Aminopyrimidine kinase inhibitors
Disclosed are compounds, pharmaceutical compositions containing those compounds, and uses of the compounds and compositions as modulators of casein kinase 1 (e.g., CK1γ), casein kinase 2 (CK2), Pim 1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, and/or the mTOR pathway. Uses are also disclosed for the treatment or prevention of a range of therapeutic indications due at least in part to aberrant physiological activity of casein kinase 1 (e.g., CK1γ), casein kinase 2 (CK2), Pim 1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, and/or the mTOR pathway.
1. A compound of formula 1:
or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
W and X are independently oxygen or sulfur;
Z 1 , Z 2 and Z 3 are independently C—R 20 or N, provided that at least one of Z 1 and Z 2 is N;
R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR 6 , —C(O)OR 6 , —SO 2 (R 6 ), —C(O)N(R 6 )(R 7 ), —SO 2 N(R 6 )(R 7 ), and —[C(R 4 ) 2 ] p —R 5 ;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R 4 ) 2 ] p —R 5 , —COR 6 , —C(O)OR 6 , —SO 2 (R 6 ), —C(O)N(R 6 )(R 7 ), —SO 2 N(R 6 )(R 7 ), —P(O)(OR 6 )(OR 7 ); or R 2 and R 3 are joined together to form an optionally substituted heterocyclic ring;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;
R 5 is selected from the group consisting of aryl, heteroaryl, heterocyclyl, —N(R 8 )(R 9 ), —N(R 8 )COR 9 , —N(R 8 )C(O)OR 9 , —N(R 8 )SO 2 (R 9 ), —CON(R 8 )(R 9 ), —OC(O)N(R 8 )—(R 9 ), —SO 2 N(R 8 )(R 9 ), —OC(O)OR 8 , —COOR 9 , —C(O)N(OH)(R 8 ), —OS(O) 2 OR 8 , —S(O) 2 OR 8 , —S(O) 2 R 8 , —OR 8 , —COR 8 , —OP(O)(OR 8 )(OR 8 ), —P(O)(OR 8 )(OR 8 ) and —N(R 8 )P(O)(OR 9 )(OR 9 );
R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R 7 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R 6 and R 7 are joined together to form a heterocyclic ring;
R 8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R 9 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R 8 and R 9 are joined together to form a heterocyclic ring;
R 20 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R 4 ) 2 ] p —R 5 , NR 14 R 15 , OR 16 , O—[C(R 4 ) 2 ] p —R 5 , NR 14 —[C(R 4 ) 2 ] p R 5 and SR 16 ;
R 14 and R 15 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R 4 ) 2 ] p —R 5 , —COR 6 , —C(O)OR 6 , —SO 2 (R 6 ), —C(O)N(R 6 )(R 7 ), —SO 2 N(R 6 )(R 7 ), and —P(O)(OR 6 )(OR 7 ); or R 14 and R 15 are joined together to form an optionally substituted heterocyclic ring;
R 16 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R 4 ) 2 ] p —R 5 , —COR 6 , and —C(O)N(R 6 )(R 7 ); and
p is 1, 2, 3, 4, 5, or 6;
wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.
2. The compound of claim 1 , wherein W and X are oxygen.
3. The compound of claim 1 , wherein Z 1 and Z 2 are nitrogen; and Z 3 is C—R 20 .
4. The compound of claim 1 , wherein R 1 is hydrogen.
5. The compound of claim 1 , wherein W and X are oxygen, Z 1 and Z 2 are each nitrogen, Z 3 is C—R 20 and R 1 is hydrogen.
6. The compound of claim 5 , wherein R 2 and R 3 are joined together to form an optionally substituted heterocyclic ring.
7. The compound of claim 6 , wherein the optionally substituted heterocyclic ring is selected from the group consisting of piperazinyl, homopiperizinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, 1,4-diazepan-5-onyl and quinolinyl.
8. The compound of claim 5 , wherein R 20 is hydrogen.
9. The compound of claim 1 , wherein the compound is a compound of formula 2:
or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR 6 , —C(O)OR 6 , —SO 2 (R 6 ), —C(O)N(R 6 )(R 7 ), —SO 2 N(R 6 )(R 7 ), and —[C(R 4 ) 2 ] p R 5 ;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R 4 ) 2 ] p —R 5 , —COR 6 , —C(O)OR 6 , —SO 2 (R 6 ), —C(O)N(R 6 )(R 7 ), —SO 2 N(R 6 )(R 7 )—P(O)(OR 6 )(OR 7 ); or R 2 and R 3 are joined together to form an optionally substituted heterocyclic ring;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl;
R 5 is selected from the group consisting of aryl, heteroaryl, heterocyclyl, —N(R 8 )(R 9 ), —N(R 8 )COR 9 , —N(R 8 )C(O)OR 9 , —N(R 8 )SO 2 (R 9 ), —CON(R 8 )(R 9 ), —OC(O)N(R 8 )—(R 9 ), —SO 2 N(R 8 )(R 9 ), —OC(O)OR 8 , —COOR 9 , —C(O)N(OH)(R 8 ), —OS(O) 2 OR 8 , —S(O) 2 OR 8 , —S(O) 2 R 8 , —OR 8 , —COR 8 , —OP(O)(OR 8 )(OR 9 ), —P(O)(OR 8 )(OR 9 ) and —N(R 8 )P(O)(OR 9 )(OR 9 );
R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R 7 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl, or R 6 and R 7 are joined together to form a heterocyclic ring;
R 8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl;
R 9 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R 8 and R 9 are joined together to form a heterocyclic ring;
R 20 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxyl, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R 4 ) 2 ] p —R 5 ; NR 14 R 15 , OR 16 , and SR 16 ;
R 14 and R 15 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R 4 ) 2 ] p —R 5 , —COR 6 , —C(O)OR 6 , —SO 2 (R 6 ), —C(O)N(R 6 )(R 7 ), —SO 2 N(R 6 )(R 7 ), and —P(O)(OR 6 )(OR 7 ); or R 14 and R 15 are joined together to form an optionally substituted heterocyclic ring;
R 16 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R 4 ) 2 ] p —R 5 , —COR 6 , and —C(O)N(R 6 )(R 7 ); and
p is 1, 2, 3, 4, 5, or 6;
wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.
10. The compound of claim 9 , wherein R 1 is hydrogen.
11. The compound of claim 10 , wherein R 20 is hydrogen.
12. The compound of claim 11 , wherein R 2 and R 3 are joined together to form an optionally substituted heterocyclic ring.
13. The compound of claim 12 , wherein R 2 and R 3 are joined together to form an optionally substituted heterocyclic ring selected from the group consisting of:
wherein, independently for each occurrence:
R 10 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R 4 ) 2 ] p —R 5 , —COR 12 , —C(O)OR 12 , —SO 2 (R 12 ), —C(O)N(R 12 )(R 13 ), —SO 2 N(R 12 )(R 13 ), and —P(O)(OR 12 )(OR 13 );
R 12 and R 13 are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R 12 and R 13 are joined together to form a heterocyclic ring;
R 11 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, haloalkyl, thio, cyano, hydroxyalkyl, alkoxy, alkylalkoxy, alkylthio, nitro, cyano, —N(R 17 )(R 18 ), —N(R 17 )COR 18 , —N(R 17 )C(O)OR 18 , —N(R 17 )SO 2 (R 18 ), —CON(R 17 )(R 18 ), —OC(O)N(R 17 )—(R 18 ), —SO 2 N(R 17 )(R 18 ), —OC(O)OR 17 , —COOR 17 , —C(O)N(OH)(R 17 ), —OS(O) 2 OR 17 , —S(O) 2 OR 17 , —S(O) 2 R 17 , —OR 17 , —COR 17 , —OP(O)(OR 17 )(OR 18 ), —P(O)(OR 17 )(OR 18 ), —N(R 17 )P(O)(OR 18 )(OR 18 ), and —[C(R 4 ) 2 ] p —R 5 ;
R 17 and R 18 selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R 17 and R 18 are joined together to form a heterocyclic ring; and
n is 0, 1, 2, or 3;
wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
16. The compound of claim 1 , wherein the compound is an inhibitor of PIM1, PIM2, or PIM3.
17. The compound of claim 16 , wherein the compound has an IC 50 of less than 5000 nM for PIM1, PIM2 or PIM3.
18. The compound of claim 17 , wherein the compound has an IC 50 of less than 1000 nM for PIM1, PIM2, or PIM3.
19. The compound of claim 18 , wherein the compound has an IC 50 of less than 500 nM for PIM1, PIM2, or PIM3.