US2016264537A1PendingUtilityA1
Cyclic protein tyrosine kinase inhibitors
Est. expiryApr 15, 2019(expired)· nominal 20-yr term from priority
Inventors:Jagabandhu DasRamesh PadmanabhaPing ChenDerek J. NorrisArthur M. P. DoweykoJoel C. BarrishJohn Wityak
A61P 37/00A61P 9/10A61P 5/14A61P 37/02A61P 43/00A61P 37/06A61P 37/08A61P 35/00A61P 27/02A61P 29/00A61P 25/00A61P 11/00A61P 17/00A61P 11/06A61P 17/06A61P 19/02A61P 11/02A61P 21/00A61P 1/00C07D 263/48C07D 277/56C07C 233/65C07D 417/06C07D 491/113C07D 231/38C07D 239/42C07D 409/12C07D 213/82C07D 471/04C07C 237/40C07D 213/81C07D 417/14C07D 233/90C07D 417/12
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Claims
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.
Claims
exact text as granted — not AI-modifiedWhat 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 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 —C(O)—NR 7 R 8 , wherein R 7 is aralkyl, which is unsubstituted or substituted with Z 1 , Z 2 and one or more groups Z 3 ;
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 8 , R 9 , R 10 , R 11 and R 12 :
(1) are each independently hydrogen or R 6 ; or
(2) 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 1 —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 1 —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 (ix)
where
R 2i is hydrogen or alkyl;
R 3i is —C(O)—NH-(alk); and
R 58 and R 59 are independently hydrogen, alkyl or halogen.
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 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 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 .
8 . 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 (preferably, one or two) 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 —C(O)—NR 7 R 8 , wherein R 7 is aralkyl, which is unsubstituted or substituted with Z 1 , Z 2 and one or more groups Z 3 ;
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 8 , R 9 , R 10 , R 11 and R 12 :
(1) are each independently hydrogen or R 6 ; or
(2) 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 (ix)
where
R 2i is hydrogen or alkyl;
R 3i is —C(O)—NH-(alk); and
R 58 and R 59 are independently hydrogen, alkyl or halogen.
9 . A compound of claim 8 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 .
10 . A compound of claim 9 , wherein R 5 is aryl which is unsubstituted or independently substituted with one or more alkyl or halo.
11 . A pharmaceutical composition, comprising a pharmaceutically acceptable vehicle ordiluent and at least one compound of claim 1 .
12 . A pharmaceutical composition, comprising a pharmaceutically acceptable vehicle ordiluent and at least one compound of claim 8 .Cited by (0)
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