Antiproliferative compounds, and their pharmaceutical compositions and uses
Compounds of formula A-I and B-I, compositions comprising the compounds, methods of making the compounds and methods of their uses are disclosed.
1. A compound of formula A-I:
or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, isotopologue or polymorph thereof, wherein:
each R is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;
R 1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
R 2 and R 3 are each halo;
where the substituents on R 1 , when present are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, —R 4 OR 5 , —R 4 SR 5 , —R 4 N(R 6 )(R 7 ), R 4 OR 4 N(R 6 )(R 7 ) or R 4 OR 4 C(J)N(R 6 )(R 7 );
J is O or S;
each R 4 is independently alkylene, alkenylene or a direct bond;
each R 5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and
R 6 and R 7 are each independently hydrogen or alkyl or R 6 and R 7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
2. The compound of claim 1 , wherein the compound is of Formula A-II:
or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, isotopologue or polymorph thereof, wherein:
each R is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;
R 1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
where the substituents on R 1 , when present are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, —R 4 OR 5 , —R 4 SR 5 , —R 4 N(R 6 )(R 7 ), R 4 OR 4 N(R 6 )(R 7 ) or R 4 OR 4 C(J)N(R 6 )(R 7 );
J is O or S;
each R 4 is independently alkylene, alkenylene or a direct bond;
each R 5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and
R 6 and R 7 are each independently hydrogen or alkyl or R 6 and R 7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
3. The compound of claim 1 , wherein each R is independently H or (C 1 -C 6 )alkyl; R 1 is optionally substituted aryl, where the substituents on R 1 , when present, are one to three groups Q, where each Q is independently halo, alkyl, —R 4 OR 5 , —R 4 SR 5 or R 4 OR 4 C(O)N(R 6 )(R 7 ); each R 4 is independently a direct bond or alkylene; each R 5 is independently hydrogen, halo, alkyl or haloalkyl; and R 6 and R 7 are each independently hydrogen or alkyl.
4. The compound of claim 1 , wherein each R is independently is H or (C 1 -C 6 )alkyl; and R 1 is optionally substituted aryl, where the substituents on R 1 , when present, are one to three groups Q, where each Q is independently fluoro, chloro, methyl, —R 4 OR 5 , —R 4 N(R 6 )(R 7 ), —R 4 SR 5 or R 4 OR 4 C(O)N(R 6 )(R 7 ); each R 4 is independently a direct bond or methylene; each R 5 is independently hydrogen, methyl, ethyl or trifluoromethyl; and R 6 and R 7 are each independently hydrogen or methyl.
5. The compound of claim 1 , wherein each R is independently H or (C 1 -C 6 )alkyl and R 1 is optionally substituted phenyl, where the substituents on R 1 , when present, are one to three groups Q, where each Q is independently fluoro, chloro, methyl, tert butyl, —R 4 OR 5 , —R 4 N(R 6 )(R 7 ), —R 4 SR 5 or R 4 OR 4 C(O)N(R 6 )(R 7 ); each R 4 is independently a direct bond or methylene; each R 5 is independently hydrogen, methyl, ethyl or trifluoromethyl; and R 6 and R 7 are each independently hydrogen or methyl.
6. The compound of claim 1 , wherein the compound is of Formula A-III:
or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, isotopologue or polymorph thereof, wherein:
each R is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;
each Q 1 is independently alkyl, halo, haloalkyl, alkoxyalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylakyl, optionally substituted aryl —R 4 OR 5 , —R 4 SR 5 , —R 4 N(R 6 )(R 7 ), R 4 OR 4 N(R 6 )(R 7 ) or R 4 OR 4 C(J)N(R 6 )(R 7 );
J is O or S;
each R 4 is independently alkylene, alkenylene or a direct bond;
each R 5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl;
R 6 and R 7 are each independently hydrogen or alkyl or R 6 and R 7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; and
n is 0-3.
7. The compound of claim 1 , wherein the compound is selected from the group consisting of:
8. A compound of Formula B-I:
or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, isotopologue or polymorph thereof, wherein:
each R′ is independently H or optionally substituted alkyl; or optionally substituted cycloalkyl;
R′ is H or optionally substituted alkyl;
R 1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
R 2 and R 3 are each halo;
where the substituents on R 1 , when present are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, —R 4 OR 5 , —R 4 SR 5 , —R 4 N(R 6 )(R 7 ), R 4 OR 4 N(R 6 )(R 7 ) or R 4 OR 4 C(J)N(R 6 )(R 7 );
J is O or S;
each R 4 is independently alkylene, alkenylene or a direct bond;
each R 5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and
R 6 and R 7 are each independently hydrogen or alkyl or R 6 and R 7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
9. The compound of claim 8 , wherein the compound is of Formula B-II:
or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, isotopologue or polymorph thereof, wherein:
each R is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;
each R′ is independently is H or optionally substituted alkyl;
R 1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
where the substituents on R 1 , when present are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, —R 4 OR 5 , —R 4 SR 5 , —R 4 N(R 6 )(R 7 ), R 4 OR 4 N(R 6 )(R 7 ) or R 4 OR 4 C(J)N(R 6 )(R 7 );
J is O or S;
each R 4 is independently alkylene, alkenylene or a direct bond;
each R 5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and
R 6 and R 7 are each independently hydrogen or alkyl or R 6 and R 7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
10. The compound of claim 8 , wherein each R is independently H or (C 1 -C 6 )alkyl; each R′ is independently is H or (C1-C6)alkyl; R 1 is optionally substituted aryl, where the substituents on R 1 , when present, are one to three groups Q, where each Q is independently halo, alkyl, —R 4 OR 5 , —R 4 SR 5 or R 4 OR 4 C(O)N(R 6 )(R 7 ); each R 4 is independently a direct bond or alkylene; each R 5 is independently hydrogen, halo, alkyl or haloalkyl; and R 6 and R 7 are each independently hydrogen or alkyl.
11. The compound of claim 8 , wherein each R is independently H or (C 1 -C 6 )alkyl; each R′ is independently H or (C1-C6)alkyl; R 1 is optionally substituted phenyl, where the substituents on R 1 , when present, are one to three groups Q, where each Q is independently fluoro, chloro, methyl, tert butyl, —R 4 OR 5 , —R 4 N(R 6 )(R 7 ), —R 4 SR 5 or R 4 OR 4 C(O)N(R 6 )(R 7 ); each R 4 is independently a direct bond or methylene; each R 5 is independently hydrogen, methyl, ethyl or trifluoromethyl; and R 6 and R 7 are each independently hydrogen or methyl.
12. The compound of claim 8 , wherein the compound is of Formula B-III:
or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, isotopologue or polymorph thereof, wherein:
each R is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;
each R′ is independently is H or optionally substituted alkyl;
each Q 1 is independently alkyl, halo, haloalkyl, alkoxyalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylakyl, optionally substituted aryl, —R 4 OR 5 , —R 4 SR 5 , —R 4 N(R 6 )(R 7 ), R 4 OR 4 N(R 6 )(R 7 ) or R 4 OR 4 C(J)N(R 6 )(R 7 );
J is O or S;
each R 4 is independently alkylene, alkenylene or a direct bond;
each R 5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl;
R 6 and R 7 are each independently hydrogen or alkyl or R 6 and R 7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; and
n is 0-3.
13. The compound of claim 8 , wherein the compound is selected from the group consisting of:
14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
15. The pharmaceutical composition of claim 14 , wherein the composition is formulated for parenteral, or intravenous administration.
16. The pharmaceutical composition of claim 14 , wherein the composition is formulated as a single unit dosage form.
17. A pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier, diluent or excipient.
18. The pharmaceutical composition of claim 17 , wherein the composition is formulated for parenteral, or intravenous administration.
19. The pharmaceutical composition of claim 17 , wherein the composition is formulated as a single unit dosage form.
20. A method of treating cancer comprising administering to a mammal having cancer a therapeutically effective amount of the compound of claim 1 .
21. The method of claim 20 , wherein the cancer is leukemia.
22. The method of claim 21 , wherein the leukemia is chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia or acute myeloid leukemia.
23. The method of claim 21 , wherein the leukemia is an acute myeloid leukemia.
24. The method of claim 21 , wherein the leukemia is relapsed, refractory or resistant to surgery, radiation therapy, chemotherapy or hormonal therapy.
25. The method of claim 20 further comprising administering a therapeutically effective amount of a second active agent or a support care therapy.
26. The method of claim 25 , wherein the second active agent is a therapeutic antibody that specifically binds to a cancer antigen, hematopoietic growth factor, cytokine, anti-cancer agent, antibiotic, cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent, corticosteroid or a pharmacologically active mutant thereof.
27. A method of treating cancer comprising administering to a mammal having cancer a therapeutically effective amount of the compound of claim 8 .
28. The method of claim 27 , wherein the cancer is leukemia.
29. The method of claim 28 , wherein the leukemia is chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia or acute myeloid leukemia.
30. The method of claim 28 , wherein the leukemia is an acute myeloid leukemia.
31. The method of claim 28 , wherein the leukemia is relapsed, refractory or resistant to surgery, radiation therapy, chemotherapy or hormonal therapy.
32. The method of claim 27 further comprising administering a therapeutically effective amount of a second active agent or a support care therapy.
33. The method of claim 32 , wherein the second active agent is a therapeutic antibody that specifically binds to a cancer antigen, hematopoietic growth factor, cytokine, anti-cancer agent, antibiotic, cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent, corticosteroid or a pharmacologically active mutant thereof.