Diaminopyrimidine derivatives and processes for the preparation thereof

Patent metadata

Field	Value
Publication number	US-10227330-B2
Application number	US-201715848760-A
Country	US
Kind code	B2
Filing date	Dec 20, 2017
Priority date	Feb 25, 2011
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

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 hydroxy, amino, halogen, cyano, nitro, hydroxycarbonyl, C 1-5 alkyl (where the C 1-5 alkyl is optionally substituted with halogen or amino), C 2-6 alkenyl, C 2-6 alkynyl, C 1-5 alkoxy (where the C 1-5 alkoxy is optionally substituted with halogen), C 1-5 alkylthio, mono- or di-C 1-5 alkylamino, C 1-5 alkylsulfonylamino, C 1-5 alkylcarbonylamino, C 1-5 alkoxycarbonyl, aminosulfonyl, aminocarbonyl, C 1-5 alkylaminocarbonyl, and benzyloxycarbonylamino; or
a heteroaryl group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, naphthyl, indanyl, quinolinyl, quinolinonyl, chromenonyl, dihydroindolonyl, isoindoline-1,3-dionyl, dihydrobenzimidazolonyl, benzoxazolonyl, benzofuranyl, benzothiophenyl, benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxinyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and indazolyl, wherein the heteroaryl group may be optionally substituted with one or more substituents selected from the group consisting of amino, di-C 1-5 alkylamino, cyano, nitro, halogen, C 1-5 alkyl (where the C 1-5 alkyl is optionally substituted with halogen), C 1-5 alkoxy (where the C 1-5 alkoxy is optionally substituted with halogen), acetyl, and C 1-5 alkylsulfonyl,
R 2 is hydrogen; a C 1-5 alkyl group optionally substituted with a substituent selected from the group consisting of hydroxy, C 1-5 alkoxy, benzylamino (where the benzylamino is optionally substituted with halogen), phenylamino, C 1-5 alkylamino, C 3-6 cycloalkylamino, pyrrolidinyl, and hydroxy-C 1-5 alkylamino; a C 1-5 alkoxycarbonyl group; a hydroxycarbonyl group; an aminocarbonyl group; a formyl group; or an oxo (═O) group,
R 3 is hydrogen; a hydroxyl group; a C 1-5 alkoxy group; a phenoxy group; a benzyloxy group; a C 1-5 alkyl group optionally substituted with a substituent selected from the group consisting of amino, C 1-5 alkoxycarbonylamino, and mono- or di-C 1-5 alkylamino; or a group selected from the group consisting of the following Formulas A to E (where * in Formulas A to E represents the position attached to the compounds of Formula 1),

R 4 is hydrogen; a hydroxyl group; or a C 1-5 alkyl group optionally substituted with hydroxy,
R 5 is a C 1-5 alkyl group optionally substituted with phenyl; or a C 2-6 alkenyl group optionally substituted with phenyl or C 3-6 cycloalkyl,
R 6 is a C 1-10 alkyl group optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 1-5 alkoxy, amino, C 1-5 alkoxycarbonylamino, benzyloxycarbonylamino, mono- or di-C 1-5 alkylamino, C 1-5 alkoxy-C 1-5 alkyloxy, phenoxy, benzyloxy, phenyl (where the phenyl is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C 1-5 alkoxy, and hydroxy), thiophenyl, pyridinyl, indolyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, piperidinyl, piperazinyl (where the piperazinyl is optionally substituted with benzyl), C 3-6 cycloalkyl, acetyl, and benzoyl; a C 3-6 cycloalkyl group; a piperidinyl group optionally substituted with C 1-5 alkoxycarbonyl; a C 1-10 alkenyl group optionally substituted with phenyl; a trifluoromethyl group; a trifluoroethyl group; or a phenyl group optionally substituted with halogen,
R 7 is hydrogen; or a C 1-5 alkyl group,
R 8 and R 9 are, independently each other, hydrogen; a C 1-10 alkyl group optionally substituted with a substituent selected from the group consisting of amino, C 1-5 alkoxycarbonylamino, hydroxy, C 1-5 alkylthio, C 3-10 cycloalkyl, phenyl (where the phenyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C 1-5 alkyl, mono- or di-C 1-5 alkylamino, trifluoromethyl, halogen, C 1-5 alkoxy, and C 1-5 alkylcarbonyloxy), thiophenyl, pyrrolyl, furanyl (where the furanyl is optionally substituted with mono- or di-C 1-5 alkyl), pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, and benzyloxy; a piperidinyl group optionally substituted with benzyl, benzoyl, C 1-5 alkyl, or C 1-5 alkylcarbonyl; an azetidinyl group optionally substituted with C 1-5 alkoxycarbonyl; a C 1-5 alkylsulfonyl group; a phenylsulfonyl group (where the phenyl moiety is optionally substituted with halogen); or a C 3-10 cycloalkyl group.

2. The compound or its pharmaceutically acceptable salt of claim 1 , wherein
R 1 is a phenyl group substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, hydroxycarbonyl, C 1-5 alkyl (where the C 1-5 alkyl is optionally substituted with halogen or amino), C 1-5 alkoxy (where the C 1-5 alkoxy is optionally substituted with halogen), C 1-5 alkylthio, aminosulfonyl, aminocarbonyl, C 1-5 alkylaminocarbonyl, and benzyloxycarbonylamino; or a heteroaryl group selected from the group consisting of quinolinyl, chromenonyl, indolyl, indolinyl, and benzimidazolyl, wherein the heteroaryl group may be optionally substituted with one or more substituents selected from the group consisting of C 1-5 alkyl (where the C 1-5 alkyl is optionally substituted with halogen) and acetyl,
R 2 is hydrogen; a C 1-5 alkyl group optionally substituted with a substituent selected from the group consisting of hydroxyl and C 1-5 alkoxy, benzylamino (where the benzylamino is optionally substituted with halogen), phenylamino, C 1-5 alkylamino, C 3-6 cycloalkylamino, and hydroxy-C 1-5 alkylamino; a C 1-5 alkoxycarbonyl group; or a formyl group,
R 3 is hydrogen; a hydroxyl group; a C 1-5 alkyl group optionally substituted with a substituent selected from the group consisting of amino, C 1-5 alkoxycarbonylamino, and mono- or di-C 1-5 alkylamino; or a group selected from the group consisting of the Formulas A, B, D and E,
R 4 is hydrogen,
R 5 is a C 1-5 alkyl group,
R 6 is a C 1-10 alkyl group optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 1-5 alkoxy, amino, C 1-5 alkoxycarbonylamino, benzyloxycarbonylamino, mono- or di-C 1-5 alkylamino, C 1-5 alkoxy-C 1-5 alkyloxy, phenoxy, benzyloxy, phenyl (where the phenyl is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C 1-5 alkoxy, and hydroxy), thiophenyl, pyridinyl, indolyl, piperidinyl, piperazinyl (where the piperazinyl is optionally substituted with benzyl), C 3-6 cycloalkyl, acetyl, and benzoyl; a C 3-6 cycloalkyl group; a piperidinyl group optionally substituted with C 1-5 alkoxycarbonyl; a C 1-10 alkenyl group optionally substituted with phenyl; a trifluoromethyl group; a trifluoroethyl group; or a phenyl group optionally substituted with halogen,
R 7 is hydrogen,
R 8 and R 9 are, independently each other, hydrogen; a C 1-10 alkyl group optionally substituted with a substituent selected from the group consisting of amino, C 1-5 alkoxycarbonylamino, hydroxy, C 1-5 alkylthio, C 3-10 cycloalkyl, phenyl (where the phenyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C 1-5 alkyl, mono- or di-C 1-5 alkylamino, trifluoromethyl, halogen, C 1-5 alkoxy, and C 1-5 alkylcarbonyloxy), thiophenyl, pyrrolyl, furanyl (where the

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

• A61P43/00

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

• A61P1/10

  Laxatives · CPC title

• C07D413/04

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

• A61P1/14

  Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents · CPC title

• C07D401/04

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