4H-chromen-4-one compounds as modulators of protein kinases
View Patent ↗The present invention provides PI3K protein kinase modulators, 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 compound of 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. A compound of claim 1 , wherein the compound has the formula:
or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
R, Cy l , R 1 , R 2 , and L 1 are as defined in claim 1 ; and
Cy 2 is selected from substituted or unsubstituted heterocyclic group and substituted or unsubstituted heteroaryl.
3. A compound of claim 1 , wherein the compound has the formula (IA-III), or (IA-IV):
or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
R, Cy 1 , R 1 , R 2 , and q are as defined in claim 1 ;
each occurrence of X is independently selected from CR 3 or N; and
each occurrence of R 3 is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR x CONR y R z , —N(R x )SOR y , —N(R x )SO 2 R y , —(═N—N(R x )R y ), —NR x C(O)OR y , —NR x R y , —NR x C(O)R y —, —NR x C(S)R y —NR x C(S)NR y R z , —SONR x R y —, —SO 2 NR y —, —OR x , —OR x C(O)NR y R z , —OR x C(O)OR y —, —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR y R z , —R x C(O)R x , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , and —ONO 2 , wherein R x , R y and R z in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of R x , R y and R z may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR w (wherein R w is hydrogen or substituted or unsubstituted alkyl) or S.
4. A compound of claim 1 , wherein R is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, or —OR f .
5. A compound of claim 1 , wherein Cy 1 is substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
6. A compound of claim 1 , wherein Cy 1 is
7. A compound of claim 1 , wherein R 1 and R 2 represent hydrogen or substituted or unsubstituted C 1-6 alkyl.
8. A compound of claim 1 , wherein L 1 is —NR a —.
9. A compound of claim 1 , wherein Cy 2 is
wherein
X is CR 3 ; and
R 3 is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted guanidine, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR X R y , —NR x CONR y R z , —N(R x )SOR y , —N(R x )SO 2 R y , —(═N—N(R x )R y ), —NR x C(O)OR y , —NR x R y , —NR x C(O)R y —, —NR x C(S)R y —NR x C(S)NR y R z , —SONR x R y —, —SO 2 NR x R y—,—OR x , —OR x C(O)NR y R z , —OR x C(O)OR y —, —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR y R z , —R x C(O)R x , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , and —ONO 2 , wherein R x , R y and R z in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring, or any two of R x , R y and R z may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR w (wherein R w is hydrogen or substituted or unsubstituted alkyl or S.
10. A compound of claim 9 , wherein L 1 is —NR a —.
11. A compound of claim 9 , wherein L 1 is —NH—.
12. A compound of claim 9 , wherein each occurrence of X is CH.
13. A compound of claim 9 , wherein Cy 2 is
14. A compound of formula (IA-VI):
or a pharmaceutically acceptable salt thereof, wherein
each occurrence of R is independently selected from hydrogen, halogen, —OR a , 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 an oxo group (═O) or 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;
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);
each occurrence of X is independently selected from CR 3 or N; and
each occurrence of R 3 is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR x CONR y R z , —N(R x )SOR y , —N(R x )SO 2 R y , —(═N—N(R x )R y ), —NR x C(O)OR —NR x R y , —NR x C(O)R y —, —NR x C(S)R y —NR x C(S)NR y R z , —SONR x R y —, —SO 2 NR x R y —, —OR x , —OR x C(O)NR y R z , —OR x C(O)OR y —, —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR y R z , —R x C(O)R x , —R x OC(O)R y , —SR X , —SOR x , —SO 2 R x , and —ONO 2 , wherein R x , R y and R z in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of R x , R y and R z may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR w (wherein R w is hydrogen or substituted or unsubstituted alkyl) or S;
each occurrence of R 5 is hydrogen, C 1-6 alkyl or halogen;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3, 4 or 5; and
q is 0, 1 or 2.
15. A compound of claim 14 , wherein R is H or halogen, n is 0 or 1 and p is 0, 1, or 2.
16. A compound of claim 14 , wherein R 5 is H or halogen.
17. A compound of claim 14 , wherein R 1 and R 2 are independently selected from H, CH 3 or C 2 H 5 .
18. A compound of claim 14 , wherein X is CH.
19. A compound selected from
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.
20. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
21. The pharmaceutical composition of claim 20 , further comprising one or more additional therapeutic agents selected from anti-cancer agents, anti-inflammatory agents, immunosuppressive agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and mixtures thereof.
22. The compound of claim 19 , wherein the compound is (S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salts thereof.
23. A compound of 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 a , 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 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 is0,1or2.