HIV-1 protease inhibitors and uses thereof
Various embodiments of the present invention are directed to compounds of the formula (I) or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein X 1 , X 2 , X 3 , R 1 , R 2 , R 11 , and n are defined herein. These compounds are useful as inhibitors of HIV-1 protease and, as a result, are useful in the treatment of HIV infection.
1. A compound of the formula (I):
or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof,
wherein:
X 1 is alkylene, —O—, —CH 2 NR 4 — or —NHR 4 —;
X 2 and X 3 are each, independently alkylene;
n is an integer from 0 to 3;
R 1 is alkoxy, hydroxyalkyl, halo or heterocyclylalkyloxy;
R 2 is alkyl, haloalkyl, aryl, arylalkyl, cycloalkylalkyl, heterocyclylcarbonyl, heterocyclyl, heterocyclylalkyl or —C(R 7 R 8 )-alkylene-R 9 ;
R 11 is —SO 2 R 3 , —N(R 12 )SO 2 R 3 , —N(R 12 )C(O)R 3 , —N(R 12 )C(O)CH(R 12 )N(R 12 )C(O)R 13 , —C(O)N(R 12 ) 2 , —C(O)-alkylene-X 4 —R 10 (wherein X 4 is S, O or NR 6 , wherein R 6 is H, alklyl, cycloalkyl or alkylaryl) or —C(O)R 10 ;
R 3 is aryl or heteroaryl;
R 4 is alkyl, aryl or heteroaryl;
R 7 and R 8 are each, independently hydrogen, alkyl, aryl, arylalky, heteroaryl, heteroarylalkyl or,
R 7 and R 8 , together with the carbon atom to which they are attached, form a cycloalkyl or a heterocyclyl group;
R 9 is hydrogen, OR 10 , OC(O)N(R 10 ) 2 , CN, NO 2 , CF 3 , OCF 3 , N(R 10 ) 2 , SR 10 , SOR 10 , SO 2 R 10 , SO 2 N(R 10 ) 2 , SO 3 R, C(O)R 10 , C(O)OR 10 , OC(O)R 10 , C(O)N(R 10 ) 2 , (CH 2 ) 0-2 N(R 10 )C(O)R 10 or (CH 2 ) 0-2 N(R 10 )C(O)OR 10 ;
R 10 is hydrogen, alkyl, acyl, cycloalkyl aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl;
R 12 is hydrogen, alkyl, alkylaryl, heterocyclyl or the two R 12 groups on an N(R 12 ) 2 , together with the nitrogen atom to which they are attached, form a heterocyclyl group; and
R 13 is hydrogen, alkyl, —N(R 12 ) 2 or —OR 12 ; or
R 2 and R 11 , together with the —CH 2 N— that connects them, form a heterocyclyl or substituted heterocyclyl group.
2. The compound of claim 1 having the formula (II):
or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:
n is an integer from 1 to 3;
R 1 is alkoxy, hydroxyalkyl, halo or heterocyclylalkyloxy;
R 2 is alkyl, haloalkyl, arylalkyl, cycloalkylalkyl, heterocyclylcarbonyl or heterocyclylalkyl:
R 3 is substituted aryl or substituted heteroaryl;
X 1 is alkylene, —O—, —CH 2 NR 4 — or —NHR 4 —, wherein R 4 is alkyl, aryl or heteroaryl; and
X 2 and X 3 are each, independently alkylene.
3. The compound of claim 1 , wherein X 1 , X 2 or X 3 is C 1 -C 4 alkylene.
4. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkoxy, hydroxy-C 1 -C 6 -alkyl, halo or C 3 -C 6 -heterocyclyl-C 1 -C 6 -alkyloxy.
5. The compound of claim 1 , wherein R 2 is C 1 -C 6 alkyl, halo-C 1 -C 6 -alkyl, C 6 -C 10 -aryl-C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl-C 1 -C 6 -alkyl, C 3 -C 6 -heterocyclylcarbonyl or C 3 -C 6 -heterocyclyl-C 1 -C 6 -alkyl.
6. The compound of claim 1 , wherein R 3 is substituted C 6 -C 10 aryl or substituted C 6 -C 8 heteroaryl.
7. The compound of claim 2 , wherein the compound of the formula (II) is a compound of the formula (IIa) or (IIb):
or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
8. The compound of claim 1 which is:
or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
9. The compound of claim 1 which is:
or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
10. The compound of claim 1 , wherein R 2 is aryl, a heterocyclyl group or —C(R 7 R 8 )-alkylene-R 9 .
11. The compound of claim 10 , wherein R 9 is —OC(O)N(R 10 ) 2 or —(CH 2 ) 0-2 N(R 10 )C(O)OR 10 , wherein R 10 is hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroarylalkyl.
12. The compound of claim 1 , wherein R 3 is aryl substituted with an alkenyl group, a cycloalkyl group or a heterocyclyl group.
13. The compound of claim 12 , wherein the heterocyclyl group is 4,5-dihydrooxazolyl, oxaxolyl, oxadiazolyl, indolyl or isoindolyl.
14. The compound of claim 12 , wherein the alkenyl group is substituted with one or more groups selected from the group consisting of alkyl, -alkyl-NR 2 , and C(O)N(R) 2 , wherein R is hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroarylalkyl.
15. The compound of claim 1 , wherein R 11 is —N(R 12 )C(O)CH(R 12 )N(R 12 )C(O)R 13 , —N(R 12 )SO 2 R 3 or —N(R 2 )C(O)R 3 .
16. The compound of claim 1 , wherein R 11 is —C(O)N(R 12 ) 2 , wherein each R 12 is, independently, hydrogen, alkyl, aryl, heterocyclyl or the two R 12 groups, together with the nitrogen atom to which they are attached, form a heterocyclyl group.
17. The compound of claim 1 , wherein the compound has an HIV-1 protease inhibition constant (K i ) of from about 1 fM to about 200 nM.
18. The compound of claim 1 , wherein the compound has an antiviral activity in vitro against a wild-type laboratory strain, HIV-1 LAI with half-maximal inhibitory concentration (IC 50 ) of from about 1 fM to about 200 nM.
19. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable excipients.
20. A method for treating an HIV infection comprising administering a therapeutically effective amount of one or more compounds as in of claim 1 to a patient in need thereof.