Substituted chromenes as kinase modulators
The present invention provides PI3K protein kinase modulators of formula (I): wherein R, R 1 , R 2 , L 1 , Cy 1 , Cy 2 and n are as described herein, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.
1. A method for the treatment of chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), or small lymphocytic lymphoma (SLL), comprising the step of administering to a subject in need thereof an effective amount of compound of the formula
or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
each occurrence of R is independently selected from hydrogen, halogen, —OR f (wherein R f is substituted or unsubstituted (C 1-6 )alkyl), CN, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, and substituted or unsubstituted heterocyclic group;
R 1 and R 2 may be the same or different and are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl, or both R 1 and R 2 directly bound to a common atom, may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring (including the carbon atom to which R 1 and R 2 are bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR a and S;
Cy 1 is a monocyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
Cy 2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
L 1 is selected from —S(═O) q — and —NR a —;
each occurrence of R a is selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, —NR c R d (wherein R c and R d are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, and (C 1-6 )alkoxy) and —OR c (wherein R c is substituted or unsubstituted (C 1-6 )alkyl);
n is an integer from 1 to 4; and
q is 0, 1 or 2.
2. The method of claim 1 , where the compound of formula (I) is selected from the group consisting of:
2-((9H-Purin-6-ylthio)methyl)-3-phenyl-4H-chromen-4 -one;
2-[(9H-Purin-6-ylthio)methyl]-6-bromo-3-phenyl-4H-chromen-4-one;
2-(1-(9H-Purin-6-ylthio)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;
(S)-2-(1 -(9H-purin-6-ylamino)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-6-bromo-3-phenyl-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-3-phenyl-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-3-(2-fluorophenyl)-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one;
(S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3 -fluorophenyl)-4H-chromen-4-one;
(R)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;
(S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one;
(S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenyl-4H-chromen-4-one;
(S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one;
(R)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;
6-Fluoro-3-(3-fluorophenyl)-2-(1-(4-methoxyphenylamino)ethyl)-4H-chromen-4-one, and pharmaceutically acceptable salts thereof.
3. A method for the treatment of a chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), or small lymphocytic lymphoma (SLL), comprising the step of administering to a subject in need thereof an effective amount of compound of the formula
or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
each occurrence of R is independently selected from hydrogen, halogen, —OR f (wherein R f is substituted or unsubstituted (C 1-6 )alkyl), substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, and substituted or unsubstituted heterocyclic group;
R 1 and R 2 may be the same or different and are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl, or both R 1 and R 2 directly bound to a common atom, may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring (including the carbon atom to which R 1 and R 2 are bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR a and S;
Cy l is a monocyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
Cy 2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
L 1 is selected from —S(═O) q — and —NR a —;
each occurrence of R a is selected from hydrogen, halogen, hydroxy, cyano, and substituted or unsubstituted (C 1-6 )alkyl;
n is an integer from 1 to 4; and
q is 0, 1 or 2.
4. The method of claim 1 , wherein the non-Hodgkin's lymphoma is indolent non-Hodgkin's lymphoma (I-NHL).
5. The method of claim 3 , wherein the non-Hodgkin's lymphoma is indolent non-Hodgkin's lymphoma (I-NHL).