Cyclic protein tyrosine kinase inhibitors
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.
1. A compound of formula I or 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, or aralkyl, 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 6 ;
(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 6 ;
(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 -Z 4 -R 6 where Z 4 is —SO 2 -, —C(O)—, or —C(O)O—;
R 4 and R 5
(1) are each independently 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 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;
R 15 is
(1) hydrogen;
(2) alkyl;
(3) aryl;
(4) arylalkyl; or
(5) cycloalkyl;
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 )- provided said compound is other than 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 2 wherein R 2 is hydrogen.
5. A compound of claim 2 wherein R 4 is hydrogen.
6. A compound of claim 2 wherein R 5 is an aryl group which is substituted with Z 1 , Z 2 and one or more groups Z 3 .
7. A compound of claim 2 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 .
8. A compound of claim 7 wherein R 5 is aryl which is unsubstituted or independently substituted with one or more alkyl or halo.
9. 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, or aralkyl, 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 —OC(O) q R 6 , where q is 1 or 2;
(5) —SO 3 H or —S(O) q R 6 ;
(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 6 ;
(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 -Z 4 -R 6 where Z 4 is —SO 2 -, —C(O)—, or —C(O)O—;
R 4 and R 5
(1) are each independently 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 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;
R 15 is
(1) hydrogen;
(2) alkyl;
(3) aryl;
(4) arylalkyl; or
(5) cycloalkyl;
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 2 , 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 6 -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—(CH2) 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 )—, provided said compound is other than 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.
10. A compound of claim 9 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 .
11. A compound of claim 10 wherein R 5 is axyl which is unsubstituted or independently substituted with one or more alkyl or halo.