Protein kinase modulators

Abstract

The invention relates in part to molecules having certain biological activities that include, but are not limited to, inhibiting cell proliferation, modulating protein kinase activity and modulating polymerase activity. Molecules of the invention can modulate Pim kinase activity and/or FMS-like tyrosine kinase (Flt) activity. The invention also relates in part to methods for using such molecules.

1 . (canceled) 
     
     
         2 . The method of  claim 23 , wherein Z 60  is N and Z 70  is CH. 
     
     
         3 . The method of  claim 23 , wherein Z 70  is N and Z 60  is CH. 
     
     
         4 . The method of  claim 23 , wherein each R 60  and R 40  is H. 
     
     
         5 . The method of  claim 23 , wherein R 3P  is an optionally substituted imidazole or triazole ring. 
     
     
         6 . The method of  claim 23 , wherein R 50  is unsubstituted phenyl or phenyl substituted with 1-3 substituents selected from halo, cyano, CF 3 , —OCF 3 , COOR 40 , and SO 2 NR 40 R 50 , and one or more of these substituents can be an optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl. 
     
     
         7 . The method of  claim 23 , wherein the compound of Formula IA is represented by Formula IB: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R 30  is as defined for  claim 23 , 
         and R 3P  is an optionally substituted imidazole or triazole ring; 
         and each Φ independently represents an optionally substituted phenyl. 
       
     
     
         8 . The method of  claim 23 , wherein the compound of Formula IA is represented by Formula IC: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R 30  is as defined for  claim 23 , 
         and R 3P  is an optionally substituted imidazole or triazole ring; 
         and each Φ independently represents an optionally substituted phenyl. 
       
     
     
         9 . The method of  claim 8 , wherein Φ is unsubstituted phenyl or phenyl substituted with 1-3 substituents selected from halo, cyano, CF 3 , —OCF 3 , COOR 40 , and SO 2 NR 40 R 50 , and one or more of these substituents can be an optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl. 
     
     
         10 . The method of  claim 23 , wherein R 50  is an optionally substituted C 3-8  carbocyclic or C 3-8  heterocyclic ring, each of which may be optionally fused to an additional optionally substituted carbocyclic or heterocyclic ring. 
     
     
         11 . The method of  claim 10 , wherein said optionally substituted C 3-8  carbocyclic or C 3-8  heterocyclic ring is an optionally substituted aromatic or heteroaromatic ring. 
     
     
         12 . The method of  claim 23 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 - 17 . (canceled) 
     
     
         18 . A method for inhibiting cell proliferation, which comprises contacting cells with a compound having a structure of Formula IA, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit proliferation of the cells, 
       
         
           
           
               
               
           
         
         wherein: 
         Z 60  and Z 70  are independently N or CR 60 , provided at least one of them is N; 
         each R 30  and each R 60  is independently H or an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl group, 
         or each R 30  and each R 60  can be halo, OR, NR 2 , NROR, NRNR 2 , SR, SOR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCSNR 2 , NRC(═NR)NR 2 , NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, COR, or NO 2 ,
 wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl,
 and wherein two R on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or more N, O or S; 
 and each R group, and each ring formed by linking two R groups together, is optionally substituted with one or more substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′ 2 , SR′, SO 7 R′, SO 2 NR′ 2 , NR′SO 2 R′, NR′CONR′ 2 , NR′CSNR′ 2 , NR′C(═NR′)NR′ 2 , NR′COOR′, NR′COR′, CN, COOR′, CONR′ 2 , OOCR′, COR′, and NO 2 ,
 wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O; 
 
 and wherein two R′ can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S, 
 
 
         each R 40  is H or optionally substituted member selected from the group consisting of C 1 -C 6  alkyl, C2-C6 heteroalkyl, and C1-C6 acyl; 
         each R 50  is independently an optionally substituted member selected from the group consisting of C 1-10  alkyl, C 2-10  alkenyl, C 2-10  heteroalkyl, C 3-8  carbocyclic ring, and C 3-8  heterocyclic ring optionally fused to an additional optionally substituted carbocyclic or heterocyclic ring;
 or R 50  can be a C 1-10  alkyl, C 2-10  alkenyl, or C 2-10  heteroalkyl substituted with an optionally substituted C 3-8  carbocyclic ring or C 3-8  heterocyclic ring; 
 
         in each —NR 40 R 50 , R 40  and R 50  together with N may form an optionally substituted 3-8 membered ring, which may optionally contain an additional heteroatom selected from N, O and S as a ring member; and 
         each R 3P  represents a polar substituent. 
       
     
     
         19 . The method of  claim 18 , wherein the cells are in a cancer cell line. 
     
     
         20 . The method of  claim 19 , wherein the cancer cell line is a breast cancer, prostate cancer, pancreatic cancer, lung cancer, hemopoietic cancer, colorectal cancer, skin cancer, ovary cancer cell line. 
     
     
         21 . The method of  claim 18 , wherein the cells are in a tumor in a subject. 
     
     
         22 . The method of  claim 18 , wherein contacting cells with a compound having a structure of Formula IA induces cell apoptosis. 
     
     
         23 . A method for treating a condition related to aberrant cell proliferation, which comprises administering a compound having a structure of Formula IA, or a pharmaceutically acceptable salt thereof, to a subject in need thereof in an amount effective to treat the cell proliferative condition, 
       
         
           
           
               
               
           
         
         wherein: 
         Z 60  and Z 70  are independently N or CR 60 , provided at least one of them is N; 
         each R 30  and each R 60  is independently H or an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl group, 
         or each R 30  and each R 60  can be halo, OR, NR 2 , NROR, NRNR 2 , SR, SOR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCSNR 2 , NRC(═NR)NR 2 , NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, COR, or NO 2 ,
 wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl,
 and wherein two R on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or more N, O or S; 
 and each R group, and each ring formed by linking two R groups together, is optionally substituted with one or more substituents selected from halo, ═O, ═N—CN, ═NR′, OR′, NR′ 2 , SR′, SO 2 R′, SO 2 NR′ 2 , NR′SO 2 R′, NR′CONR′ 2 , NR′CSNR′ 2 , NR′C(═NR′)NR′ 2 , NR′COOR′, NR′COR′, CN, COOR′, CONR′ 2 , OOCR′, COR′, and NO 2 ,
 wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O; 
 
 and wherein two R′ can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S, 
 
 
         each R 40  is H or optionally substituted member selected from the group consisting of C 1 -C 6  alkyl, C2-C6 heteroalkyl, and C1-C6 acyl; 
         each R 50  is independently an optionally substituted member selected from the group consisting of C 1-10  alkyl, C 2-10  alkenyl, C 2-10  heteroalkyl, C 3-8  carbocyclic ring, and C 3-8  heterocyclic ring optionally fused to an additional optionally substituted carbocyclic or heterocyclic ring;
 or R 50  can be a C 1-10  alkyl, C 2-10  alkenyl, or C 2-10  heteroalkyl substituted with an optionally substituted C 3-8  carbocyclic ring or C 3-8  heterocyclic ring; 
 
         in each —NR 40 R 50 , R 40  and R 50  together with N may form an optionally substituted 3-8 membered ring, which may optionally contain an additional heteroatom selected from N, O and S as a ring member; and 
         each R 3P  represents a polar substituent. 
       
     
     
         24 . The method of  claim 23 , wherein the cell proliferative condition is a tumor-associated cancer. 
     
     
         25 . The method of  claim 24 , wherein the cancer is of the colorectum, breast, lung, liver, pancreas, lymph node, colon, prostate, brain, head and neck, skin, liver, kidney, blood and heart. 
     
     
         26 . The method of  claim 23 , wherein the cell proliferative condition is a non-tumor cancer. 
     
     
         27 . The method of  claim 26 , wherein the non-tumor cancer is a hematopoietic cancer. 
     
     
         28 . The method of  claim 27 , wherein the hematopoietic cancer is acute myelogenous leukemia. 
     
     
         29 . The method of  claim 28 , wherein the leukemia is refractory AML or wherein the AML is associated with a mutated Flt3. 
     
     
         30 . A method for treating pain or inflammation in a subject, which comprises administering a compound of Formula IA, or a pharmaceutically acceptable salt thereof, to a subject in need thereof in an amount effective to treat the pain or the inflammation, 
       
         
           
           
               
               
           
         
         wherein: 
         Z 60  and Z 70  are independently N or CR 60 , provided at least one of them is N; 
         each R 30  and each R 60  is independently H or an optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl group, 
         or each R 30  and each R 60  can be halo, OR, NR 2 , NROR, NRNR 2 , SR, SOR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCSNR 2 , NRC(═NR)NR 2 , NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, COR, or NO 2 ,
 wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl,
 and wherein two R on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or more N, O or S; 
 and each R group, and each ring formed by linking two R groups together, is optionally substituted with one or more substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′ 2 , SR′, SO 2 R′, SO 2 NR′ 2 , NR′SO 2 R′, NR′CONR′ 2 , NR′CSNR′ 2 , NR′C(═NR′)NR′ 2 , NR′COOR′, NR′COR′, CN, COOR′, CONR′ 2 , OOCR′, COR′, and NO 2 ,
 wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O; 
 
 and wherein two R′ can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S, 
 
 
         each R 40  is H or optionally substituted member selected from the group consisting of C 1 -C 6  alkyl, C2-C6 heteroalkyl, and C1-C6 acyl; 
         each R 50  is independently an optionally substituted member selected from the group consisting of C 1-10  alkyl, C 2-10  alkenyl, C 2-10  heteroalkyl, C 3-8  carbocyclic ring, and C 3-8  heterocyclic ring optionally fused to an additional optionally substituted carbocyclic or heterocyclic ring;
 or R 50  can be a C 1-10  alkyl, C 2-10  alkenyl, or C 2-10  heteroalkyl substituted with an optionally substituted C 3-8  carbocyclic ring or C 3-8  heterocyclic ring; 
 
         in each —NR 40 R 50 , R 40  and R 50  together with N may form an optionally substituted 3-8 membered ring, which may optionally contain an additional heteroatom selected from N, O and S as a ring member; and 
         each R 3P  represents a polar substituent.