Diaminopyrimidine derivatives and processes for the preparation thereof

• US 10,227,330 B2
• Filed: 12/20/2017
• Issued: 03/12/2019
• Est. Priority Date: 02/25/2011
• Status: Active Grant

• Current Assignee: Yuhan Corporation
• Original Assignee: Yuhan Corporation
• 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
• Primary Examiner(s): Klinkel, Kortney L.
• Assistant Examiner(s): Strong, Tori
• Application Number:
  US15/848,760
• Publication Number:
  US 20180111918A1
• Time in Patent Office: 447 Days
• Field of Search: None
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

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-HT₄ 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.

Claims

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

2. The compound or its pharmaceutically acceptable salt of claim 1, wherein

R₁ 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,

R₂ 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,

R₃ 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,

R₄ is hydrogen,

R₅ is a C_1-5 alkyl group,

R₆ 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,

R₇ is hydrogen,

R₈ and R₉ 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, 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.

3. A pharmaceutical composition for agonizing a 5-HT₄ receptor, comprising a therapeutically effective amount of a compound of Formula 1 or its pharmaceutically acceptable salt;

and a pharmaceutically acceptable carrier;

4. The pharmaceutical composition of claim 3, wherein

R₁ 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,

R₂ 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,

R₃ 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,

R₄ is hydrogen,

R₅ is a C_1-5 alkyl group,

R₆ 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,

R₇ is hydrogen,

R₈ and R₉ 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, 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.

5. A method of agonizing a 5-HT₄ receptor and treating a dysfunction in gastrointestinal motility in a disease selected from the group consisting of gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, post-operative ileus, delayed gastric emptying, gastroparesis, intestinal pseudo-obstruction, drug-induced delayed transit, and diabetic gastric atony, comprising administering an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof:

6. The method of claim 5, wherein

R₁ 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,

R₂ 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,

R₃ 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,

R₄ is hydrogen,

R₅ is a C_1-5 alkyl group,

R₆ 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,

R₇ is hydrogen,

R₈ and R₉ 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, 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.