Quinolin-2-one derivatives

Patent metadata

Field	Value
Publication number	US-10669251-B2
Application number	US-201616069326-A
Country	US
Kind code	B2
Filing date	Dec 16, 2016
Priority date	Jan 11, 2016
Publication date	Jun 2, 2020
Grant date	Jun 2, 2020

Abstract

Compounds of the formula I

in which X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , Q and Y have the meanings indicated in Claim 1,

are inhibitors of c-Kit kinase, and can be employed for the treatment of cancer.

First claim

The invention claimed is:

1. Compounds of the formula I

in which
X 1 , X 2 , X 3 , X 4 each, independently of one another, denote CH or N,
Y denotes N or CH,
Q denotes H or CH 3 ,
R 1 denotes H, F, Cl, Br, CN, CH 3 , CF 3 or OCH 3 ,
R 2 denotes H, F or Cl,
R 3 denotes phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, thiophenyl, dihydroisoindolyl or benzimidazolyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, CN, NO 2 , A, (CR 4 ) n OR 4 , (CR 4 ) n N(R 4 ) 2 , (CR 4 ) n S(O) m R 4 , (CR 4 ) n CON(R 4 ) 2 , (CR 4 ) n COHet, (CR 4 ) n SO 2 N(R 4 ) 2 , (CR 4 ) n SO 2 Het, (CR 4 ) n N(R 4 ) 2 , (CR 4 ) n Het, O(CR 4 ) n COHet, (CR 4 ) n O(CR 4 ) n Het, (CR 4 ) n N(R 4 )(CR 4 ) n Het, (CR 4 ) n CON(R 4 )(CR 4 ) n Het, (CR 4 ) n CON(R 4 )(CR 4 ) n N(R 4 ) 2 , (CR 4 ) n N(R 4 )COA, (CR 4 ) n N(R 4 )COHet′, (CR 4 ) n OCyc and/or (CR 4 ) n COOR 4 ,
R 4 denotes H or A′,
A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein two adjacent carbon atoms may form a double bond and/or one or two non-adjacent CH- and/or CH 2 -groups may be replaced by N-, O- and/or S-atoms and wherein 1-7 H-atoms may be replaced by R 5 ,
or cyclic alkyl having 3-7 C atoms,

A′ denotes unbranched or branched alkyl with 1-6 C-atoms, wherein one or two non-adjacent CH- and/or CH 2 -groups may be replaced by O-atoms,
Cyc denotes cyclobutyl, cyclopentyl or cyclohexyl, each of which is unsubstituted or mono- or disubstituted by A, Hal, OR 4 , N(R 4 ) 2 , Het′, (CR 4 ) n O(CR 4 ) n Het′, CON(R 4 ) 2 and/or ═O,
R 5 denotes F, Cl or OH,
Het denotes pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, [1,4]-diazepanyl, oxazolidinyl, hexahydro-pyrrolo[3,4-c]pyrrolyl, 2-oxa-6-aza-spiro[3.4]octanyl, 2-oxa-6-aza-spiro[3.5]nonanyl, 2-oxa-7-aza-spiro[3.5]nonanyl, 2,5-dioxa-8-aza-spiro[3.5]nonanyl, oxetanyl, 2-oxa-5-aza-spiro[3.4]octanyl, 2-oxa-6-aza-spiro[3.3]heptanyl, 3-aza-bicyclo[3.1.0]hexanyl, 2-oxa-7-aza-spiro[3.5]nonanyl, isoxazolidinyl, azetidinyl, 2,6-diaza-spiro[3.4]octanyl, hexahydro-pyrrolo[3,4-b]pyrrolyl, tetrahydrofuranyl or isothiazolidinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, Hal, OR 4 , OCOA, COA, (CR 4 ) n N(R 4 ) 2 , (CR 4 ) n Het′, (CR 4 ) n O(CR 4 ) n Het′, CON(R 4 ) 2 , COHet′, (CR 4 ) n S(O) m R 4 , and/or ═O,
Het′ denotes pyrrolidinyl, morpholinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrazolyl or piperazinyl, each of which is unsubstituted or mono- or disubstituted by A, Hal, OR 4 , N(R 4 ) 2 and/or ═O,
Hal denotes F, Cl, Br or I,
n denotes 0, 1, 2 or 3,
m denotes 0, 1 or 2,
with the proviso that only one or two of X 1 , X 2 , X 3 , X 4 denote N,
and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

2. Compounds according to claim 1 in which
R 1 denotes H, F, Cl, Br, CN, CH 3 , CF 3 or OCH 3 ,
R 2 denotes H or F,
and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

3. Compounds according to claim 1 , in which
R 3 denotes phenyl, pyridyl, pyrimidinyl, indolyl, indazolyl, thiophenyl, dihydroisoindolyl or benzimidazolyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, (CR 4 ) n OR 4 , (CR 4 ) n N(R 4 ) 2 , (CR 4 ) n S(O) m R 4 , (CR 4 ) n CON(R 4 ) 2 , (CR 4 ) n COHet, (CR 4 ) n SO 2 Het, (CR 4 ) n Het, O(CR 4 ) n COHet, (CR 4 ) n O(CR 4 ) n Het, (CR 4 ) n N(R 4 )(CR 4 ) n Het, (CR 4 ) n CON(R 4 )(CR 4 ) n Het, (CR 4 ) n CON(R 4 )(CR 4 ) n N(R 4 ) 2 , (CR 4 ) n N(R 4 )COA, (CR 4 ) n N(R 4 )COHet′, (CR 4 ) n OCyc and/or (CR 4 ) n COOR 4 ,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

4. Compounds according to claim 1 , in which
A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein two adjacent carbon atoms may form a double bond and/or one or two non-adjacent CH- and/or CH 2 -groups may be replaced by N- and/or O-atoms and wherein 1-7 H-atoms may be replaced by R 5 ,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

5. Compounds according to claim 1 , in which
Het + denotes pyrrolidinyl,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

6. Compounds according to claim 1 , in which
X 1 , X 2 , X 3 , X 4 each, independently of one another, denote CH or N,
Y denotes N or CH,
Q denotes H or CH 3 ,
R 1 denotes H, F, Cl, Br, CN, CH 3 , CF 3 or OCH 3 ,
R 2 denotes H or F,
R 3 denotes phenyl, pyridyl, pyrimidinyl, indolyl, indazolyl, thiophenyl, dihydroisoindolyl or benzimidazolyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, (CR 4 ) n OR 4 , (CR 4 ) n N(R 4 ) 2 , (CR 4 ) n S(O) m R 4 , (CR 4 ) n CON(R 4 ) 2 , (CR 4 ) n COHet, (CR 4 ) n SO 2 Het, (CR 4 ) n Het, O(CR 4 ) n COHet, (CR 4 ) n O(CR 4 ) n Het, (CR 4 ) n N(R 4 )(CR 4 ) n Het, (CR 4 ) n CON(R 4 )(CR 4 ) n Het, (CR 4 ) n CON(R 4 )(CR 4 ) n N(R 4 ) 2 , (CR 4 ) n N(R 4 )COA, (CR 4 ) n N(R 4 )COHet′, (CR 4 ) n OCyc and/or (CR 4 ) n COOR 4 ,
R 4 denotes H or A′,
A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein two adjacent carbon atoms may form a double bond and/or one or two non-adjacent CH- and/or CH 2 -groups may be replaced by N- and/or O-atoms and wherein 1-7 H-atoms may be replaced by R 5 ,
Cyc denotes cyclobutyl, cyclopentyl or cyclohexyl, each of which is unsubstituted or mono- or disubstituted by A, Hal, OR 4 , N(R 4 ) 2 , Het′, (CR 4 ) n O(CR 4 ) n Het′, CON(R 4 ) 2 and/or ═O,
A′ denotes unbranched or branched alkyl with 1-6 C-atoms, wherein one or two non-adjacent CH- and/or CH 2 -groups may be replaced by O-atoms,
R 5 denotes F, Cl or OH,
Het denotes pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, [1,4]-diazepanyl, oxazolidinyl, hexahydro-pyrrolo[3,4-c]pyrrolyl, 2-oxa-6-aza-spiro[3.4]octanyl, 2-oxa-6-aza-spiro[3.5]nonanyl, 2-oxa-7-aza-spiro[3.5]nonanyl, 2,5-dioxa-8-aza-spiro[3.5]nonanyl, oxetanyl, 2-oxa-5-aza-spiro[3.4]octanyl, 2-oxa-6-aza-spiro[3.3]heptanyl, 3-aza-bicyclo[3.1.0]hexanyl, 2-oxa-7-aza-spiro[3.5]nonanyl, isoxazolidinyl, azetidinyl, 2,6-diaza-spiro[3.4]octanyl, hexahydro-pyrrolo[3,4-b]pyrrolyl, tetrahydrofuranyl or isothiazolidinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, Hal, OR 4 , OCOA, COA, (CR 4 ) n N(R 4 ) 2 , (CR 4 ) n Het′, (CR 4 ) n O(CR 4 ) n Het′, CON(R 4 ) 2 , COHet′, (CR 4 ) n S(O) m R 4 , and/or ═O,
Het′ denotes pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl or pyrazolyl,
Hal denotes F, Cl, Br or I,
N denotes 0, 1, 2 or 3,
m denotes 0, 1 or 2,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

7. Compounds according to claim 1 , selected from the group consisting of
6-fluoro-3-{1-[4-(morpholine-4-carbonyl)-phenyl]-1H-[1,2,3]triazol-4-yl}-1H-quinolin-2-one,
3-{1-[4-(morpholine-4-carbonyl)-phenyl]-1H-[1,2,3]triazol-4-yl}-1H-quinolin-2-one,
N,N-dimethyl-4-[4-(2-oxo-1,2-dihydro-[1,8]naphthyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide,
N,N-dimethyl-4-[4-(2-oxo-1,2-dihydro-quinolin-3-yl)-[1,2,3]triazol-1-yl]-benzamide,
3-[1-(4-dimethylaminomethyl-phenyl)-1H-[1,2,3]triazol-4-yl]-1H-[1,8]naphthyridin-2-one,
3-(1-phenyl-1H-[1,2,3]triazol-4-yl)-1H-[1,8]naphthyridin-2-one,
3-[1-(4-hydroxymethyl-phenyl)-1H-[1,

Assignees

• Merck Patent Gmbh

Inventors

• Dorsch Dieter
• Muzerelle Mathilde
• Burgdorf Lars
• Wucherer-Plietker Margarita
• Czodrowski Paul
• Esdar Christina
• Tsaklakidis Christos

Classifications

• C07D487/10

  Spiro-condensed systems · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D497/10

  Spiro-condensed systems · CPC title