Cyclic protein tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9382219-B2
Application number	US-201514620244-A
Country	US
Kind code	B2
Filing date	Feb 12, 2015
Priority date	Apr 15, 1999
Publication date	Jul 5, 2016
Grant date	Jul 5, 2016

Abstract

Novel cyclic compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.

First claim

What is claimed is:

1. A cyclic compound of the following formula I or a salt thereof:

where
Q is thiazole optionally substituted with R 1 ;
Z is a single bond;
X 1 and X 2 together form ═O;
R 1 is:
(1) hydrogen or R 6 ,
where R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z 1 , Z 2 and one or more groups Z 3 ;

(2) —OH or —OR 6 ;
(3) —SH or —SR 6 ;
(4) —C(O) 2 H, —C(O) q R 6 , or —O—C(O) q R 6 , where q is 1 or 2;
(5) —SO 3 H or —S(O) q R 8 ;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z 4 —NR 7 R 8 ;
(10) —Z 4 —N(R 9 )—Z 5 —NR 10 R 11 ;
(11) —Z 4 —N(R 12 )—Z 5 —R 8 ;
(12) —P(O)(OR 6 ) 2 ;

R 2 is hydrogen, R 6 , —Z 4 —R 6 or —Z 13 —NR 7 R 8 ;
R 3 is —C(O)— heterocyclo, wherein the heterocyclo is unsubstituted or substituted with Z 1 , Z 2 and one or more groups Z 3 ;
R 4 is
(1) hydrogen or R 6 ;
(2) —Z 4 —N(R 9 )—Z 5 —NR 10 R 11 ;
(3) —N(R 9 )Z 4 R 6 ; or
(4) together with the nitrogen atom to which they are attached complete a 3-to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z 1 , Z 2 and Z 3 , which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z 1 , Z 2 and Z 3 ;

R 5 is an aryl group which is substituted with Z 1 , Z 2 and one or more groups Z 3 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 :
(1) are each independently hydrogen or R 6 ;
(2) R 7 and R 8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ; or
(3) any two of R 9 , R 10 and R 11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ;

R 13 is:
(1) cyano;
(2) nitro;
(3) —NH 2 ;
(4) —NHOalkyl;
(5) —OH;
(6) —NHOaryl;
(7) —NHCOOalkyl;
(8) —NHCOOaryl;
(9) —NHSO 2 alkyl;
(10) —NHSO 2 aryl;
(11) aryl;
(12) heteroaryl;
(13) —Oalkyl; or
(14) —Oaryl;

R 14 is:
(1) —NO 2 ;
(2) —COOalkyl; or
(3) —COOaryl;

Z 1 , Z 2 and Z 3 are each independently:
(1) hydrogen or Z 6 , where Z 6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z 1 , Z 2 and Z 3 ;
(2) —OH or —OZ 6 ;
(3) —SH or —SZ 6 ;
(4) —C(O) q H, —C(O) q Z 6 , or —O—C(O) q Z 6 ;
(5) —SO 3 H, —S(O) q Z 6 ; or S(O) q N(Z 9 )Z 6 ;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z 4 —NZ 7 Z 8 ;
(10) —Z 4 —N(Z 9 )—Z 5 —NZ 7 Z 8 ;
(11) —Z 4 —N(Z 10 )—Z 5 —Z 6 ;
(12) —Z 4 —N(Z 10 )—Z 5 —H;
(13) oxo;
(14) —O—C(O)—Z 6 ;
(15) any two of Z 1 , Z 2 , and Z 3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
(16) any two of Z 1 , Z 2 , and Z 3 may together be —O—(CH 2 ) r —O—, where r is 1 to 5, completing a 4- to 8-membered ring together with the atoms to which they are attached;

Z 4 and Z 5 are each independently:
(1) a single bond;
(2) —Z 11 —S(O) q —Z 12 —;
(3) —Z 11 -C(O)—Z 12 —;
(4) —Z 11 -C(S)—Z 12 —;
(5) —Z 11 —O—Z 12 —;
(6) —Z 11 —S—Z 12 —;
(7) —Z 11 —O—C(O)—Z 12 —; or
(8) —Z 11 -C(O)—O—Z 12 —;

Z 7 , Z 8 , Z 9 and Z 10 :
(1) are each independently hydrogen or Z 6 ;
(2) Z 7 and Z 8 , or Z 6 and Z 10 , may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ; or
(3) Z 7 or Z 8 , together with Z 9 , may be alkylene or alkenylene completing a 3-to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ;

Z 11 and Z 12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene; or
(4) alkynylene; and

Z 13 is:
(1) a single bond;
(2) —Z 11 —S(O) q —Z 12 —;
(3) —Z 11 -C(O)—Z 12 —;
(4) —Z 11 -C(S)—Z 12 —;
(5) —Z 11 —O—Z 12 —;
(6) —Z 11 —S—Z 12 —;
(7) —Z 11 —O—C(O)—Z 12 —;
(8) —Z 11 -C(O)—O—Z 12 —;
(9) —C(NR 13 )—;
(10) —C(CHR 14 )—; or
(11) —C(C(R 14 ) 2 )—;

providing that said compound is other than
(a) a compound of formula (i)

where
R 1a is alkyl or —C(O)NHNH 2 ;
R 2a and R 3a are independently hydrogen, alkyl, —C(O)-(alk); and
R 4a is hydrogen and R 5a is aryl, alkyl-substituted aryl, halo-substituted aryl, aralkyl, cycloalkyl or amino;
Or R 4a is alkyl and R 5a is alkyl or aryl;
Or R 4a and R 5a together with the nitrogen atom to which they are bonded together from morpholino.

2. A compound of claim 1 , wherein R 1 is hydrogen, halo, alkyl, aryl, alkoxy, alkoxycarbonyl, or aryloxycarbonyl.

3. A compound of claim 2 , wherein R 1 is hydrogen.

4. A compound of claim 1 , wherein R 2 is hydrogen.

5. A compound of claim 1 , wherein R 4 is hydrogen.

6. A compound of claim 1 wherein R 1 is hydrogen or alkyl, R 2 and R 4 are independently hydrogen or alkyl, and R 5 is aryl which is unsubstituted or substituted with Z 1 , Z 2 and one or more groups Z 3 .

7. A compound of formula II or salt thereof:

where
n is 1;
X 3 is oxygen;
A is nitrogen;
B is sulfur
R 1 is:
(1) hydrogen or R 6 ,
where R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z 1 , Z 2 and one or more groups Z 3 ;

(2) —OH or —OR 6 ;
(3) —SH or —SR 6 ;
(4) —C(O) 2 H, —C(O) q R 6 , or —O—C(O) q R 6 , where q is 1 or 2;
(5) —SO 3 H or —S(O) q R 8 ;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z 4 —NR 7 R 8 ;
(10) —Z 4 —N(R 9 )—Z 5 —NR 10 R 11 ;
(11) —Z 4 —N(R 12 )—Z 5 —R 8 ;
(12) —P(O)(OR 6 ) 2 ;

R 2 is hydrogen, R 6 , —Z 4 —R 6 or —Z 13 —NR 7 R 8 ;
R 3 is —C(O)— heterocyclo, wherein the heterocyclo is unsubstituted or substituted with Z 1 , Z 2 and one or more groups Z 3 ;
R 4 is
(1) hydrogen or R 6 ;
(2) —Z 4 —N(R 9 )—Z 5 —NR 10 R 11 ;
(3) —N(R 9 )Z 4 R 6 ; or
(4) together with the nitrogen atom to which they are attached complete a 3-to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z 1 , Z 2 and Z 3 , which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z 1 , Z 2 and Z 3 ;

R 5 is an aryl group which is substituted with Z 1 , Z 2 and one or more groups Z 3 R 7 , R 8 , R 9 , R 10 , R 11 and R 12 :
(1)

Assignees

• Bristol Myers Squibb Co

Inventors

• Das Jagabandhu
• Padmanabha Ramesh
• Chen Ping
• Norris Derek
• Doweyko Arthur M P
• Barrish Joel C
• Wityak John

Classifications

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title