Arylquinazolines

Patent metadata

Field	Value
Publication number	US-10172859-B2
Application number	US-201715633064-A
Country	US
Kind code	B2
Filing date	Jun 26, 2017
Priority date	May 11, 2013
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

The invention relates to novel compounds of the formula (I) which can be used for the inhibition of serine-threonine protein kinases and for the sensitization of cancer cells to anticancer agents and/or ionizing radiation.

First claim

The invention claimed is:

1. A compound of formula (I)

in which
X is CH, CF, S or N,
Y is CH, S or N,
Z is C or N,
---- forms, if Z═C, a double bond together with the single bond,
is absent if Z=N,

n is 1 or 2, where
if n=1, X=S, and if n=2, both X=CH, or the X linked to the pyrimidine ring is CF and the X not linked to the pyrimidine ring is CH, or one X is CH and the other X is N;

m is 1 or 2, where
if m=1, Y=S, and if m=2, both Y=CH, or one Y is CH and the other Y is N;

R 1 , R 2 , R 3 , R 4 , independently of one another, are H, Hal, CN, OH, CONH 2 , CONH(LA) or LA;
R 5 is H, Hal, CN or C≡CH;
Cyc is phenyl, which may be unsubstituted or mono- or disubstituted, independently of one another, by R 6 , or is Het 1 ;
Het 1 is a mono- or bicyclic, 5-10-membered heterocycle, having 1-3 N, O or S atoms, or 1-4 N atoms, which may be unsubstituted or mono-, di- or trisubstituted, independently of one another, by R 6 , or may be monosubstituted by Het 2 ;
R 6 is Hal, LA, oxo, CN, or NH 2 ;
LA is unbranched or branched alkyl having 1-5 C atoms, which may be saturated or partially unsaturated, in which 1-3 H atoms may be replaced by Hal, or one H atom may be replaced by CN or Het 2 , or one or two CH 2 groups may be replaced by O, NH, N(CH 3 ) or CO;
Het 2 is a 3-5-membered aliphatic homo- or heterocycle having 0, 1, 2 or 3 N, O or S atoms, which is unsubstituted; and
Hal is F, Cl, Br or I;

wherein any H, C, N, O, P, F, and Cl can be in the form of a heavier isotope thereof;
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

2. The compound according to claim 1 , wherein said compound is of formula (Ib),

or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

3. A compound of formula (II)

in which
X is CH, CF, S or N,
Y is CH, S or N,
Z is C or N,
n is 1 or 2, where
if n=1, X=S, and if n=2, both X=CH, or the X linked to the pyrimidine ring is CF and the X not linked to the pyrimidine ring is CH, or one X is CH and the other X is N;

m is 1 or 2, where
if m=1, Y=S, and if m=2, both Y=CH, or one Y is CH and the other Y is N;

R 1 and R 2 independently of one another, are H, Hal, CN, OH, CONH 2 , CONH(LA) or LA;
R 3 is Hal, CN, OH, CONH 2 , CONH(LA) or LA;
R 5 is H, Hal, CN or C≡CH,
LA is unbranched or branched alkyl having 1-5 C atoms, which may be saturated or partially unsaturated, in which 1-3 H atoms may be replaced by Hal, or one H atom may be replaced by CN or Het 2 , or one or two CH 2 groups may be replaced by O, NH, N(CH 3 ) or CO;
Hal is F, Cl, Br or I;
Cyc is Het 1 ;
Het 1 is a mono- or bicyclic, 5-10-membered heterocycle, having 1-3 N, O or S atoms, or 1-4 N atoms, which may be monosubstituted by Het 2 ;
Het 2 is a 3-5-membered aliphatic homo- or heterocycle having 0, 1, 2 or 3 N, O or S atoms, which is unsubstituted;
R 6′ , R 6″ , independently of one another, are H, Hal, LA, oxo, CN, NH 2 or Het 2 ;
Q 1 , Q 2 , independently of one another, are CH, N or NH and are in each case unsubstituted; and
---- denotes the presence or absence of double bonds in Cyc;
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

4. A compound of formula (IIa)

in which
Y is CH, S or N,
R 1 is H, Hal, CN, OH, CONH 2 , CONH(LA) or LA;
LA is unbranched or branched alkyl having 1-5 C atoms, which may be saturated or partially unsaturated, in which 1-3 H atoms may be replaced by Hal, or one H atom may be replaced by CN or Het 2 , or one or two CH 2 groups may be replaced by O, NH, N(CH 3 ) or CO;
Hal is F, Cl, Br or I;
R 2 , R 3 , independently of one another, are Hal, CN, OH, CONH 2 , CON(LA) or LA;
R 5 is H, Hal, CN or C≡CH,
Cyc is Het 1 ;
Het 1 is a mono- or bicyclic, 5-10-membered heterocycle, having 1-3 N, O or S atoms, or 1-4 N atoms, which may be monosubstituted by Het 2 ;
Het 2 is a 3-5-membered aliphatic homo- or heterocycle having 0, 1, 2 or 3 N, O or S atoms, which is unsubstituted;
R 6′ , R 6″ , independently of one another, are H, Hal, LA, oxo, CN, NH 2 or Het 2 ;
Q 1 , Q 2 , independently of one another, are CH, N or NH and are in each case unsubstituted;
X 1 is CH, CF or N;
X 2 is CH or N,
where X 1 , X 2 are not simultaneously N;

Y is CH or N; and
---- denotes the presence or absence of double bonds in Cyc;
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

5. The compound according to claim 3 , wherein said compound is of formula (IIb)

in which
R 2 , R 3 , independently of one another, are Hal, CN, OH, CONH 2 , CON(LA) or LA;
R 6′ , R 6″ , independently of one another, are H, Hal, LA, oxo, CN, NH 2 or Het 2 ;
Q 1 ,Q 2 , independently of one another, are CH, N or NH and are in each case unsubstituted;
Y is CH or N; and
--- denotes the presence or absence of double bonds in Cyc;
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

6. The compound according to claim 4 , wherein one of the following apply:
in the case of the sub-formula (IIa-A)
X 1 is CH,
R 1 is F or Cl, and
R 2 is F or Cl; or
in the case of the sub-formula (IIa-B)
R 1 is F, and
R 2 is F or Cl; or
in the case of the sub-formula (IIa-C)
X 1 , X 2 is CH; or
in the case of the sub-formula (IIa-D)
X 1 is CH, and
R 5 is H
in the case of the sub-formula (IIa-E)
R 3 is OH; or
in the case of the sub-formula (IIa-F)
X 1 is CH, and
R 3 is OH; or
in the case of the sub-formula (IIa-G)
X 1 is CH, and
Y is CH; or
in the case of the sub-formula (IIa-H)
X 1 is CH, and
Cyc is pyridine, pyrazine or pyridazine, or pyrazolo[1,5-a]pyrimidinyl or imidazo[1,2-b]-pyridazinyl; or
in the case of the sub-formula (IIa-J)
Cyc is pyridine, pyrazine, pyridazine, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, furo[2,3-c]pyridinyl, furo[2,3-d}pyridazinyl, thieno[2,3-d}pyridazinyl, thieno[2,3-d}-pyrimidinyl or imidazo[4,5-c]pyridinyl, each of which may be unsubstituted, or may be mono- or disubstituted by methoxy, methyl, oxo, Cl or CHF 2 O; or
in the case of the sub-formula (IIa-K)
R 1 is F or Cl,
R 2 is F or Cl,
R 3 is OH,
R 5 is H, and
X 1 , X 2 is CH; or
in the case of the sub-formula (IIa-L)
R 1 is F,
R 2 is F or Cl,
R 3 is OH, and
R 5 is H; or
in the case of the sub-formula (IIa-M)
R 1 is F or Cl,
R 2 is F or Cl,
R 3 is OH,
R 5 is H,
X 1 , X 2 is CH, and
Cyc is pyridine, pyrazine or pyridazine, or pyrazolo[1,5-a]pyrimidinyl or imidazo[1,2-b]-pyridazinyl; or
in the case of the sub-formula (IIa-N)
R 1 is F,
R 2 is F or Cl,
R 3 is OH,
R 5 is H, a

Assignees

• Merck Patent Gmbh

Inventors

• Fuchss Thomas
• Emde Ulrich
• Buchstaller Hans-Peter
• Mederski Werner

Classifications

• A61P43/00

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

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title