TRICYCLIC COMPOUNDS AND PHARMACEUTICAL USES THEREOF
The invention provides compounds that inhibit CK2 and/or Pim kinases and compositions containing such compounds. These tricyclic compounds and compositions containing them are useful for treating proliferative disorders such as cancer, as well as other kinase-associated conditions including inflammation, pain, pathogenic infections, and certain immunological disorders.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof; wherein:
each of Z 1 , Z 2 , Z 3 and Z 4 is independently CR 1 or N, provided no more than two of Z 1 to Z 4 are N, and the ring containing Z 1 to Z 4 is aromatic;
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, SR, SO 2 R, COOR, COONR 7 R 8 , or —NR 7 R 8 ;
each of Y 1 and Y 4 is C or N, and Y 1 and Y 4 are not both simultaneously N; provided at least one of Y 1 to Y 4 is N;
Y 2 is N, NR 2 , CR 2 or CX 2 ,
wherein each R 2 is independently H, —OR, halo, CN, or optionally substituted C1-C4 alkyl,
and each X 2 is —(CH 2 ) 0-2 COOR or a polar group;
X is —(CH 2 ) 0-2 COOR or a polar group, or X is R 2 when Y 2 is CX 2 ;
each R is independently H or optionally substituted C1-C4 alkyl;
Y 3 is N, NR 3 , or CR 3 , and the ring containing Y 2 and Y 3 is aromatic;
wherein each R 3 is independently H, halo, —OR CN, or optionally substituted C1-C4 alkyl;
A is a bond, NR 4 , O or S, where R 4 is H or optionally substituted C1-C4 acyl;
W is optionally substituted aryl or optionally substituted arylalkyl; optionally substituted heteroaryl or optionally substituted heteroarylalkyl; optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or optionally substituted C3-C8 cycloalkyl or optionally substituted cycloalkylalkyl;
or alternatively, -A-W is —NR 7 R 8 ;
each R 7 and R 8 is independently selected from H, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
and wherein R 7 and R 8 in NR 7 R 8 can be taken together along with N to form a 4-8 membered ring that can be optionally substituted, and can contain an additional heteroatom selected from N, O and S as a ring member.
2 . The compound of claim 1 , wherein each of Z 1 to Z 4 is CR 1 .
3 . The compound of claim 1 , wherein one of Z 1 to Z 4 is N and the others are each CR 1 .
4 . The compound of claim 1 , wherein exactly one of Y 1 to Y 4 is N or NR 2 .
5 . The compound of claim 1 , wherein exactly two of Y 1 to Y 4 are selected from the group consisting of N and NR 2 .
6 . The compound of claim 1 , wherein X is COOR or a polar group.
7 . The compound of claim 1 , wherein X is R 2 , and Y 2 is CX 2 , wherein X 2 is COOR or a polar group.
8 . The compound of claim 1 , wherein Y 1 is N.
9 . The compound of claim 1 , wherein Y 4 is N.
10 . The compound of claim 1 , wherein A is NH.
11 . The compound of claim 1 , wherein W is optionally substituted aryl.
12 . The compound of claim 11 , wherein W is optionally substituted phenyl.
13 . The compound of claim 1 , wherein Formula (I) is represented by Formula (Ia), (Ib), (Ic), or (Id):
14 . The compound of claim 13 , wherein
A is NR 4 , O or S, where R 4 is H or optionally substituted C1-C4 acyl;
W is optionally substituted aryl or optionally substituted arylalkyl; optionally substituted heteroaryl or optionally substituted heteroarylalkyl; optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or optionally substituted C3-C8 cycloalkyl or optionally substituted cycloalkylalkyl; and
X is —COOR or a polar group.
15 . The compound of claim 13 , wherein
A is a bond;
W is optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclyl; or optionally substituted C3-C8 cycloalkyl; and
X is COOR or a polar group.
16 . The compound of claim 13 , wherein
A is a bond;
W is optionally substituted arylalkyl; optionally substituted heteroarylalkyl; optionally substituted heterocyclylalkyl; or optionally substituted cycloalkylalkyl; and
X is COOR or a polar group.
17 . The compound of claim 13 , wherein
-A-W is —NR 7 R 8 ; and
X is COOR or a polar group.
18 . The compound of claim 1 , wherein the polar group is selected from the group consisting of
19 . A compound of Formula (II):
or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof; wherein:
each of Z 5 and Z 6 and Z 7 is independently CR 1 , NR 2 , N, O or S, provided at least one of Z 5 to Z 7 is not CR 1 , and no more than one of Z 5 to Z 7 is O or S, and the ring containing Z 5 -Z 7 is aromatic;
each of Y 1 and Y 4 is independently C or N, and Y 1 and Y 4 are not both simultaneously N; provided at least one of Y 1 to Y 4 is N;
Y 2 is N, CR 1 or CX 2 , where X 2 is —(CH 2 ) 0-2 COOR or a polar group;
Y 3 is CR 3 , and the ring containing Y 2 and Y 3 is aromatic;
each R 1 is independently H, halo, CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, OR, SR, SO 2 R, COOR, COONR 7 R 8 , or —NR 7 R 8 ;
each R 2 is independently H, CN, —OR, COOR, CONR 2 , SO 2 R, or optionally substituted C1-C4 alkyl;
each R 3 is independently H, halo, CN, —OR, or optionally substituted C1-C4 alkyl;
X is —(CH 2 ) 0-2 COOR or a polar group, or X can be R 1 when Y 2 is CX 2 ;
R is independently at each occurrence H or an optionally substituted C1-C4 alkyl;
A is a bond, NR 4 , O or S;
wherein R 4 is H or optionally substituted C1-C4 acyl;
W is optionally substituted aryl or arylalkyl; optionally substituted heteroaryl or heteroarylalkyl; optionally substituted heterocyclyl or heterocyclylalkyl; or
optionally substituted C3-C8 cycloalkyl or cycloalkylalkyl;
or alternatively, -A-W is —NR 7 R 8 ;
each R 7 and R 8 is independently selected from H, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
and wherein R 7 and R 8 in NR 7 R 8 can be taken together along with N to form a 4-8 membered ring that can be optionally substituted, and can contain an additional heteroatom selected from N, O and S as a ring member.
20 . The compound of claim 19 , wherein Z 5 is N, O or S.
21 . The compound of claim 19 , wherein Z 6 is N, O or S.
22 . The compound of claim 19 , wherein Z 7 is N, O or S.
23 . The compound of claim 19 , wherein exactly one of Y 1 to Y 4 is N or NR 2 .
24 . The compound of claim 19 , wherein exactly two of Y 1 to Y 4 are N or NR 2 .
25 . The compound of claim 19 , wherein X is COOR or a polar group.
26 . The compound of claim 19 , wherein X is R 2 , and X 2 is COOR or a polar group.
27 . The compound of claim 19 , wherein Y 1 is N.
28 . The compound of claim 19 , wherein Y 4 is N.
29 . The compound of claim 27 , wherein A is NH.
30 . The compound of any claim 19 , wherein W is optionally substituted aryl.
31 . The compound of claim 19 , wherein W is optionally substituted phenyl.
32 . The compound of claim 19 , wherein Formula (II) is represented by Formula (IIa), (IIb), (IIc), or (IId):
33 . The compound of claim 19 , wherein
A is NR 4 , O or S, where R 4 is H or optionally substituted C1-C4 acyl;
W is optionally substituted aryl or optionally substituted arylalkyl; optionally substituted heteroaryl or optionally substituted heteroarylalkyl; optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or optionally substituted C3-C8 cycloalkyl or optionally substituted cycloalkylalkyl;
X is —COOR or a polar group.
34 . The compound of claim 19 , wherein
A is a bond;
W is optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclyl; or optionally substituted C3-C8 cycloalkyl; and
X is COOR or a polar group.
35 . The compound of claim 19 , wherein
A is a bond;
W is optionally substituted arylalkyl; optionally substituted heteroarylalkyl; optionally substituted heterocyclylalkyl; or optionally substituted cycloalkylalkyl; and
X is COOR or a polar group.
36 . The compound of claim 19 , wherein
-A-W is —NR 7 R 8 ; and
X is COOR or a polar group.
37 . The compound of claim 1 , wherein the polar group is selected from the group consisting of
38 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
39 . A method of modulating casein kinase 2 activity and/or Pim kinase activity in a cell comprising contacting the cell with an effective amount of a compound of claim 1 .
40 . A method of treating a condition or disease associated with casein kinase 2 activity and/or Pim kinase activity in a patient comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .
41 . The method of claim 40 , wherein the condition or disease associated with casein kinase 2 activity and/or Pim kinase activity is selected from the group consisting of a cancer, a vascular disorder, a inflammation, a pathogenic infection, a immunological disorder, and a combination thereof.
42 . The method of claim 41 , the cancer is of the colorectum, breast, lung, liver, pancreas, lymph node, colon, prostate, brain, head and neck, skin, liver, kidney, blood and heart.
43 . A method for inhibiting cell proliferation, which comprises contacting cells with the compound of claim 1 , in an amount effective to inhibit proliferation of the cells.
44 . The method of claim 43 , wherein the cells are in a cancer cell line or in a tumor in a subject.
45 - 47 . (canceled)