Five-member-heterocycle fused pyridine compounds, method of producing the same, and use thereof

Patent metadata

Field	Value
Publication number	US-9988381-B2
Application number	US-201414895832-A
Country	US
Kind code	B2
Filing date	Jun 18, 2014
Priority date	Jun 19, 2013
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

This invention provides a class of five-member-heterocycle fused pyridine compounds as shown below in Formula (X), pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, a method of producing the same, pharmaceutical compositions containing the compound, and use of the compounds in preparing medicament for preventing and/or treating diseases and tumors associated with abnormal protein tyrosine kinase.

First claim

We claim:

1. A 5-member-heterocycle-fused pyridine compound having a structure of Formula II), pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof,

wherein:
R 1 is substituted or unsubstituted C 6 -C 20 aryl; substituted or unsubstituted 5- to 10- membered heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, O, and S; or substituted or unsubstituted 4- to 10-membered heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, O, and S; wherein, substituent in the substituted group is halogen, nitro, cyano, hydroxyl, unsubstituted or halogen- or morpholinyl-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, —NR a R b , —C(O)(NR a R b ), unsubstituted phenyl or phenyl substituted by 1-4 of R 3 , or unsubstituted 4- to 7-membered heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, O, and S, or 4- to 7-membered heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, O, and S substituted by 1-4 of R 4;
R 2 is substituted or unsubstituted C 6 -C 20 aryl; substituted or unsubstituted 5- to 10- membered heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, O, and S; or substituted or unsubstituted 4- to 10-membered heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, O, and S; wherein, substituent in the substituted group is halogen, nitro, cyano, C 1 -C 4 alkylenedioxy, unsubstituted or halogen- or —NR c R d -substituted C 1 - C 6 alkyl or C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 sulfamido, —NR a R b , —C(O)R′, morpholinyl, or unsubstituted or R″-substituted piperidinyl;
R 3 is halogen, nitro, cyano, C 1 -C 4 alkylenedioxy, unsubstituted or halogen- or morpholinyl-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NR a R b , —C(O)R′, or morpholinyl;
R 4 is halogen, nitro, cyano, unsubstituted or halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NR a R b , —C(O)R′, or unsubstituted or C 1 -C 6 alkoxycarbonyl-substituted piperidinyl;
R′ is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NR a R b , or unsubstituted or halogen- or C 1 -C 6 alkyl-substituted 4 - to 7-membered heterocyclyl;
R″ is C 1 -C 6 alkyl; C 3 -C 6 cycloalkyl; C 1 -C 6 alkylcarbonyl; C 1 -C 6 alkoxycarbonyl; C 3 -C 6 cycloalkylcarbonyl; or unsubstituted benzoyl or benzoyl substituted by substituent(s) selected from the group consisting of halogen, C 1 -C 6 alkyl, and halogen-substituted C 1 -C 6 alkyl;
R a and R b are each independently H, C 1 -C 6 alkyl or C 1 -C 6 alkylcarbonyl; and
R c and R d are each independently H or C 1 -C 6 alkyl; or, R c and R d , together with the N atom to which they are attached, form 3- to 7-membered heterocyclyl.

2. The 5-member-heterocycle-fused pyridine compound, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, according to claim 1 , wherein, R 1 is selected from phenyl, naphthyl, isoxazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl, benzo[1,2,5]oxadiazolyl, imidazo[1,2-b]pyridazinyl, pyrazolo[1,5-a]imidazolyl, imidazo[1,2-a]pyrimidinyl; wherein substituent in the substituted group is halogen; nitro; hydroxyl; cyano; unsubstituted or halogen- or morpholinyl-substituted C 1 -C 5 alkyl; C 1 -C 5 alkoxy; C 1 -C 5 alkylcarbonyl; C 1 -C 5 alkoxycarbonyl; —NR a R b ; —C(O)(NR a R b ); unsubstituted phenyl or phenyl substituted by 1-3 of R 3 ; or unsubstituted 5-7 membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S or 5-7 membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S substituted by 1-3 of R 4 , wherein said heteroaryl is selected from the group consisting of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyranyl, pyridinyl, morpholinyl, oxazinyl and pyrazinyl;
R 2 is substituted or unsubstituted C 6 -C 10 aryl; substituted or unsubstituted 5-10 membered heteroaryl comprising 1-5 heteroatoms selected from N, O, and S; or substituted or unsubstituted 5-10 membered heterocyclyl comprising 1-5 heteroatoms selected from N, O, and S; wherein, substituent in the substituted group is halogen, nitro, cyano, C 1 -C 4 alkylenedioxy; unsubstituted C 1 -C 5 alkyl or C 1 -C 5 alkyl substituted by halogen or —NR c R d ; C 1 -C 5 alkoxy; C 1 -C 5 sulfamido; —NR a R b ; —C(O)R′; morpholinyl; or unsubstituted or R″-substituted piperidinyl;
R 3 is halogen; nitro; cyano; C 1 -C 4 alkylenedioxy; unsubstituted or halogen- or morpholinyl-substituted C 1 -C 5 alkyl; C 1 -C 5 alkoxy; —NR a R b ; —C(O)R′; or morpholinyl;
R 4 is halogen, nitro, cyano, unsubstituted or halogen-substituted C 1 -C 5 alkyl; C 1 -C 5 alkoxy;
—NR a R b ; —C(O)R′; or unsubstituted or C 1 -C 5 alkoxycarbonyl-substituted piperidinyl;
R′ is C 1 -C 5 alkyl; C 1 -C 5 alkoxy; —NR a R b ; or unsubstituted or halogen- or C 1 -C 5 alkyl-substituted 5-6 membered heterocyclyl;
R″ is C 1 -C 5 alkyl; C 3 -C 6 cycloalkyl; C 1 -C 5 alkylcarbonyl; C 1 -C 5 alkoxycarbonyl; C 3 -C 6 cycloalkylcarbonyl; or unsubstituted benzoyl or benzoyl substituted by substituent(s) selected from halogen, C 1 -C 5 alkyl, halogen-substituted C 1 -C 5 alkyl;
R a and R b are independently H or C 1 -C 5 alkyl; and
R c and R d are independently H or C 1 -C 5 alkyl; or, R c and R d , together with the N atom to which they are attached, form 3-7 membered heterocyclyl.

3. The 5-member-heterocycle-fused pyridine compound, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, according to claim 1 , wherein R 1 is—

wherein, R m is H, halogen, nitro, cyano; unsubstituted or halogen- or morpholinyl-substituted C 1 -C 4 alkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkylcarbonyl; C 1 -C 4 alkoxycarbonyl; —NR a R b ; —C(O)(NR a R b ); unsubstituted phenyl or phenyl substituted by 1-3 of R 3 ; or unsubstituted 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, and S or 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, and S substituted by 1-3 of R 4 , wherein said heteroaryl is selected from the group consisting of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyranyl, pyridinyl, morpholinyl, oxazinyl, and pyrazinyl;
R 2 is substituted or unsubstituted C 6 -C 20 aryl; substituted or unsubstituted 5- to 10- membered heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, O, and S; or substituted or unsubstituted 4- to 10-membered heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, O, and S; wherein, substituent in the substituted group is halogen, nitro, cyano, C 1 -C 4 alkylenedioxy, unsubstituted or halogen- or —NR c R d -substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 sulfamido, —NR a R b , —C(O)R′, morpholinyl, or unsubstituted or R″-substituted piperidinyl;
R 3 is halogen, nitro, cyano, C 1 -C 2 alkylenedioxy, unsubstituted or halogen- or morpholinyl-substituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NR a R b , —C(O)R′, or 4-morpholinyl;
R 4 is halogen, nitro, cyano, unsubstituted or halogen-substituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NR a R b , —C(O)R′, 4-piperidinyl, or 1-t-butoxycarbonyl-4-piperidinyl;
R′ is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NR a R b , or 4-methylpiperazinyl;
R″ is C 1 -C 4 alkyl, C 3 -C6 cycloalkyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, C 3 -C 6 cycloalkylcarbonyl, or p-trifluoromethylbenzoyl;
R a and R b are each independently H, C 1 -C 4 alkyl

Assignees

• Shanghai Inst Materia Medica Cas
• Shanghai Green Valley Pharmaceutical Co Ltd
• Shanghai Haihe Pharmaceutical Co Ltd

Inventors

• Shen Jingkang
• Geng Meiyu
• Ding Jian
• Xiong Bing
• Al Jing
• Ma Yuchi
• Wang Xin
• Peng Xia
• Chen Yuelei
• Chen Danqi
• Meng Tao
• Ma Lanping
• Ji Yinchun

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title