IP Library Granted Patent US 10,383,874
Granted Patent B2
US 10,383,874 · App. 16/189,113 · Granted Aug 20, 2019

Arylquinazolines

Inventors: Thomas Fuchss (Bensheim-Auerbach, DE); Ulrich Emde (Darmstadt, DE); Hans-Peter Buchstaller (Griesheim, DE); Werner Mederski (Zwingenberg, DE)
Assignee: Merk Patent GMBH
A61K31/519A61K31/5377A61K31/5386A61K45/06C07C25/02C07D237/14C07D239/72C07D239/74C07D265/30C07D285/01C07D401/10C07D403/10C07D403/14C07D405/04C07D405/14C07D417/10C07D417/14C07D471/04C07D473/00C07D487/04C07D491/048C07D495/04C07D498/08C07D513/04
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Quick Facts
Patent No.
US 10,383,874
App. No.
16/189,113
Granted
Aug 20, 2019
Kind
B2
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.

Claims (120)

1. A compound of formula (III)

in which

R 6 is Hal, LA, oxo, CN, NH 2 or Het 2 ;

R 6″ is H, Hal, LA, oxo, CN, NH 2 or Het 2 ;

- - - - denotes the presence or absence of double bonds in Cyc;

X is CH, CF, S or N,

Y is CH, S 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;

Cyc is phenyl, which may be 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 mono-, di- or trisubstituted, independently of one another, by R 6 , or may be monosubstituted by Het 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 physiologically acceptable salts, tautomers or stereoisomers thereof, including mixtures thereof in all ratios.

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

in which

R 3 is Hal, CN, OH, CONH 2 , CON(LA) or LA;

R 6 is Hal, LA, oxo, CN, NH 2 or Het 2 ;

R 6″ is H, Hal, LA, oxo, CN, NH 2 or Het 2 ;

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 physiologically acceptable salts, tautomers or stereoisomers thereof, including mixtures thereof in all ratios.

3. The compound according to claim 1 , wherein said compound is of formula (IIIb)

in which

R 3 is Hal, CN, OH, CONH 2 , CON(LA) or LA;

R 6 is Hal, LA, oxo, CN, NH 2 or Het 2 ;

R 6″ is H, Hal, LA, oxo, CN, NH 2 or Het 2 ;

Y is CH or N; and

- - - - denotes the presence or absence of double bonds in Cyc;

or physiologically acceptable salts, tautomers or stereoisomers thereof, including mixtures thereof in all ratios.

4. The compound according to claim 2 , in which

in the case of sub-formula (IIIa-B)

R 1 is F; or

in the case of sub-formula (IIIa-C)

X 1 , X 2 is CH; or

in the case of sub-formula (IIIa-D)

X 1 is CH, and

R 5 is H; or

in the case of sub-formula (IIIa-E)

R 3 is OH; or

in the case of sub-formula (IIIa-F)

X 1 is CH, and

R 3 is OH; or

in the case of sub-formula (IIIa-G)

X 1 is CH, and

Y is CH; or

in the case of sub-formula (IIIa-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 (IIIa-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 mono- or disubstituted by methoxy, methyl, oxo, Cl or CHF 2 O; or

in the case of sub-formula (IIIa-K)

R 1 is F or Cl,

R 3 is OH,

R 5 is H, and

X 1 , X 2 is CH; or

in the case of sub-formula (IIIa-L)

R 1 is F,

R 3 is OH, and

R 5 is H; or

in the case of sub-formula (IIIa-M)

R 1 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 sub-formula (IIIa-N)

R 1 is F,

R 3 is OH,

R 5 is H, and

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 mono- or disubstituted by methoxy, methyl, oxo, Cl or CHF 2 O; or

in the case of sub-formula (IIIa-O)

R 1 is F,

R 3 is OH,

R 5 is H, and

Cyc is 5-methoxypyridazin-3-yl, imidazo[1,2-b]pyridazin-6-yl, 3-chloro-6-methoxypyrazin-2-yl, 3-chloropyrazin-2-yl, pyridazin-4-yl, 3-methoxypyrazin-2-yl, 6-methoxypyridazin-3-yl, 3-difluoromethoxypyridin-2-yl, 3-methylpyrazin-2-yl, thieno[2,3-d}pyrimidin-4-yl, 1-methyl-1H-pyridin-2-one-6-yl, 1H-pyridazin-6-one-3-yl, furo[2,3-d}pyridazin-7-yl, thieno[2,3-d}pyridazin-7-yl, 3,5-dimethylpyrazin-2-yl, furo[2,3-d}pyrimidin-4-yl, 3-methyl-3H-imidazo[4,5-c]pyridin-4-yl,

or physiologically acceptable salts, tautomers or stereoisomers thereof, including mixtures thereof in all ratios.

5. The compound according to claim 3 , in which

in the case of sub-formula (IIIb-Q)

R 1 is F or Cl,

R 3 is OH,

R 5 is H, and

Y is CH; or

in the case of sub-formula (IIIb-R)

R 1 is F,

R 3 is OH,

R 5 is H, and

Y is CH; or

in the case of sub-formula (IIIb-S)

Cyc is pyridine, pyrazine or pyridazine; or

in the case of sub-formula (IIIb-T)

R 1 is F or Cl,

R 3 is OH,

R 5 is H, and

Cyc is pyridine, pyrazine or pyridazine; or

in the case of sub-formula (IIIb-U)

R 1 is F,

R 3 is OH,

R 5 is H, and

Cyc is pyridine, pyrazine, pyridazine or 3-methylpyrazin-2-yl; or

or physiologically acceptable salts, tautomers or stereoisomers thereof, including mixtures thereof in all ratios.

6. The compound according to claim 1 , wherein said compound is selected from the following:

(R)-(3-Chloropyrazin-2-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]methanol,

(R)-[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methyl pyrazin-2-yl)methanol,

(R)-[4-Fluoro-3-(7-morpholin-4-ylpyrido[3,2-d}pyrimidin-4-yl)phenyl]-(3-methylpyrazin-2-yl)methanol, or

(R)-[4-Fluoro-3-(5-fluoro-7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methylpyrazin-2-yl)methanol;

or physiologically acceptable salts, tautomers or stereoisomers thereof, including mixtures thereof in all ratios.

7. A pharmaceutical composition comprising, as active compound, an effective amount of at least one compound according to claim 1 or physiologically acceptable salts, tautomers or stereoisomers thereof, including mixtures thereof in all ratios, together with pharmaceutically tolerated adjuvants.

8. The pharmaceutical composition according to claim 7 , further comprising an effective amount of at least one anticancer agent.

9. A kit comprising separate packs of (a) an effective amount of at least one compound according to claim 1 or physiologically acceptable salts, tautomers or stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of at least one anticancer agent.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 3, 2018
From: FUCHSS, THOMAS; EMDE, ULRICH; BUCHSTALLER, HANS-PETER; MEDERSKI, WERNER
To: MERCK PATENT GMBH
Reel/Frame 047648/0256 →
Priority Claims (1)
DE 10 2013 008 118 · May 11, 2013 · national
Continuity (3)
Continuation 15633064 · Jun 26, 2017
Division 14890214
Related Publication 20190142833A1 · May 16, 2019