Oxindole compounds

Abstract

The invention provides compounds that inhibit PIM kinases and Flt3 kinase, 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.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from H, alkyl, substituted alkyl, —SO 2 NR 2 , and —C(═O)R; 
         R 2  is selected from H, D, alkyl, and substituted alkyl; 
         Y 1  is O or S; 
         Y 2  is O, S or NR 1 ; 
         each X 1 , X 2 , and X 3  is independently selected from halo, CN, CF 3 , NO 2 , alkyl, substituted alkyl, OR, and NR 2 , COR, CONR, SO q R, NSO q R, NRCONR, and NRC(O)OR; 
         m, n and p each independently represent 0, 1 or 2; 
         W 1 , W 2  and W 3  are each independently C or N, wherein each C is substituted with H or X 3  or Ar, provided that either W 2  or W 3  is the point of attachment for Ar; 
         Ar is a 5-10 membered aromatic or heteroaromatic group that is optionally substituted with (X 2 ) n ; 
         A is selected from the group consisting of CH 2 Q, —O—Z, —NRZ, SO q Z, SO q NRZ, NRSO q Z, NR—C(O)Z, NRC(O)—OZ, NRC(O)—NRZ, NRC(O)—OZ, OC(O)NRZ, —C(═O)OZ and —C(═O)NRZ,
 where Z is H, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, aryl, or substituted aryl, 
 and Q is OZ or NRZ; 
 
         R is independently selected at each occurrence from the group consisting of H, alkyl or substituted alkyl, and two R on NR 2  can cyclize to form a 5-7 membered ring that can be substituted and may optionally contain one additional heteroatom selected from N, O and S as a ring member, 
         and R and Z, when both present on A or Q, can optionally cyclize to form a 5-7 membered ring that can be substituted and can include an additional O, N or S as a ring member; and 
         each q is independently 0, 1 or 2; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein Y 1  is O. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is H or Me. 
     
     
         4 . The compound of  claim 1 , wherein R 2  is H, D, Me, Et, Cyclopropyl, isopropyl or CH 2 OH. 
     
     
         5 . The compound of  claim 1 , wherein W 1  and W 2  are each independently CH or CMe. 
     
     
         6 . The compound of  claim 1 , wherein m is 1 and X 1  is halo. 
     
     
         7 . The compound of  claim 1 , wherein W 3  is the point of attachment for Ar. 
     
     
         8 . The compound of  claim 1 , wherein W 2  is the point of attachment for Ar. 
     
     
         9 . The compound of  claim 1 , wherein Ar is phenyl or pyridyl, each of which can be substituted. 
     
     
         10 . The compound of  claim 9 , wherein Ar is substituted with one group selected from halo, amino, alkyl, and hydroxyl, in addition to A. 
     
     
         11 . The compound of  claim 1 , wherein A is —NR—C(O)Z or —C(═O)NRZ, wherein R is H or Me, or wherein R and Z can optionally cyclize to form a 5-7 membered ring that can be substituted and can include an additional O, N or S as a ring member. 
     
     
         12 . The compound of  claim 11 , wherein Z is a group of the formula —(CH 2 ) r Z′, wherein r is 0, 1, 2, 3, or 4, and Z′ is —NR 1 R 2  or a 5-6 membered heteroaryl or heterocyclic ring containing at least one N as a ring member, and optionally substituted. 
     
     
         13 . The compound of  claim 1 , wherein the compound is a compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein A, R 1 , R 2 , X 1 , X 2 , X 3 , m, n, and p are as defined for Formula (I), 
         and each of Z 2 , Z 3 , Z 4 , Z 5  and Z 6  is independently C or N, provided not more than two of Z 2 , Z 3 , Z 4 , Z 5  and Z 6  are N, and wherein each C is CH or CX 2  or is the point of attachment for A;
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         14 . The compound of  claim 13 , wherein A is —C(═O)—NRZ or —NRC(O)Z, wherein R is H or Me, or wherein R and Z can optionally cyclize to form a 5-7 membered ring that can be substituted and can include an additional O, N or S as a ring member. 
     
     
         15 . The compound of  claim 13 , wherein m is 1 and X 1  is halo. 
     
     
         16 . The compound of  claim 13 , wherein Z 3  is C-A. 
     
     
         17 . The compound of  claim 13 , wherein Z 4  is C-A. 
     
     
         18 . The compound of  claim 13 , which is a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein X 1  is Cl or F, and in is 0 or 1; 
         X 2  is halo, NH 2 , OH, or CH 2 OH, and n is 0 or 1; 
         X 3  is Me, and p is 0 or 1; 
         R 2  is II, D, Me, Et, cyclopropyl, isopropyl or CH 2 OH; 
         one of Z 3  and Z 4  is CH and the other of Z 3  and Z 4  is CA; 
         Z 5  is N or CH, or Z 5  can be CX if n is 1; 
         R 1  is H or —C(O)R; 
         A is COOH, OH, CH 2 OH, NH 2 , CONH 2 , —SO 2 NH 2 , —NRSO 2 CF 3 , tetrazole, or a group of the formula -L-Az, wherein L is a linker selected from the group consisting of —NR—, —C(O)—, —O—, —NRC(O)—, —C(O)NR—, —NRSO 2 —, —SO 2 NR—, —NRC(O)—(CH 2 ) r , and —C(O)NR—(CH 2 ) r —, where each r is independently 1-3; 
         each R is independently H, alkyl or substituted alkyl; and 
         Az represents a 5-7-membered nitrogen-containing heterocyclic or heteroaryl group; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         19 . A compound of the formula (IIIa): 
       
         
           
           
               
               
           
         
         wherein m is 1, and X 1  is Cl or F; 
         X 2  is selected from H, Cl, OH, OMe, NH 2 , NHMe, Me, and F; 
         R 2  is H, or Me; and 
         R is H, Me, Et, or isopropyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         20 . A compound formula (IV): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from H, alkyl, substituted alkyl, —SO 2 NR 2 , and —C(═O)R; 
         R 2  is selected from H, D, alkyl, and substituted alkyl; 
         R 3  is selected from H, D, F, OH, alkyl, and substituted alkyl; 
         Y 1  is O or S; 
         Y 2  is O, S or NR 1 ; 
         each X 1 , X 2 , and X 3  is independently selected from halo, CN, CF 3 , NO 2 , alkyl, substituted alkyl, OR, and NR 2 , COR, CONR, SO q R, NSO q R, NRCONR, and NRC(O)OR; 
         n and p each independently represent 0, 1 or 2; 
         W 1 , W 2  and W 3  are each independently C or N, wherein each C is substituted with H or X 3  or Ar, provided that either W 2  or W 3  is the point of attachment for Ar; 
         Ar is a 5-10 membered aromatic or heteroaromatic group that is optionally substituted with (X 2 ) n ; 
         A is selected from the group consisting of CH 2 Q, —O—Z, —NRZ, SO q Z, SO q NRZ, NRSO q Z, NR—C(O)Z, NRC(O)—OZ, NRC(O)—NRZ, NRC(O)—OZ, OC(O)NRZ, —C(═O)OZ and —C(═O)NRZ,
 where Z is H, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, aryl, or substituted aryl, 
 and Q is OZ or NRZ; 
 
         R is independently selected at each occurrence from the group consisting of H, alkyl or substituted alkyl, and two R on NR 2  can cyclize to form a 5-7 membered ring that can be substituted and may optionally contain one additional heteroatom selected from N, O and S as a ring member, 
         and R and Z, when both present on A or Q, can optionally cyclize to form a 5-7 membered ring that can be substituted and can include an additional O, N or S as a ring member; and 
         each q is independently 0, 1 or 2; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         21 . A pharmaceutical composition comprising at least one compound of formula (I) according to  claim 1  admixed with at least one pharmaceutically acceptable excipient. 
     
     
         22 . A method to treat cancer, comprising administering to a subject in need of treatment for cancer an effective amount of a compound of formula (I) according to  claim 1 . 
     
     
         23 . The method of  claim 22 , wherein the cancer is selected from the group consisting of colon cancer, pancreatic cancer, prostate cancer, and leukemia. 
     
     
         24 . The method of  claim 23 , wherein the leukemia is acute myelogenous leukemia (AML). 
     
     
         25 . The method of  claim 24 , wherein the leukemia is refractory AML or wherein the AML is associated with a mutated Flt3. 
     
     
         26 . A method to treat inflammation, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I) according to  claim 1 .