Diaminopyrimidine derivatives and processes for the preparation thereof

Patent metadata

Field	Value
Publication number	US-10640490-B2
Application number	US-201715813741-A
Country	US
Kind code	B2
Filing date	Nov 15, 2017
Priority date	Feb 25, 2011
Publication date	May 5, 2020
Grant date	May 5, 2020

Abstract

The present invention provides a diaminopyrimidine derivative or its pharmaceutically acceptable salt, a process for the preparation thereof, a pharmaceutical composition comprising the same, and a use thereof. The diaminopyrimidine derivative or its pharmaceutically acceptable salt functions as a 5-HT 4 receptor agonist, and therefore can be usefully applied for preventing or treating dysfunction in gastrointestinal motility, one of the gastrointestinal diseases, such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, post-operative ileus, delayed gastric emptying, gastroparesis, intestinal pseudo-obstruction, drug-induced delayed transit, or diabetic gastric atony.

First claim

The invention claimed is:

1. A compound of Formula 1 or its pharmaceutically acceptable salt:

wherein,
R 1 is a phenyl group substituted with one or more substituents selected from the group consisting of amino, halogen, cyano, nitro, C 1-3 alkyl (where the C 1-3 alkyl is optionally substituted with halogen), C 1-5 alkoxy, C 1-5 alkylthio, and aminocarbonyl; or
a heteroaryl group selected from the group consisting of quinolinyl, chromenonyl, benzofuranyl, indolyl, indolinyl, benzimidazol-5-yl, benzimidazol-6-yl, and indazolyl, wherein the heteroaryl group is optionally substituted with one or more C 1-5 alkyl (where the C 1-5 alkyl is optionally substituted with halogen),
R 2 is a nitrogen-containing cyclic group of the following Formula B (where * in Formula B represents the position attached to the compound of Formula 1),

R 3 is a C 2-5 alkyl group,
R 4 is hydrogen; a C 1-5 alkyl group optionally substituted with hydroxy; or a C 1-5 alkoxycarbonyl group,
R 5 is hydrogen; a hydroxyl group; a benzyloxy group; a C 1-5 alkyl group; or a group selected from the group consisting of the following Formulas E and I (where * in Formulas E and I represents the position attached to the compound of Formula B),

R 6 is hydrogen,
X is —CH(R 7 )—; —N(R 8 )—; or —O—,
R 7 is hydrogen,
R 4 and R 5 are optionally joined to each other to form a pentagonal or hexagonal ring,
R 8 is a C 1-5 alkyl group,
R 9 is a C 1-10 alkyl group optionally substituted with hydroxy,
R 10 is hydrogen,
R 11 and R 12 are, independently each other, hydrogen; or a C 1-10 alkyl group optionally substituted with a substituent selected from the group consisting of C 1-5 alkylthio, C 3-10 cycloalkyl, phenyl (where the phenyl is optionally substituted with hydroxy), thiophenyl, pyrrolyl, and furanyl (where the furanyl is optionally substituted with mono- or di-C 1-5 alkyl).

2. The compound or its pharmaceutically acceptable salt of claim 1 , which is selected from the group consisting of:
N-(4-fluorophenyl)-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(4-fluorophenyl)-4-morpholino-6-propylpyrimidin-2-amine;
N-(4-fluorophenyl)-4-(2-methylpiperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(4-fluorophenyl)-4-(3-methylpiperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(4-fluorophenyl)-4-(decahydroquinolin-1(2H)-yl)-6-propylpyrimidin-2-amine;
N-(4-fluorophenyl)-4-(piperazin-1-yl)-6-propylpyrimidin-2-amine;
4-(2-ethylpiperidin-1-yl)-N-(4-fluorophenyl)-6-propylpyrimidin-2-amine;
2-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]piperidin-2-yl}ethanol;
ethyl 1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]piperidin-2-carboxylate;
4-butyl-N-(4-fluorophenyl)-6-(piperidin-1-yl)pyrimidin-2-amine;
4-butyl-6-(2-ethylpiperidin-1-yl)-N-(4-fluorophenyl)pyrimidin-2-amine;
2-{1-[6-butyl-2-(4-fluorophenylamino)pyrimidin-4-yl]piperidin-2-yl}ethanol;
4-butyl-N-(4-fluorophenyl)-6-morpholinopyrimidin-2-amine;
2-{1-[2-(4-chloro-3-nitrophenylamino)-6-propylpyrimidin-4-yl]piperidin-2-yl}ethanol;
2-(1-{2-[3-(methylthio)phenylamino]-6-propylpyrimidin-4-yl}piperidin-2-yl)ethanol;
N-{1-[2-(4-fluorophenylamino)-6-propylpyrimidin-4-yl]piperidin-3-yl}acetamide;
4-[3-(benzyloxy)piperidin-1-yl]-N-(4-fluorophenyl)-6-propylpyrimidin-2-amine;
N-[4-(piperidin-1-yl)-6-propylpyrimidin-2-yl]-1H-indol-5-amine;
N-(3-chloro-4-methylphenyl)-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
N-[4-(piperidin-1-yl)-6-propylpyrimidin-2-yl]quinolin-6-amine;
4-(piperidin-1-yl)-6-propyl-N-[3-(trifluoromethyl)phenyl]pyrimidin-2-amine;
N-[4-(piperidin-1-yl)-6-propylpyrimidin-2-yl]-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-amine;
N-[3-(methylthio)phenyl]-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(5-methoxy-2-methylphenyl)-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(5-chloro-2-methylphenyl)-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(4-fluoro-3-nitrophenyl)-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(4-methoxyphenyl)-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(3-methoxyphenyl)-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(3-chlorophenyl)-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(3-nitrophenyl)-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(4-chloro-3-nitrophenyl)-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
3-[4-(piperidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitrile;
N-(4-methyl-3-nitrophenyl)-4-(piperidin-1-yl)-6-propylpyrimidin-2-amine;
N-[4-(octahydroquinolin-1(2H)-yl)-6-propylpyrimidin-2-yl]-1H-indol-6-amine;
2-{1-[2-(1H-indol-6-ylamino)-6-propylpyrimidin-4-yl]piperidin-2-yl}ethanol;
N-[4-(piperidin-1-yl)-6-propylpyrimidin-2-yl]-1H-indol-6-amine;
N-(4-morpholino-6-propylpyrimidin-2-yl)-1H-indol-6-amine;
N-[4-(2-ethylpiperidin-1-yl)-6-propylpyrimidin-2-yl]-1H-indol-6-amine;
(R)-3-[4-(3-ethylmorpholino)-6-propylpyrimidin-2-ylamino]benzonitrile;
(R)-3-[4-(2-methylpiperazin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitrile;
4-morpholino-N-(3-nitrophenyl)-6-propylpyrimidin-2-amine;
N-(4-fluoro-3-nitrophenyl)-4-morpholino-6-propylpyrimidin-2-amine;
N-(4-chloro-3-nitrophenyl)-4-morpholino-6-propylpyrimidin-2-amine;
N-(3-methoxyphenyl)-4-morpholino-6-propylpyrimidin-2-amine;
N-(4-methoxyphenyl)-4-morpholino-6-propylpyrimidin-2-amine;
N-[3-(methylthio)phenyl]-4-morpholino-6-propylpyrimidin-2-amine;
N-(3-chlorophenyl)-4-morpholino-6-propylpyrimidin-2-amine;
N-(3-chloro-4-methylphenyl)-4-morpholino-6-propylpyrimidin-2-amine;
4-morpholino-6-propyl-N-[3-(trifluoromethyl)phenyl]pyrimidin-2-amine;
N-(4-morpholino-6-propylpyrimidin-2-yl)-1H-indol-5-amine;
N-(4-morpholino-6-propylpyrimidin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-amine;
N-(4-morpholino-6-propylpyrimidin-2-yl)quinolin-6-amine;
3-(4-morpholino-6-propylpyrimidin-2-ylamino)benzonitrile;
N-(5-methoxy-2-methylphenyl)-4-morpholino-6-propylpyrimidin-2-amine;
N-(5-chloro-2-methylphenyl)-4-morpholino-6-propylpyrimidin-2-amine;
N-(4-morpholino-6-propylpyrimidin-2-yl)quinolin-3-amine;
4-(2-ethylpiperidin-1-yl)-N-(3-nitrophenyl)-6-propylpyrimidin-2-amine;
4-(2-ethylpiperidin-1-yl)-N-(4-fluoro-3-nitrophenyl)-6-propylpyrimidin-2-amine;
N-(4-chloro-3-nitrophenyl)-4-(2-ethylpiperidin-1-yl)-6-propylpyrimidin-2-amine;
4-(2-ethylpiperidin-1-yl)-N-(3-methoxyphenyl)-6-propylpyrimidin-2-amine;
4-(2-ethylpiperidin-1-yl)-N-(4-methoxyphenyl)-6-propylpyrimidin-2-amine;
4-(2-ethylpiperidin-1-yl)-N-[3-(methylthio)phenyl]-6-propylpyrimidin-2-amine;
N-(3-chlorophenyl)-4-(2-ethylpiperidin-1-yl)-6-propylpyrimidin-2-amine;
N-(3-chloro-4-methylphenyl)-4-(2-ethylpiperidin-1-yl)-6-propylpyrimidin-2-amine;
4-(2-ethylpiperidin-1-yl)-6-propyl-N-[3-(trifluoromethyl)phenyl]pyrimidin-2-amine;
N-[4-(2-ethylpiperidin-1-yl)-6-propylpyrimidin-2-yl]-1H-indol-5-amine;
N-[4-(2-ethylpiperidin-1-yl)-6-propylpyrimidin-2-yl]-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-amine;
N-[4-(2-ethylpiperidin-1-yl)-6-propylpyrimidin-2-yl]quinolin-6-amine;
3-[4-(2-ethylpiperidin-1-yl)-6-propylpyrimidin-2-ylamino]benzonitrile;
4-(2-ethylpiperidin-1-yl)-N-(5-methoxy-2-methyl phenyl)-6-propylpyrimidin-2-amine;
N-(5-chloro-2-methylphenyl)-4-(2-ethylpiperidin-1-yl)-6-propylpyrimidin-2-amine;
N-[4-(2-ethylpiperidin-1-yl)-6-propylpyrimidin-2-yl]quinolin-3-amine;
(R)—N-(4-chloro-3-nitrophenyl)-4-(2-methyl piperazin-1-yl)-6-propylpyrimidin-2-amine;
(R)—N-[4-(2-methylpiperazin-1-yl)-6-propylpyrimidin-2-yl]-1H-indol-6-amine;
(R)—N-(2-methylpiperazin-1-yl)-6-propyl-N-[3-(trifluo

Assignees

• Yuhan Corp

Inventors

• Lee Hyun-Joo
• Kim Dong-Hoon
• Kim Tae-Kyun
• Yoon Young-Ae
• Sim Jae-Young
• Cha Myung-Hun
• Jung Eun-Jung
• Ahn Kyoung-Kyu
• Lee Tai-Au

Classifications

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P1/12

  Antidiarrhoeals · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title