Quinolin-2-one derivatives

Patent metadata

Field	Value
Publication number	US-11174241-B2
Application number	US-202016796046-A
Country	US
Kind code	B2
Filing date	Feb 20, 2020
Priority date	Jan 11, 2016
Publication date	Nov 16, 2021
Grant date	Nov 16, 2021

Abstract

Compounds of the formula Iin which X1, X2, X3, X4, R1, R2, R3, 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. Medicaments comprising at least one compound 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, pyridyl, pyrimidinyl, 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 no more than two of X 1 , X 2 , X 3 , X 4 denote N,
and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and optionally a pharmaceutically acceptable carrier, excipient or vehicle.

2. The medicaments of claim 1 further comprising at least one further medicament active ingredient.

3. The medicaments of claim 1 , where
R 1 denotes H, F, Cl, Br, CN, CH 3 , CF 3 or OCH 3 ,
R 2 denotes H or F,

and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

4. The medicaments of claim 1 , wherein
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.

5. The medicaments of claim 1 , wherein
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.

6. The medicaments of claim 1 , wherein
Het′ denotes pyrrolidinyl,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

7. The medicaments of claim 1 , wherein
X, 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.

8. The medicaments of 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-dimethylaminome

Assignees

• Merck Patent Gmbh

Inventors

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

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D497/10

  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

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title