The form of hydrochlorate or formates provides, or in the case where the compound of the present invention of abundant acidity, such as with the shape of ammonium salt Formula provides.The salt of the type can be changed into its free alkali or trip by a variety of methods well known by persons skilled in the art respectively It is used in the form of salts from sour form, or in subsequent bioassay.It is to be understood that the sheet for separating and describing herein The concrete form (such as salt, free alkali etc.) of the compound of invention is not necessarily the wherein compound and can be applied to biometric Determine to carry out specific bioactivity quantitative unique forms.

Analysis and chromatographic process

Analysis and preparative liquid chromatography

(UP) LC-MS is analyzed to be implemented by means of different device as described below.Quality (m/z) negative mode unless indicated (ESI-), it is otherwise reported by holotype electrospray ionisation.

Method L0:

Instrument type: Waters UPLC system；Column: 2,1 mm of Zorbax Eclipse Plus C18,50 mm x, 1,8 µm；Eluant, eluent A :+1 ml formic acid of acetonitrile/L, eluant, eluent B :+0,9 ml formic acid of millipore water/L；Gradient: 0.0 min 10% A → 1.7 min 95% A → 2.40 min 95% A → 2.41 min 10% A→ 2.5 min 10% A；Thermostat: 55 °C；Flow velocity: 0.85 ml/min；UV- detection: 210 nm.Waters SQD2 MS detector: 100-1000 Amu, ES- ionization, positivity.

¹H-NMR data

¹H-NMR data (are equipped with flow cell (60 μ l volume) with Bruker Avance 400, or are freezed with 1.7 mm are equipped with The Bruker AVIII 400 of CPTCI probe, or the Bruker AVIII 400 (400.13MHz) to be popped one's head in 5 mm are equipped with, or The Bruker AVII 600 (600.13 MHz) to be popped one's head in 5 mm freezing TCI is equipped with, or CPMNP probe is freezed with 5 mm are equipped with Bruker AVIII 600 (601.6 MHz), be equipped with 5 broadbands mm head or 5 mm Prodigy probe Bruker AVIII 500 (500.13MHz) is determined, is used as using tetramethylsilane referring to (0.0) and solvent C D₃CN、 CDCl₃Or D₆-DMSO.Alternatively¹H- and¹³C-NMR instrument type: Bruker DMX300 (¹H NMR: 300 MHz；¹³C NMR: 75 MHz)、Bruker Avance III 400 (¹H NMR: 400 MHz；¹³C NMR:100 MHz) or Bruker 400 Ultrashield (¹H NMR: 400 MHz；¹³C NMR: 100 MHz)。

Chemical shift (δ) is with parts per million [ppm] display；Use following abbreviations: s=unimodal, d=doublet, t= Triplet, q=quartet, m=multiplet, br.=broad peak；Coupling constant is with hertz [Hz] display.

Experimental section-general procedure

The synthesis of the compound of formula (I) and (II) can be implemented according to or similar to following proposal 1.

Scheme 1

Wherein substituent group has such as above-mentioned midbody compound, such as especially above-mentioned midbody compound (VI-INT) and (IV- INT), very especially above-mentioned midbody compound (VI-INT-1), (VI-INT-2), (VI-INT-3) and (IV-INT-1) institute The meaning of definition.

Certain substituted pyrazol thiones (pyrazolothiones) can be easily with the 2- chlorine being dissolved in alcohol such as ethyl alcohol Keto ester (wherein R^AIt is preferably selected from methyl, ethyl or tert-butyl) pyrazolo [5,1-b] is converted into (preferably under the conditions of boiling) [1,3] thiazole -2- carboxylate VI-INT-1 (as described in the similar system in US 20040132708), then preferably in environment temperature N- bromine succinimide bromination is used under degree, in atent solvent such as methylene chloride or tetrachloromethane to obtain ester VI-INT-2.Such as Journal of Organic Chemistry, 2004,69 (21), described in the similar synthesis in 7058-7065, it is this kind of in Mesosome ester reacts under hydrolysising condition, generates pyrazolo [5,1-b] [1,3] thiazole -2- carboxylic acid VI-INT-3.Pyrazolo [5,1- B] [1,3] thiazole -2- carboxylic acid VI-INT-3 can be by amide coupling conditions, such as the formyl chloride by being formed from VI-INT-3 (formyl chloride at alkaline condition (such as pyridine, triethylamine or N, N- diisopropylethylamine) with amine R¹- NH-A combination) or By forming amide (VI-INT-3 and amine R from carboxylic acid VI-INT-3¹- NH-A and dehydrating agent are such asN(3- dimethylamino is different Propyl)-N'Ethyl carbodiimide-hydrochloride (EDC) combination) it is converted into corresponding amide IV-INT-1.For example, in WO Similar synthesis is described in 2001016138.

As described in the similar reaction in WO 2015154630, pyrazolo [5,1-b] [1,3] thiazole -2- carboxylic acid amides IV- INT-1 can by with boric acid or borate Q-B (OR)₂(R=H；R=methyl or R, R=pinacol ester)Suzuki Cross-coupling reaction is converted into aryl-or the substituted final compound II of heteroaryl-.

Experimental section-embodiment

Embodiment 1

7- (3,5- dichlorophenyl)-N- [(4S) -3,4- dihydro -2H- chromene -4- base] -3- isopropyl -6- methylpyrazole simultaneously [5, 1-b] [1,3] thiazole -2- formamide

Step 1

5- methyl -2,4- dihydro -3H- pyrazoles -3- thioketones

3- methyl-1 H- pyrazoles -5- alcohol (20 g, 200 mmol) is dissolved in toluene (500 mL), then, Lawson's examination is added Agent (42 g, 100 mmol).Gained mixture is flowed back 9 hours and is being stored at room temperature overnight.By mixture be concentrated and without It is further purified and is used in next step.

Step 2

3- isopropyl -6- methylpyrazole simultaneously [5,1-b] [1,3] thiazole -2- Ethyl formate

Will be from Bioorganic & Medicinal Chemistry Letters, 2012,22 (20), known to 6338-6342 The chloro- 4- methyl -3- oxopentanoic acid methyl ester of 2- (120 g, 600 mmol) and 5- methyl -2,4- dihydro -3H- pyrazoles -3- thioketones Mixture 8 h of reflux of (23 g, 200 mmol (theoretically desired)) in ethyl alcohol (600 mL), and then vacuum is dense Contracting.It is extracted with ethyl acetate by residue water process, and by gained mixture.Combined organic solvent is dried over sodium sulfate And it is concentrated in vacuo.Gained grease is purified by silicagel column (95:5 hexane/ethyl acetate) to obtain title compound, is nothing Color solid.

Yield: 3.7 g (14.7 mmol；7.33 theoretical %).

Step 3

The bromo- 3- isopropyl -6- methylpyrazole of 7- simultaneously [5,1-b] [1,3] thiazole -2- Ethyl formate

To 3- isopropyl -6- methylpyrazole simultaneously [5,1-b] [1,3] thiazole -2- Ethyl formate (3.7 g, 14.7 mmol) Yu Gan It is added in solution in dry carbon tetrachloride (100 mL)NBromine succinimide (2.9 g, 16 mmol).By gained mixture It is stirred at room temperature 4 hours.Then, it is diluted and is washed with water with methylene chloride, be then washed with brine.By the organic of separation Layer is dried over sodium sulfate.Product is used in next step without further purification.

Yield: 4.8 g (14.5 mmol；98.6 theoretical %).

Step 4

The bromo- 3- isopropyl -6- methylpyrazole of 7- simultaneously [5,1-b] [1,3] thiazole -2- formic acid

To the bromo- 3- isopropyl -6- methylpyrazole of 7- simultaneously [5,1-b] [1,3] thiazole -2- Ethyl formate (4.8 g, 14.5 mmol) LiOH (1 g, 41.67 mmol) are added in solution in EtOH (100 mL), water (100mL) and THF (50 mL). Acquired solution is stirred at room temperature overnight.By mixture concentration until remaining aqueous solution, washed with methylene chloride three times and with dense HCl acidification.The solid of precipitating is filtered, is washed with water and dries.

Yield: 3 g (85 % of purity；8.41 mmol；58.0 theoretical %)

LC-MS (method L0): R_t= 1.39 min；MS (ESIpos): m/z = 302.9；304.9 [M+H]⁺。

¹H-NMR (399,95) MHz, DMSO-d6) δ [ppm]: 14.00 (bs, 1H, COOH), 4.37 (hept, 1H), 2.33 (s, 1H), 1.44 (d, 6H)。

Step 5

The bromo- N- of 7- [(4S) -3,4- dihydro -2H- chromene -4- base] -3- isopropyl -6- methylpyrazole simultaneously [5,1-b] [1,3] thiophene Azoles -2- formamide

The bromo- 3- isopropyl -6- methylpyrazole of the 7- being incorporated in into flask in 125 mL methylene chloride simultaneously [5,1-b] [1,3] thiophene Azoles -2- formic acid (3.0 g, 85 % purity, 8.41 mmol), (4S)-chroman -4- amine hydrochlorate (1.87 g, 10.09 mmol)、N,NDiisopropyl ethyl amine (2.17 g, 16.82 mmol), 4- (N,NDimethylamino) pyridine (513.8 mg, 4.21 mmol), 1- hydroxyl -1HBenzotriazole (568.3 mg, 4.21 mmol) and 1- ethyl -3- (3- dimethylamino third Base) carbodiimide hydrochloride (1.61 g, 8.41 mmol).Reaction mixture is stirred overnight in environment temperature, then with water Mixing separates methylene chloride phase, is dried by sodium sulphate/silica gel pillar and removes solvent under reduced pressure.Residue is passed through into silicon Rubber column gel column chromatography (eluant cyclohexane/ethyl acetate gradient) is purified to obtain title compound.

Yield: 2.0 g (4.6 mmol, 54.7 theoretical %)

LC-MS (method L0): R_t= 1.70 min；MS (ESIpos): m/z = 434.0；435.9 [M+H]⁺。

¹H-NMR (399,95) MHz, DMSO-d6) δ [ppm]: 8.91 (d, 1H, NH), 7.20 – 7.15 (m, 2H), 6.92 – 6.89 (dd, 1H), 6.81 (d, 1H), 5.24 – 5.19 (m, 1H), 4.30 – 4.20 (m, 2H), 4.09 – 4.02 (hept, 1H), 2.32 (s, 3H), 2.16 – 2.05 (m, 2H), 1.47 (d, 6H)。

Step 6

7- (3,5- dichlorophenyl)-N- [(4S) -3,4- dihydro -2H- chromene -4- base] -3- isopropyl -6- methyl pyrazole simultaneously [5, 1-b] [1,3] thiazole -2- formamide

3 mL dioxanes, the bromo- N- of 7- [(4S) -3,4- dihydro -2H- chromene -4- base] -3- isopropyl -6- are packed into microwave tube Methylpyrazole simultaneously [5,1-b] [1,3] thiazole -2- formamide (150 mg, 0.34 mmol), 3,5- dichlorophenyl boric acid (54.9 Mg, 0.28 mmol), 2M aqueous sodium carbonate (1.44 mL) and (1,1 '-bis- (diphenylphosphinos)-ferrocene-palladium-dichloros Methane complex compound (21 mg, 0.02 mmol).By reaction mixture argon-degassed 5min, and at microwave device (Biotage) In in 100 DEG C of 40 min of processing.Crude mixture is filtered and passes through silica gel/sodium sulfate pillar and is washed.The solvent of filtrate is being subtracted Pressure evaporation；Remaining unprocessed substance is gradient-purified to obtain using cyclohexane/ethyl acetate by flash column chromatography Title compound is pale solid.

Yield: 92.6 mg (0.185 mmol, theoretical 66.1 % (about boric acid))

LC-MS (method L0): R_t= 1.93 min；MS (ESIpos): m/z = 500.0；501.9 [M+H]⁺。

¹H-NMR (399,95) MHz, DMSO-d6) δ [ppm]: 8.92 (d, 1H, NH), 7.53 (s, 1H), 7.46 (s, 2H), 7.21 – 7.15 (m, 2H), 6.91 (t, 1H), 6.81 (d, 1H), 5.26 – 5.21 (q, 1H), 4.32 – 4.19 (m, 3H), 2.56 (s, 3H), 2.12 – 2.06 (m, 2H), 1.51 (d, 6H)。

Following embodiment 2-15 are similarly prepared:

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