Combination of atr kinase inhibitors with 2,3-dihydroimidazo[1,2-c]quinazoline compounds

Patent metadata

Field	Value
Publication number	US-2021369724-A1
Application number	US-201917285858-A
Country	US
Kind code	A1
Filing date	Oct 9, 2019
Priority date	Oct 16, 2018
Publication date	Dec 2, 2021
Grant date	—

Abstract

The present invention relates to combinations of: component A: one or more 2,3-dihydroimidazo[1,2-c]quinazoline compounds of general formula (A1) or (A2) as defined herein, or a stereoisomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof; and component B: one or more ATR kinase inhibitor(s) as defined herein, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof; and, optionally, component C: one or more further pharmaceutical agent(s); and, optionally, in which either or both of components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical composition which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.

First claim

1 : A combination of component A and component B, wherein component A comprises one or more compounds of formula (A1):

wherein
X is CR 5 R 6 or NH;
Y 1 is CR 3 or N;
Y 2 and Y 3 are connected by a bond that is a single bond or a double bond,
with the proviso that when the bond is a double bond, Y 2 and Y 3 are independently CR 4 or N, and
when the bond is a single bond, Y 2 and Y 3 are independently CR 3 R 4 or NR 4 ;

Z 1 , Z 2 , Z 3 and Z 4 are independently CH, CR 2 or N;
R 1 is aryl optionally having 1 to 3 substituents selected from R 11 , C 3-8 cycloalkyl optionally having 1 to 3 substituents selected from R 11 ,
C 1-6 alkyl optionally substituted by
aryl, heteroaryl, C 1-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
C 1-6 alkoxy optionally substituted by
carboxy, aryl, heteroaryl, C 1-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,

or
a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that is saturated or unsaturated, and contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, and optionally having 1 to 3 substituents selected from R 11 , wherein

R 11 is halogen, nitro, hydroxy, cyano, carboxy, amino, N—(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N-(formyl)-N—(C 1-6 alkyl)amino, N—(C 1-6 alkanesulfonyl) amino, N-(carboxyC 1-6 alkyl)-N—(C 1-6 alkyl)amino, N—(C 1-6 alkoxycabonyl)amino, N—[N,N-di(C 1-6 alkyl)amino methylene]amino, N—[N,N-di(C 1-6 alkyl)amino(C 1-6 alkyl)methylene]amino, N—[N,N-di(C 1-6 alkyl)aminoC 2-6 alkenyl]amino, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di(C 1-6 alkyl)aminocarbonyl, C 3-8 cycloalkyl, C 1-6 alkylthio, C 1-6 alkanesulfonyl, sulfamoyl, C 1-6 alkoxycarbonyl, N-arylamino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R 101 , N-(aryl C 1-6 alkyl)amino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R 101 , arylC 1-6 alkoxycarbonyl wherein said aryl moiety is optionally having 1 to 3 substituents selected from R 101 ,
C 1-6 alkyl optionally substituted by mono-, di- or tri-halogen, amino, N—(C 1-6 alkyl)amino or N,N-di(C 1-6 alkyl)amino, C 1-6 alkoxy optionally substituted by mono-, di- or tri-halogen, N—(C 1-6 alkyl)sulfonamide, or N-(aryl)sulfonamide,

or
a 5 to 7 membered saturated or unsaturated ring having 1 to 3 heteroatoms selected from the group consisting of O, S and N, and optionally having 1 to 3 substituents selected from R 101 , wherein

R 101 is halogen, carboxy, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di(C 1-6 alkyl)aminocarbonyl, pyridyl, C 1-6 alkyl optionally substituted by cyano or mono- di- or tri-halogen,
or
C 1-6 alkoxy optionally substituted by cyano, carboxy, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di(C 1-6 alkyl)aminocarbonyl or mono-, di- or tri-halogen;

R 2 is hydroxy, halogen, nitro, cyano, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)-N—(C 1-6 alkyl)amino, C 1-6 acyloxy, aminoC 1-6 acyloxy, C 2-6 alkenyl, aryl,
a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, C 1-6 alkyl, C 1-6 alkoxy, oxo, amino, aminoC1-6alkyl, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N—(C 1-6 alkyl)carbonylamino, phenyl, phenylC1-6alkyl, carboxy, C 1-6 alkoxycarbonyl, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, or N,N-di(C 1-6 alkyl)amino,
—C(O)— R 20 ,
C 1-6 alkyl optionally substituted by R 21 , or C 1-6 alkoxy optionally substituted by R 21 ;

R 20 is C 1-6 alkyl, C 1-6 alkoxy, amino, N—(C 1-6 alkyl)amino,
N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, oxo, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, phenyl, or benzyl,

R 21 is cyano, mono-, di or tri-halogen, hydroxy, amino,
N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)amino, N-(halophenylC 1-6 alkyl)amino, aminoC 2-6 alkylenyl, C 1-6 alkoxy,
hydroxyC 1-6 alkoxy, —C(O)—R 201 , —NHC(O)—R 201 , C 3-8 cycloalkyl, isoindolino, phthalimidyl, 2-oxo-1,3-oxazolidinyl, aryl or a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N optionally substituted by hydroxy, C 1-6 alkyl, C 1-6 alkoxy,
C 1-6 alkoxycarbonyl, hydroxyC 1-6 alkoxy, oxo, amino, aminoC 1-6 alkyl, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, or benzyl, wherein

R 201 is hydroxy, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(halophenylC 1-6 alkyl)amino, C 1-6 alkyl, aminoC 1-6 alkyl, aminoC 2-6 alkylenyl, C 1-6 alkoxy, a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N optionally substituted by hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl,
hydroxyC 1-6 alkoxy, oxo, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino or benzyl;

R 3 is hydrogen, halogen, aminocarbonyl, or C 1-6 alkyl optionally substituted by arylC 1-6 alkoxy or mono-, di- or tri-halogen;
R 4 is hydrogen or C 1-6 alkyl;
R 5 is hydrogen or C 1-6 alkyl; and
R 6 is halogen, hydrogen or C 1-6 alkyl;
or a stereoisomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof; and
wherein component B comprises one or more ATR kinase inhibitor(s), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.

2 : The combination according to claim 1 , wherein component A is one or more compounds of formula (A2):

wherein:
X is CR 5 R 6 or NH;
Y 1 is CR 3 or N;
the bond between Y 2 and Y 3 is a single bond or a double bond, with the proviso that when the bond between Y 2 and Y 3 is a double bond, Y 2 and Y 3 are independently CR 4 or N, and
when the bond between Y 2 and Y 3 is a single bond, Y 2 and Y 3 are independently CR 3 R 4 or NR 4 ;

Z 1 , Z 2 , Z 3 and Z 4 are independently CH, CR 2 or N;
R 1 is aryl optionally having 1 to 3 substituents selected from R 11 , C 3-8 cycloalkyl optionally having 1 to 3 substituents selected from R 11 ,
C 1-6 alkyl optionally substituted by aryl, heteroaryl, C 1-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
C 1-6 alkoxy optionally substituted by carboxy, aryl, heteroaryl, C 1-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,

or
a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that is saturated or unsaturated, optionally having 1 to 3 substituents selected from R 11 , and contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, wherein

R 11 is halogen, nitro, hydroxy, cyano, carboxy, amino, N—(C 1-6 alkyl)amino, N-(hydroxyC 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N—(C 1-6 acyl)amino, N-(formyl)-N—(C 1-6 alkyl)amino, N—(C 1-6 alkanesulfonyl) amino, N-(carboxyC 1-6 alkyl)-N—(C 1-6 alkyl)amino, N—(C 1-6 alkoxycabonyl)amino, N—[N,N-di(C 1-6 alkyl)amino methylene]amino, N—[N,N-di(C 1-6 alkyl)amino (C 1-6 alkyl)methylen

Assignees

• Bayer Ag

Inventors

• Wengner Antje Margret
• Siemeister Gerhard
• Grünewald Sylvia
• Haendler Bernard
• Liu Ningshu

Classifications

• A61K31/5377 Primary

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title