Granted Patent B2

US 8,232,274 · App. 12/046,755 · Granted Jul 31, 2012

Abstract

Claims (77)

1. A compound of Formula I:

or a pharmaceutically acceptable salt, or ester thereof, wherein:

represents a double bond or a single bond, as permitted by the valency requirement, with the proviso that when E is N, the double bond is present and R 6 is absent;

A is O or S;

D and E are independently C or N,

provided that when D is carbon, D is substituted with hydrogen, alkyl, —Oalkyl, —Nalkyl or —Salkyl;

R 3 is a moiety selected from the group consisting of aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclenyl, heterocyclenylalkyl, heterocyclenylalkenyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkenoxylalkyl, and cycloalkenyoxylalkenyl,

wherein each of said alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclenyl, heterocyclenylalkyl, heterocyclenylalkenyl, arylalkoxylalkyl, arylalkoxylalkenyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkenoxylalkyl, cycloalkenyoxylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR 9 2 , —OR 9 , —SR 9 , —NO 2 , —CN, —NR 16 COR 9 , —NR 16 SO 2 R 9 , —COR 9 , —CO 2 R 9 , —SO 2 R 9 , —CONR 9 , R 16 , and —N═C═O;

 or a single bond,

provided that when Y is O, Y—R 4 taken together is not alkoxyl of the formula

 wherein —CH 2 R 11 and —OR 10 together with the CH to which they are attached, form a heterocyclyl that is substituted with one or more moieties, which can be the same or different , selected from the group consisting of alkyl and aryl, or

wherein R 10 is H and R 11 is hydroxyl or butylamine;

R 4 is alkyl, alkenyl, alkynyl, alkoxyalkyl, alkenyl-O-alkyl, alkoxyalkenyl, alkenyl-O-alkenyl, alkynyl-O-alkyl, hydroxyalkyl, hydroxyalkenyl, alkyl-S-alkyl, alkenyl-S-alkyl, alkyl-S-alkenyl, alkenyl-S-alkenyl, alkyl-SO-alkyl, alkenyl-SO-alkyl, alkyl-SO-alkenyl, alkenyl-SO-alkenyl, alkyl-SO 2 -alkyl, alkenyl-SO 2 -alkyl, alkyl-SO 2 -alkenyl, alkenyl-SO 2 -alkenyl, alkyl-NR 9 -alkyl, alkenyl-NR 9 -alkyl, alkyl-NR 9 -alkenyl, alkenyl-NR 9 -alkenyl, alkyl-CO 2 -alkyl, alkenyl-CO 2 -alkyl, alkyl-CO 2 -alkenyl, alkenyl-CO 2 -alkenyl, alkyl-O 2 C-alkyl, alkenyl-O 2 C-alkyl, alkyl-O 2 C-alkenyl, alkenyl-O 2 C-alkenyl, alkyl-CO-alkyl, alkenyl-CO-alkyl, alkyl-CO-alkenyl, alkenyl-CO-alkenyl, cycloalkyl, cycloalkylalkyl, spiroheteroaryl, spiroheterocyclenyl, spiroheterocyclyl, spiroheteroarylalkyl, spiroheteroarylalkenyl, spiroheterocyclenylalkyl, spiroheterocyclenylalkenyl, spiroheterocyclylalkyl, spiroheterocyclylalkenyl, spirocycloalkyl, spirocycloalkylalkyl, spirocycloalkylalkenyl, spirocyclenyl, spirocyclenylalkyl, spirocyclenylalkenyl, spiroaryl, spiroarylalkyl, spiroarylalkenyl, alkylcycloalkyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, heterocyclenyl, heterocyclenylalkyl heterocyclenylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, benzofused-cycloalkyl, benzofused-heterocycloalkyl, benzofused-cycloalkylalkyl or benzofused-heterocycloalkylalkyl;

wherein said alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkenyl-O-alkyl, alkoxyalkenyl, alkenyl-O-alkenyl, alkynyl-O-alkyl, hydroxyalkyl, hydroxyalkenyl, alkyl-S-alkyl, alkenyl-S-alkyl, alkyl-S-alkenyl, alkenyl-S-alkenyl, alkyl-SO-alkyl, alkenyl-SO-alkyl, alkyl-SO-alkenyl, alkenyl-SO-alkenyl, alkyl-SO 2 -alkyl, alkenyl-SO 2 -alkyl, alkyl-SO 2 -alkenyl, alkenyl-SO 2 -alkenyl, alkyl-NR 9 -alkyl, alkenyl-NR 9 -alkyl, alkyl-NR 9 -alkenyl, alkenyl-NR 9 -alkenyl, alkyl-CO 2 -alkyl, alkenyl-CO 2 -alkyl, alkyl-CO 2 -alkenyl, alkenyl-CO 2 -alkenyl, alkyl-O 2 C-alkyl, alkenyl-O 2 C-alkyl, alkyl-O 2 C-alkenyl, alkenyl-O 2 C-alkenyl, alkyl-CO-alkyl, alkenyl-CO-alkyl, alkyl-CO-alkenyl, alkenyl-CO-alkenyl, cycloalkyl, cycloalkylalkyl, spiroheteroaryl, spiroheterocyclenyl, spiroheterocyclyl, spiroheteroarylalkyl, spiroheteroarylalkenyl, spiroheterocyclenylalkyl, spiroheterocyclenylalkenyl, spiroheterocyclylalkyl, spiroheterocyclylalkenyl, spirocycloalkyl, spirocycloalkylalkyl, spirocycloalkylalkenyl, spirocyclenyl, spirocyclenylalkyl, spirocyclenylalkenyl, spiroaryl, spiroarylalkyl, spiroarylalkenyl, alkylcycloalkyl, alkylcycloalkylalkyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, heterocyclenyl, heterocyclenylalkyl heterocyclenylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, benzofused-cycloalkyl, benzofused-heterocycloalkyl, benzofused-cycloalkylalkyl or benzofused-heterocycloalkylalkyl can be unsubstituted or substituted with at least one moiety independently selected from the group consisting of alkyl, alkenyl, aryl, OR 9 , arylalkyl, arylalkenyl, cyclenylalkyl, cyclenylalkenyl, cycloalkylalkyl, cycloalkylalkenyl, alkylCO 2 alkyl-, halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, cycloalkyl, cyclenyl, hydroxyalkyl, hydroxyalkenyl, thiohydroxyalkyl, thiohydroxyalkenyl, hydroxyalkenyl, heteroaryl, heteroarylalkyl, heterocyclenyl, heterocyclenylalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, —CN, —NO 2 , —OSiR 9 3 , —NR 16 COR 9 , —OCONR 9 2 , —NR 16 CONR 9 2 , —NR 16 SO 2 R 9 , —NR 9 2 , —N═C═O,

 —NR 16 CO 2 R 9 , —COR 9 , —CO 2 R 9 , —OCOR 9 , —SO 2 R 9 , —SOR 9 , —SR 9 , —SO 2 N(R 9 ) 2 or —CONR 9 R 16 , wherein each of said alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cyclenylalkyl, cyclenylalkenyl, cycloalkylalkyl, cycloalkylalkenyl, halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, cycloalkyl, cyclenyl, hydroxyalkyl, hydroxyalkenyl, thiohydroxyalkyl, thiohydroxyalkenyl, hydroxyalkenyl, heteroaryl, heteroarylalkyl, heterocyclenyl, heterocyclenylalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, can be unsubstituted or substituted with one or more moieties which can be the same or different, each moiety being independently selected from R 9 ;

Z is a linker attached at either end of said linker to the parent ring of Formula I,

wherein said linker is selected from the group consisting of:

wherein

n is 1 to 4,

p is 0 to 2,

q is 1 to 3;

R 5 is

 wherein each of said

 is attached at one end to Z and at the second end substituted with a moiety, selected from the group consisting of alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, —OR 9 and —NR 9 2 , further, wherein each of said alkyl, alkenyl, cycloalkyl, cyclenyl, aryl, heterocyclyl, heterocyclenyl, heteroaryl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, or heteroarylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, alkenyl, cycloalkyl, —OR 9 , alkylOR 9 , alkylCO 2 R 9 , alkylNR 16 COR 9 , alkylNR 16 CONR 9 , alkylSO 2 R 9 , alkylCOR 9 , alkylSO 2 NR 9 2 , alkylNR 9 2 , alkylaryl, alkylheteroaryl, alkylSR 9 , alkylSOR 9 , —CN, —CO 2 R 9 , trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR 16 COR 9 , —NR 16 CONR 9 2 , —NR 16 SO 2 —R 13 , —SO 2 R 9 , —COR 9 , —NO 2 , —SO 2 NR 9 2 , aryl, heteroaryl, —NR 9 2 , —SR 9 , —SOR 9 , —C(═NOH)—NR 13 ,

or Y—R 4 taken together are H, provided that R 6 is not H; or Y—R 4 taken together are H and R 6 is H, provided that when Z is

 R 8 is not H;

or Z and R 5 taken together is

wherein

r is 1 or 2;

s is 0 or 1;

or —Y—R 4 , —ZR 5 and the carbons to which they are attached form the group

 wherein J is —O—, —S—, or —NR 13 —;

R 6 is H, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, arylalkoxylalkyl, arylalkoxylalkenyl, arylalkoxyl, cycloalkoxyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkylalkoxyl, cycloalkenoxyl, cycloalkenoxylalkyl, cycloalkenyoxylalkenyl, —NR 9 2 , —OR 9 , —NO 2 , —NR 16 COR 9 , —NR 16 CON(R 17 ) 2 , —NR 16 SO 2 R 9 , —COR 9 , —CO 2 R 9 , or —CONR 9 R 16 ;

wherein each of said alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, arylalkoxylalkyl, arylalkoxylalkenyl, arylalkoxyl, cycloalkoxyl, cycloalkoxylalkyl, cycloalkoxylalkenyl, cycloalkylalkoxyl, cycloalkenoxyl, cycloalkenoxylalkyl, cycloalkenyoxylalkenyl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR 9 2 , —OR 9 , —SR 9 , —NO 2 , —CN, —NR 16 COR 9 , —NR 16 SO 2 R 9 , —COR 9 , —CO 2 R 9 , —SO 2 R 9 , —CONR 9 R 16 and —NR 16 CON(R 17 ) 2 ;

each R 7 is independently selected from the group consisting of H and alkyl;

R 8 is one or more moieties, which can be the same or different, each being independently selected from the group consisting of H, aryl, arylalkyl, alkyl,

 arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, alkenyl, alkynyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR 9 2 , —OR 9 , —SR 9 , —NR 16 COR 9 , —NR 16 CON(R 17 ) 2 , —NR 16 SO 2 R 9 , —COR 9 , —CO 2 R 9 , —SO 2 R 9 , and —CONR 9 R 16 ,

wherein each of said aryl, arylalkyl, alkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cyclenyl, cyclenylalkyl, cyclenylalkenyl, alkenyl and alkynyl can be unsubstituted or substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, —NR 9 2 , —OR 9 , —SR 9 , —NO 2 , —CN, —NR 16 COR 9 , —NR 16 SO 2 R 9 , —COR 9 , —CO 2 R 9 , —SO 2 R 9 , —CONR 9 R 16 and —NR 16 CON(R 17 ) 2 ;

R 9 is one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cyclenyl, aryl, heteroalkyl, heterocycloalkyl, heterocyclenyl, heteroaryl, hydroxyalkyl, hydroxyalkenyl, alkylthioalkyl, alkylthioalkenyl, alkenylthioalkyl, alkenylthioalkenyl, alkoxylalkyl, arylalkyl, cycloalkylalkyl, cyclenylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, arylalkenyl, cycloalkyalkenyl, cyclenylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, alkoxyaryl, trihaloalkyl, trihaloalkenyl, dihaloalkyl, dihaloalkenyl, monohaloalkyl, and monohaloalkenyl,

wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cyclenyl, aryl, heterocycloalkyl, heterocyclenyl, heteroaryl, hydroxyalkyl, hydroxyalkenyl, alkoxylalkyl, arylalkyl, cycloalkylalkyl, cyclenylalkyl, heterocyclylalkyl, heterocyclenylalkyl, heteroarylalkyl, arylalkenyl, cycloalkyalkenyl, cyclenylalkenyl, heterocyclylalkenyl, heterocyclenylalkenyl, heteroarylalkenyl, and alkoxyaryl can be unsubstituted or substituted with one or more moieties, which can be the same or different, each moiety being independently selected from the group consisting of halogen, trihaloalkyl, dihaloalkyl, monohaloalkyl, trihaloalkenyl, dihaloalkenyl, monohaloalkenyl, hydroxyl, alkoxy, hydroxyalkyl, —N(R 12 ) 2 , alkyl, alkynyl , cycloalkyl, alkenyl, cyclenyl, aryl, heteroaryl, heterocycloalkyl, heterocyclenyl, cycloalkylalkyl, cyclenylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heterocyclenylalkyl, cycloalkylalkenyl, cyclenylalkenyl, arylalkenyl, heteroarylalkenyl, heterocycloalkylalkenyl, heterocyclenylalkenyl, —CN, —NO 2 , —SO 2 R 17 , —C(O)N(R 20 ) 2 , —CO 2 R 19 ,

 —NR 16 —C(O)R 19 , —NR 16 CON(R 17 ) 2 , —NR 16 SO 2 R 17 , trihaloalkoxy, dihaloalkoxy, monohaloalkoxy,

further wherein when two R 9 moieties are attached to a N, the two R 9 moieties, together with the N to which they are attached, can form a heterocyclyl or heterocyclenyl ring of 4 to 7 members, wherein 1 or 2 of said ring members can be —O—, —S— or —NR 18 —, provided that there are no heteroatoms adjacent to each other; and wherein the heterocyclyl or heterocyclenyl ring is optionally substituted on 1 or 2 ring carbon atoms by a substituent independently selected from the group consisting of alkyl, alkoxy, —OH and —NR 16 , or two hydrogen atoms on the same carbon are replaced by ═O;

each R 12 is independently selected from the group consisting of H, alkyl, aryl and arylalkyl;

each R 13 is independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl and cycloalkylalkyl;

R 14 is alkyl or alkoxy;

R 15 is aryl, arylalkyl, —N(R 13 )-aryl, —N(R 13 )-alkylaryl, —O-aryl or —O-alkylaryl;

R 16 is independently selected from the group consisting of H and alkyl;

R 17 is alkyl, aryl or arylalkyl;

R 18 is H, alkyl, —COOR 19 , —COR 17 or —CON(R 17 ) 2 ;

each R 19 is independently selected from the group consisting of H, alkyl and benzyl;

each R 20 is independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and alkoxyalkyl;

provided that Formula I does not include the compounds of Table A:

TABLE A

2. The compound of claim 1 , wherein A is O.

3. The compound of claim 1 , wherein D is N.

4. The compound of claim 1 , wherein E is C.

5. The compound of claim 1 , wherein Y is O.

6. The compound of claim 1 , wherein Y is

7. The compound of claim 1 , wherein Y is —S—,

8. The compound of claim 1 , wherein Y a single bond.

9. The compound of claim 1 , wherein Z is

10. The compound of claim 1 , wherein R 5 is

11. The compound of claim 1 , wherein R 5 is

12. The compound of claim 1 , wherein R 5 is

13. The compound of claim 1 , wherein E is C and R 6 is H.

14. A compound of claim 1 having the structure

wherein R 3 is mono- or dihalo-phenyl;

R 4 is alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted benzyl, or optionally substituted benzofused cycloalkyl;

R 5 is —SO 2 —, wherein the second end substituent is alkyl, haloalkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or —N(R 9 ) 2 , wherein one R 9 is H and the other is optionally substituted arylalkyl or optionally substituted heteroarylalkyl.

15. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

16. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, or ester thereof, in combination with at least one pharmaceutically acceptable carrier.

18. The pharmaceutical composition according to claim 17 , further comprising one or more anti-fungal agents different from the compound of claim 1 .

19. The pharmaceutical composition according to claim 18 , wherein the one or more anti-fungal agents are selected from the group consisting of azoles, echinocandins, polyenes, allylamines, thiocarbamates, nikkomycins, pradimicins, 5-fluorocytosines, oxaboroles, ciclopiroxolamine, griseofulvin and morpholines.

20. The pharmaceutical composition according to claim 18 , wherein the one or more anti-fungal agents are selected from the group consisting of fluconazole, miconazole, itraconazole, voriconazole, posaconazole, caspofungin, micafungin, anidulafungin, amphotericin B, liposomal formulations of amphotericin B, nystatin, terbinafine, tolnaftate, ciclopiroxolamine, griseofulvin and fenpropimorph.

Assignments (10)