Aminoquinazoline and pyridopyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-9592235-B2
Application number	US-201615184310-A
Country	US
Kind code	B2
Filing date	Jun 16, 2016
Priority date	May 31, 2012
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

The invention provides a method of treating cancer in a patient by administering a compound of formula (I):

wherein R 1 R 2 and R 3 are as defined herein, compositions including the compounds and methods of using the compounds.

First claim

We claim:

1. A method for the treatment of cancer in a patient in need thereof which method comprises administering to a patient a therapeutically effective amount of a compound of claim formula (I)

and stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:
R 1 is —NR—C 1 -C 12 -hydroxyalkyl, —NR—(C 1 -C 12 -alkylenyl) n -C 3 -C 6 -cycloalkyl, —NR—(C 1 -C 12 -alkylenyl) n -heterocyclyl, —NR—(C 1 -C 12 -alkylenyl) n -C 6 -C 20 -aryl, —NR—(C 1 -C 12 -alkylenyl) n -heteroaryl, —NR—(C 1 -C 12 -alkylenyl) n -C 6 -C 20 -aryloxy, C 6 -C 20 -aryl, pyridine, N-linked piperidine, N-linked pyrrolidine, N-linked piperazine, N-linked morpholine, 1H-pyrazol-4-yl, C 6 -C 20 -aryloxy or heteroaryloxy, each of which can be unsubstituted or substituted by one or more substituent(s) selected from the group consisting of:
CN;
oxo;
OH;
NH 2 ;
halo;
C 1 -C 12 -alkyl;
(C 1 -C 12 -alkylenyl) n -C 1 -C 12 -alkoxy, unsubstituted or substituted by one or more substituent(s) selected from the group consisting of C 3 -C 6 -cycloalkyl, heterocyclyl, aryl and heteroaryl;
C 1 -C 12 -hydroxyalkyl;
C 1 -C 12 -haloalkyl;
C 1 -C 12 -haloalkoxy;
(C 1 -C 12 -alkylenyl) n -C(O)O—C 1 -C 12 -alkyl;
—C(O)—C 1 -C 12 -alkyl;
O—R′, wherein R′ is C 3 -C 6 -cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which are unsubstituted or substituted by one or more R g ;
(C 1 -C 12 -alkylenyl) n -cycloalkyl or (C 1 -C 12 -alkylenyl) n -heterocyclyl unsubstituted or substituted by one or more substituent(s) selected from the group consisting of:
halo, oxo, OH, NH 2 , C 1 -C 12 -alkyl, C 1 -C 12 -hydroxyalkyl, C 1 -C 12 -haloalkyl, (C 1 -C 12 -alkylenyl) n -C 1 -C 12 -alkoxy, —NH(C 1 -C 12 -alkyl), —N(C 1 -C 12 -alkyl) 2 , —N(C 1 -C 12 -alkyl)-C(O)—C 1 -C 12 -alkyl, —C(O)—C 1 -C 12 -alkyl, —C(O)O—C 1 -C 12 -alkyl, (C 1 -C 12 -alkylenyl) n -C(O)—NH 2 , (C 1 -C 12 -alkylenyl) n -C(O)—NH(C 1 -C 12 -alkyl), —C(O)—NH(C 1 -C 12 -hydroxyalkyl), (C 1 -C 12 -alkylenyl) n -C(O)—N(C 1 -C 12 -alkyl) 2 , —C(O)—NH(C 1 -C 12 -haloalkyl), —C(O)—NH-heterocyclyl, —S(O) 2 —C 1 -C 12 -alkyl, —S(O) 2 —N(C 1 -C 12 -alkyl) 2 , —C(O)OH, —C(O)-heterocyclyl, (C 1 -C 12 -alkylenyl) n -heterocyclyl and (C 1 -C 12 -alkylenyl) n -heteroaryl, which heterocyclyl and heteroaryl group(s) can be unsubstituted or substituted by one or more substituent(s) selected from the group consisting of:
OH, NH 2 , halo, C 1 -C 12 -alkyl, C 1 -C 12 -alkoxy, C 1 -C 12 -haloalkyl and C 1 -C 12 -hydroxyalkyl;

(C 1 -C 12 -alkylenyl) n -aryl or (C 1 -C 12 -alkylenyl) n -heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one or more substituent(s) selected from the group consisting of:
halo, OH, NH 2 , C 1 -C 12 -alkyl, C 1 -C 12 -hydroxyalkyl, C 1 -C 12 -haloalkyl, (C 1 -C 12 -alkylenyl) n -C 1 -C 12 -alkoxy, —NH(C 1 -C 12 -alkyl), —N(C 1 -C 12 -alkyl) 2 , —N(C 1 -C 12 -alkyl)C(O)—C 1 -C 12 -alkyl, —C(O)—NH 2 , —C(O)—NH(C 1 -C 12 -alkyl), —C(O)—NH(C 1 -C 12 -hydroxyalkyl), —C(O)—N(C 1 -C 12 -alkyl) 2 , —C(O)—NH(C 1 -C 12 -haloalkyl), —C(O)—NH-heterocyclyl, —S(O) 2 —C 1 -C 12 -alkyl, —S(O) 2 —N(C 1 -C 12 -alkyl) 2 , C 1 -C 12 -alkylenyl-C(O)N(C 1 -C 12 -alkyl) 2 , —C(O)OH, —C(O)-heterocyclyl and heterocyclyl, which heterocyclyl group(s) can be unsubstituted or substituted by one or more substituent(s) selected from the group consisting of:
OH, NH 2 , halo, C 1 -C 12 -alkyl, C 1 -C 12 -alkoxy, C 1 -C 12 -haloalkyl, and C 1 -C 12 -hydroxyalkyl;

(C 1 -C 12 -alkylenyl) n -NR a R b , wherein R a and R b are independently selected from:
H,
C 1 -C 12 -alkyl,
C 1 -C 12 -hydroxyalkyl,
C 1 -C 12 -haloalkyl,
(C 1 -C 12 -alkylenyl) n -C 1 -C 12 -alkoxy,
—S(O) 2 —(C 1 -C 12 -alkylenyl) n -heterocyclyl unsubstituted or substituted by one or more R g ,
(C 1 -C 12 -alkylenyl) n -C 6 -C 20 -aryl, which aryl is unsubstituted or substituted by one or more R g ,
(C 1 -C 12 -alkylenyl) n -C 3 -C 6 -cycloalkyl unsubstituted or substituted by one or more R g ,
(C 1 -C 12 -alkylenyl) n -heterocyclyl unsubstituted or substituted by one or more oxo, —C(O)—C 1 -C 12 -alkyl, —C(O)O—C 1 -C 12 -alkyl or R g ,
C 1 -C 12 -alkylenyl-C(O)-heteroaryl unsubstituted or substituted by one or more R g ,
C 1 -C 12 -alkylenyl-NH 2 ,
C 1 -C 12 -alkylenyl-NH(C 1 -C 12 -alkyl),
C 1 -C 12 -alkylenyl-N(C 1 -C 12 -alkyl) 2 ,
C 1 -C 12 -alkylenyl-C(O)NH 2 ,
C 1 -C 12 -alkylenyl-C(O)NH(C 1 -C 12 -alkyl), or,
C 1 -C 12 -alkylenyl-C(O)N(C 1 -C 12 -alkyl) 2 ,

(C 1 -C 12 -alkylenyl) n -C(O)NR c R d , wherein R e and R d are independently selected from:
H,
C 1 -C 12 -alkyl,
C 1 -C 12 -hydroxyalkyl,
C 1 -C 12 -haloalkyl,
(C 1 -C 12 -alkylenyl) n -C 1 -C 12 -alkoxy,
C 1 -C 12 -alkylenyl-NH(C 1 -C 12 -alkyl),
C 1 -C 12 -alkylenyl-N(C 1 -C 12 -alkyl) 2 ,
(C 1 -C 12 -alkylenyl) n -heterocyclyl, unsubstituted or substituted by one or more substituent(s) selected from the group consisting of oxo, —C(O)—C 1 -C 12 -alkyl and R g ,
(C 1 -C 12 -alkylenyl) n -C 3 -C 6 -cycloalkyl unsubstituted or substituted by one or more R g ,
(C 1 -C 12 -alkylenyl) n -C 6 -C 20 -aryl unsubstituted or substituted by one or more R g ,
—NH—C 3 -C 6 -cycloalkyl; or
or R c and R d together with the nitrogen atom to which they are attached, form a 5 or 6 membered heterocyclyl which can or cannot comprise 1 or 2 additional heteroatom selected from N, O or S; and,

(C 1 -C 12 -alkylenyl) n -NR e C(O)R f , wherein R e is H or C 1 -C 12 -alkyl, R f is halo, CN, OH, C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, (C 1 -C 12 -alkylenyl) n -C 1 -C 12 -alkoxy, C 1 -C 12 -hydroxyalkyl, C 1 -C 12 -cyanoalkyl, (C 1 -C 12 -alkylenyl) n -NH 2 , (C 1 -C 12 -alkylenyl) n -NH(C 1 -C 12 -alkyl), (C 1 -C 12 -alkylenyl) n -N(C 1 -C 12 -alkyl) 2 , (C 1 -C 12 -alkylenyl) n -C 3 -C 6 -cycloalkyl, (C 1 -C 12 -alkylenyl) n -heterocyclyl, or (C 1 -C 12 -alkylenyl) n -NH—C 3 -C 6 -cycloalkyl, wherein said cycloalkyl, heterocyclyl or heteroaryl are unsubstituted or substituted by oxo, —C(O)—C 1 -C 12 -alkyl or one or more R g ;

R 2 is H, CN, —C(O)—NH(C 1 -C 12 -alkyl)-NH—C(O)—C 1 -C 12 -alkyl, —C(O)—N(C 1 -C 12 -alkyl)(C 1 -C 12 -alkoxy), —C(O)—N(C 1 -C 12 -alkyl)(C 1 -C 12 -alkylalkoxy), —C(O)—NH(heterocyclyl), —C(O)—NH(C 1 -C 12 -alkyl-heterocyclyl), —C(O)—N(C 1 -C 12 -alkyl)(heterocyclyl), or —C(O)-heterocyclyl, which heterocyclyl groups are unsubstituted or substituted by one or more R g , —N(C 1 -C 12 -alkyl)-C(O)—C 1 -C 12 -alkyl, or —N(C 1 -C 12 -alkyl) 2 ;
R 3 is H, i-butyl, C 1 -C 12 -haloalkyl, cyclobutyl, —C(O)—C 1 -C 12 -alkyl-C 3 -C 6 -cycloalkyl, —C(O)—C 1 -C 12 -alkyl-heterocyclyl —C(O)—C 1 -C 12 -alkyl-C 6 -C 20 -aryl, —C(O)—C 1 -C 12 -alkyl-heteroaryl or pyridinyl;
R is H or C 1 -C 12 -alkyl;
R g is H, OH, halo, NH 2 , C 1 -C 12 -alkyl, (C 1 -C 12 -alkylenyl) n -C 1 -C 12 -alkoxy, C 1 -C 12 -haloalkyl, C 1 -C 12 -haloalkoxy, C 1 -C 12 -hydroxyalkyl, or C 1 -C 12 -cyanoalkyl;
n is 0 or 1;
wherein in the preceeding heteroaryl groups are 5 or 6 membered heteroaryls comprising 1, 2 or 3 heteroatom(s) selected from N, O or S and heterocyclyl groups are 5 to 10 membered heterocyclyls comprising 1, 2 or 3 heteroatom(s) selected from N, O or S;
with the proviso that the compound of Formula I is not:
6-(3-(trifluoromethyl)phenyl)pyrido[3,2-d]pyrimidin-4-amine

6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine

6-phenylpyrido[3,2-d]pyrimadin-4-amine

Assignees

• Genentech Inc

Inventors

• Chen Huifen
• Crawford Terry
• Harris Seth F
• Magnuson Steven R
• Ndubaku Chudi
• Wang Lan

Classifications

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/519 Primary

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D239/95

  with hetero atoms directly attached in positions 2 and 4 · CPC title

• A61K31/5377

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