Cyclic amine azaheterocyclic carboxamides

Patent metadata

Field	Value
Publication number	US-9586938-B2
Application number	US-201113810860-A
Country	US
Kind code	B2
Filing date	Jul 28, 2011
Priority date	Jul 29, 2010
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

The invention provides novel cyclic amine azaheterocyclic carboxamide according to Formula (I), Formula (II) and Formula (III) their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

First claim

The invention claimed is:

1. A compound of Formula (I)

and pharmaceutically acceptable salts, solvates, or solvates of salts thereof,
wherein:
X is N,
Y is NH or is absent,
R 1 is

each Y′ is independently CH2 or NH such that when Y′ is NH, Z is CH2 or absent and when Y′ is CH2, Z is NH,
each Z is independently CH2, NH or is absent such that when Z is CH2 or absent, Y′ is NH and when Z is NH, Y′ is CH2, and
each Z′ is independently Ar, alkyl, halogen, OMe, CF3, CN, OCF3, SO 2 Me, H (mono, di, or tri-substituted with any above combination)
R 2 is A, or H,
Ar is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O and/or S atoms and 5, 6, 7, 8, 9, or 10 skeleton atoms, which may be unsubstituted or, independently of one another, mono-, di- or trisubstituted by Hal, A, OH, SH, OA, NH 2 , NHA, NA 2 , NO 2 , CN, OCN, SCN, COOH, COOA, CONH 2 , CONHA, CONA 2 , NHCOA, NHCONHA, NHCONH 2 , NHSO 2 A, CHO, COA, SO 2 NH 2 , SO 2 A and/or SO 2 Hal, and in which a ring N-atom may be substituted by an O-atom to form an N-oxide group, and in which in the case of a bicyclic aromatic cycle on of the two rings may be partly saturated,
A is unbranched or branched linear or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH2 groups may be replaced by an O or S atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—, —N(LA)-, —CONH—, —NHCO— or —CH═CH— group, and in which 1-3 H atoms may be replaced by Hal, and in which one or two CH 3 groups may be replaced by OH, SH, NH 2 , NH(LA), N(LA) 2 , NHCOOH, NHCONH 2 or CN,
LA is unbranched or branched, linear alkyl having 1, 2, 3 or 4 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal and
Hal is F, Cl, Br or I.

2. The compound according to claim 1 and pharmaceutically acceptable salts, solvates, or solvates of salts thereof, wherein:
X is N,
Y is NH,
R 2′ is A or H,
A is unbranched or branched linear or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH 2 groups may be replaced by an O or S atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—, —N(LA)-, —CONH—, —NHCO— or —CH═CH— group, and in which 1-3 H atoms may be replaced by Hal, and in which one or two CH 3 groups may be replaced by OH, SH, NH 2 , NH(LA), N(LA) 2 , NHCOOH, NHCONH 2 or CN,
LA is unbranched or branched, linear alkyl having 1, 2, 3 or 4 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal and
Hal is F, Cl, Br or I.

3. The compound of claim 1 of Formula (II)

and pharmaceutically acceptable salts, solvates, or solvates of salts,
wherein:

X is N,
R 2 is A or H,
Y′ is CH2 or NH such that when Y′ is NH, Z is CH2 or absent and when Y′ is CH2, Z is NH,
Z is CH2, NH or is absent such that when Z is CH2 or absent, Y is NH and when Z is NH, Y is CH2, and
Z′ Ar, alkyl, halogen, OMe, CF3, CN, OCF3, SO 2 Me, H (mono, di, or tri-substituted with any above combination).

4. A compound selected from the group consisting of:
trans racemic 4-((4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
trans racemic 4-((4-phenylpyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-((4-(2-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-((4-(4-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-((4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-((4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide,
4-((4-(2-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 4-((4-(3-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 4-((4-(2-chloro-6-fluorophenyl)pyrrolidin-3-yl)amino)-quinazoline-8-carboxamide;
trans, racemic 4-((4-(3-bromophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 4-((4-(3-fluorophenyl)-1-methylpyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 4-((-4-(naphthalen-2-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 4-((4-(naphthalen-1-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
6-methyl-4-((4-phenylpyrrolidin-3-yl)amino)quinazoline-8-carboxamide,
2-methyl-4-((4-phenylpyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-((4-(4-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;
4-((4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;
4-((4-(4-fluorophenyl)-1-methylpyrrolidin-3-yl)amino)quinoline-8-carboxamide;
4-((4-phenylpyrrolidin-3-yl)amino)quinoline-8-carboxamide;
4-((4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide;
4-((4-(2-fluorophenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide;
4-((4-(2-methoxyphenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide;
4-((4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide;
4-((4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide;
trans-4-(4-Phenylcarbamoyl-pyrrolidin-3-ylamino)-quinazoline-8-carboxylic acid amide;
trans, racemic 4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide;
racemic, trans 4-((4-(3-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;
cis, racemic 4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 4-((4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 4-((4-(m-tolyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 4-((4-(4-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic Benzyl 3-((8-carbamoylquinazolin-4-yl)amino)-4-(3-fluoro-4-methylphenyl)piperidine-1-carboxylate;
racemic, trans 4-((4-(3-fluoro-4-methylphenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 4-((4-(3-fluorophenyl)piperidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;
trans, racemic 2-ethyl-4-((4-(3-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 2-ethyl-4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 2-methyl-4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide;
trans, racemic 4-((4-phenylpiperidin-3-yl)amino)quinoline-8-carboxamide;
trans, racemic Ethyl 8-carbamoyl-4-(4-phenylpiperidin-3-yl)amino)quinoline-3-carboxylate;
trans, racemic 8-carbamoyl-4-((4-phenylpiperidin-3-yl)amino)quinoline-3-carboxylic acid;
4-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(((3S,4R)-4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(((3R,4S)-4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(((3S,4R)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(((3R,4S)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(((3R,4S)-4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(((3R,4R)-4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;
4-(((3R,4S)-4-(3-(tri

Assignees

• Huck Bayard R
• Chen Xiaoling
• Neagu Constantin
• Jones Reinaldo
• Xiao Yufang
• Mochalkin Igor
• Merck Patent Gmbh

Inventors

• Huck Bayard R
• Chen Xiaoling
• Neagu Constantin
• Jones Reinaldo
• Xiao Yufang
• Mochalkin Igor

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title