RHODANINES AND RELATED HETEROCYCLES AS KINASE INHIBITORS
The invention provides compounds that inhibit PIM kinases and/or CK2, and compositions containing such compounds. These compounds and compositions are useful for treating proliferative disorders such as cancer, as well as other kinase-associated conditions including inflammation, pain, vascular disorders, pathogenic infections and certain immunological disorders.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
each of Z 1 , Z 2 , Z 3 and Z 4 is independently CR 1 or N, provided no more than three of Z 1 , Z 2 , Z 3 and Z 4 is N;
each R 1 is independently H, halo, CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 alkoxy, or —NR 6 R 7 ,
where R 6 and R 7 are independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl, or
R 6 and R 7 taken together with the N in —NR 6 R 7 can form an optionally substituted 5-8 membered ring that optionally contains an additional heteroatom selected from N, O and S as a ring member;
R 2 is H or C1-C4 alkyl;
R 3 is H or optionally substituted C1-C10 alkyl;
α is a single bond,
X is O, S, or NR 4 , where R 4 is H or an optionally substituted group selected from C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, and
Y is C=Q, where Q is O or S; or
α is a double bond,
X is CR 5 , where R 5 is H or an optionally substituted group selected from C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, and
Y is N;
W is optionally substituted aryl or optionally substituted heteroaryl, or is —NR 10 R 11 ,
wherein said aryl or heteroaryl group may be optionally substituted with a substituent selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, CN, —COOR 8 , —CONR 8 R 9 , —CONR 8 NR 8 R 9 , —SO 2 NR 8 R 9 , —NR 8 R 9 , —NR 8 COR 8 , and —NR 8 CONR 8 R 9 ,
where each R 8 , R 9 , R 10 and R 11 is independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; or
R 8 and R 9 taken together with the N in NR 8 R 9 , and R 10 and R 11 taken together with the N in NR 10 R 11 can independently form an optionally substituted 5-8 membered ring that optionally contains an additional heteroatom selected from N, O and S as a ring member;
provided that when W is phenyl, said phenyl is substituted with at least one substituent selected from the group consisting of —CONR 8 R 9 , —CONR 8 NR 8 R 9 , —SO 2 NR 8 R 9 , —NR 8 R 9 , —NR 8 COR 8 , and —NR 8 CONR 8 R 9 ,
and further provided that when said substituent on phenyl is —SO 2 NR 8 R 9 , both of R 8 and R 9 are not H.
2 . The compound of claim 1 , wherein each of Z 1 , Z 2 , Z 3 and Z 4 is CR 1 .
3 . The compound of claim 1 , wherein at least one of Z 1 , Z 2 , Z 3 and Z 4 is N.
4 . The compound of claim 1 , wherein α is a single bond and X is S.
5 . The compound of claim 1 , wherein W is optionally substituted aryl or optionally substituted heteroaryl.
6 . The compound of claim 1 , which is a compound of Formula I-A:
or a pharmaceutically acceptable salt thereof,
wherein W is optionally substituted aryl or optionally substituted heteroaryl; and
Q is O or S.
7 . A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
Z 5 is O, S, or NR 21 , where R 21 is H or optionally substituted C1-C10 alkyl;
each of Z 6 and Z 7 is independently CR 1 or N;
each R 1 is independently H, halo, CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 alkoxy, or —NR 6 R 7 ,
where R 6 and R 7 are independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl, or
R 6 and R 7 taken together with the N in —NR 6 R 7 can form an optionally substituted 5-8 membered ring that optionally contains an additional heteroatom selected from N, O and S as a ring member;
R 2 is H or C1-C4 alkyl;
R 3 is H or optionally substituted C1-C10 alkyl;
α is a single bond,
X is O, S, or NR 4 , where R 4 is H or an optionally substituted group selected from C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, and
Y is C=Q, where Q is O or S; or
α is a double bond,
X is CR 5 , where R 5 is H or an optionally substituted group selected from C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, and
Y is N;
W is optionally substituted aryl or optionally substituted heteroaryl, or is —NR 10 R 11 ,
wherein said aryl or heteroaryl group may be optionally substituted with a substituent selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, CN, —COOR 8 , —CONR 8 R 9 , —CONR 8 NR 8 R 9 , —SO 2 NR 8 R 9 , —NR 8 R 9 , —NR 8 COR 8 , and —NR 8 CONR 8 R 9 ,
where each R 8 , R 9 , R 10 and R 11 is independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; or
R 8 and R 9 taken together with the N in NR 8 R 9 , and R 10 and R 11 taken together with the N in NR 10 R 11 can independently form an optionally substituted 5-8 membered ring that optionally contains an additional heteroatom selected from N, O and S as a ring member;
provided that when W is phenyl, said phenyl is substituted with at least one substituent selected from the group consisting of —CONR 8 R 9 , —CONR 8 NR 8 R 9 , —SO 2 NR 8 R 9 , —NR 8 R 9 , —NR 8 COR 8 , and —NR 8 CONR 8 R 9 ,
and further provided that when said substituent on phenyl is —SO 2 NR 8 R 9 , both of R 8 and R 9 are not H.
8 . The compound of claim 7 , wherein each of Z 6 and Z 7 is CR 1 and Z 5 is O.
9 . The compound of claim 7 , wherein α is a single bond and X is S.
10 . The compound of claim 7 , wherein W is optionally substituted aryl or optionally substituted heteroaryl.
11 . The compound of claim 7 , which is a compound of Formula II-A:
or a pharmaceutically acceptable salt thereof,
wherein W is optionally substituted aryl or optionally substituted heteroaryl; and
Q is O or S.
12 . A compound of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
Z 8 is O, S, or NR 31 , where R 31 is H or optionally substituted C1-C10 alkyl;
each of Z 9 and Z 10 is independently CR 1 or N;
each R 1 is independently H, halo, CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 alkoxy, or —NR 6 R 7 ,
where R 6 and R 7 are independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl, or
R 6 and R 7 taken together with the N in —NR 6 R 7 can form an optionally substituted 5-8 membered ring that optionally contains an additional heteroatom selected from N, O and S as a ring member;
R 2 is H or C1-C4 alkyl;
R 3 is H or optionally substituted C1-C10 alkyl;
α is a single bond,
X is O, S, or NR 4 , where R 4 is H or an optionally substituted group selected from C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, and
Y is C=Q, where Q is O or S; or
α is a double bond,
X is CR 5 , where R 5 is H or an optionally substituted group selected from C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, and
Y is N;
W is optionally substituted aryl or optionally substituted heteroaryl, or is —NR 10 R 11 ,
wherein said aryl or heteroaryl group may be optionally substituted with a substituent selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, CN, —COOR 8 , —CONR 8 R 9 , —CONR 8 NR 8 R 9 , —SO 2 NR 8 R 9 , —NR 8 R 9 , —NR 8 COR 8 , and —NR 8 CONR 8 R 9 ,
where each R 8 , R 9 , R 10 and R 11 is independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; or
R 8 and R 9 taken together with the N in NR 8 R 9 , and R 10 and R 11 taken together with the N in NR 10 R 11 can independently form an optionally substituted 5-8 membered ring that optionally contains an additional heteroatom selected from N, O and S as a ring member;
provided that when W is phenyl, said phenyl is substituted with at least one substituent selected from the group consisting of —CONR 8 R 9 , —CONR 8 NR 8 R 9 , —SO 2 NR 8 R 9 , —NR 8 R 9 , —NR 8 COR 8 , and —NR 8 CONR 8 R 9 ,
and further provided that when said substituent on phenyl is —SO 2 NR 8 R 9 , both of R 8 and R 9 are not H.
13 . The compound of claim 12 , wherein Z 8 is S and each of Z 9 and Z 10 is CR 1 .
14 . The compound of claim 12 , wherein α is a single bond and X is S.
15 . The compound of claim 12 , wherein W is optionally substituted aryl or optionally substituted heteroaryl.
16 . The compound of claim 12 , which is a compound of Formula III-A:
or a pharmaceutically acceptable salt thereof,
wherein W is optionally substituted aryl or optionally substituted heteroaryl; and
Q is O or S.
17 . A compound selected from the compounds disclosed in Tables 1-7 or in the Examples, or a pharmaceutically acceptable salt thereof.
18 . A pharmaceutical composition comprising the compound of claim 1 , admixed with a pharmaceutically acceptable excipient.
19 . A pharmaceutical composition comprising the compound of claim 7 , admixed with a pharmaceutically acceptable excipient.
20 . A pharmaceutical composition comprising the compound of claim 12 , admixed with a pharmaceutically acceptable excipient.
21 . A method to treat cancer, a vascular disorder, inflammation, a pathogenic infection, or an immunological disorder, comprising administering to a subject in need of such treatment an effective amount of the compound of claim 1 .
22 . A method to treat cancer, a vascular disorder, inflammation, a pathogenic infection, or an immunological disorder, comprising administering to a subject in need of such treatment, an effective amount of the compound of claim 7 .
23 . A method to treat cancer, a vascular disorder, inflammation, a pathogenic infection, or an immunological disorder, comprising administering to a subject in need of such treatment, an effective amount of the compound of claim 12 .