Substituted thieno[3,2-d]pyrimidine PIM kinase inhibitors as cancer chemotherapeutics
View Patent ↗Compounds of formula I wherein A 1 , A 2 , and A 3 are as defined herein are inhibitors of PIM kinase. The compounds of formula I are useful for the treatment of diseases such as cancer.
1. A compound having formula (I)
or a salt thereof, wherein
A 1 is H or R 1 ;
A 2 is H or R 4 ;
R 1 is phenyl; which is substituted with one or two of independently selected alkyl, heterocycloalkyl, OR 16 , SR 16 , S(O)R 16 , SO 2 R 16 , C(O)R 16 , CO(O)R 16 , OC(O)R 16 , OC(O)OR 16 , NH 2 , NHR 16 , N(R 16 ) 2 , C(O)NH 2 , C(O)NHR 16 , C(O)N(R 16 ) 2 , SO 2 NH 2 , SO 2 NHR 16 , SO 2 N(R 16 ) 2 , CF 3 , CF 2 CF 3 , C(O)H, C(O)OH, OH, N 3 , NO 2 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;
R 4 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two of independently selected CF 3 , F, Cl, Br or I;
A 3 is R 15 ;
R 15 is alkyl, which is substituted with one or two of independently selected NH 2 , NHW 1 , N(W 1 ) 2 , or heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with one or two of independently selected alkyl, OR 16 , or OH;
W 1 is phenyl or alkyl; wherein the phenyl is unsubstituted or substituted with one or two of independently selected alkyl, OR 16 , NH 2 , CF 3 , CF 2 CF 3 , OH, NO 2 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; and
R 16 is H or alkyl.
2. The compound of claim 1 , wherein
A 2 is H.
3. A compound having formula (I)
or a salt thereof, wherein
A 1 is H or R 4 ;
A 2 is H or R 1 ;
R 1 is phenyl; which is unsubstituted or substituted with one or two of independently selected alkyl, heterocycloalkyl, OR 16 , SR 16 , S(O)R 16 , SO 2 R 16 , C(O)R 16 , CO(O)R 16 , OC(O)R 16 , OC(O)OR 16 , NH 2 , NHR 16 , N(R 16 ) 2 , C(O)NH 2 , C(O)NHR 16 , C(O)N(R 16 ) 2 , SO 2 NH 2 , SO 2 NHR 16 , SO 2 N(R 16 ) 2 , CF 3 , CF 2 CF 3 , C(O)H, C(O)OH, OH, N 3 , NO 2 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;
R 4 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two of independently selected CF 3 , F, Cl, Br or I;
A 3 is R 15 ;
R 15 is alkyl, which is substituted with one or two of independently selected NH 2 , NHW 1 , N(W 1 ) 2 , or heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with one or two of independently selected alkyl, OR 16 , or OH;
W 1 is phenyl or alkyl; wherein the phenyl is unsubstituted or substituted with one or two of independently selected alkyl, OR 16 , NH 2 , CF 3 , CF 2 CF 3 , NO 2 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; and
R 16 is H or alkyl.
4. The compound of claim 3 , wherein
A 1 is H.
5. A compound having formula (I)
or a salt thereof, wherein
A 1 is R 1 ;
A 2 is R 1 ;
R 1 is phenyl; which is unsubstituted or substituted with one or two of independently selected alkyl, heterocycloalkyl, OR 16 , SR 16 , S(O)R 16 , SO 2 R 16 , C(O)R 16 , CO(O)R 16 , OC(O)R 16 , OC(O)OR 16 , NH 2 , NHR 16 , N(R 16 ) 2 , C(O)NH 2 , C(O)NHR 16 , C(O)N(R 16 ) 2 , SO 2 NH 2 , SO 2 NHR 16 , SO 2 N(R 16 ) 2 , CF 3 , CF 2 CF 3 , C(O)H, C(O)OH, OH, N 3 , NO 2 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;
A 3 is H or R 15 ;
R 15 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two of independently selected NH 2 , NHW 1 , N(W 1 ) 2 , or heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with one or two of independently selected alkyl, OR 16 , SR 16 , S(O)R 16 , SO 2 R 16 , C(O)R 16 , CO(O)R 16 , OC(O)R 16 , OC(O)OR 16 , NH 2 , NHR 16 , N(R 16 ) 2 , C(O)NH 2 , C(O)NHR 16 , C(O)N(R 16 ) 2 , SO 2 NH 2 , SO 2 NHR 16 , SO 2 N(R 16 ) 2 , CF 3 , CF 2 CF 3 , C(O)H, C(O)OH, OH, (O), N 3 , NO 2 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;
W 1 is phenyl or alkyl; wherein the phenyl is unsubstituted or substituted with one or two of independently selected alkyl, OR 16 , SR 16 , S(O)R 16 , SO 2 R 16 , C(O)R 16 , CO(O)R 16 , OC(O)R 16 , OC(O)OR 16 , NH 2 , NHR 16 , N(R 16 ) 2 , C(O)NH 2 , C(O)NHR 16 , C(O)N(R 16 ) 2 , SO 2 NH 2 , SO 2 NHR 16 , SO 2 N(R 16 ) 2 , CF 3 , CF 2 CF 3 , C(O)H, C(O)OH, OH, N 3 , NO 2 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; and
R 16 is H or alkyl.
6. The compound of claim 5 , wherein
A 3 is H.
7. The compound of claim 5 , wherein
A 3 is R 15 , and R 15 is alkyl, which is unsubstituted.
8. The compound of claim 5 , wherein
A 3 is R 15 , and R 15 is alkyl, which is substituted with one or two of independently selected NH 2 , NHW 1 , N(W 1 ) 2 , or heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with alkyl, OR 16 or OH; and
W 1 is phenyl or alkyl; wherein the phenyl is unsubstituted or substituted with one or two of independently selected alkyl, OR 16 , NH 2 , CF 3 , CF 2 CF 3 , OH, NO 2 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I.