HIV-1 protease inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9670225-B2
Application number	US-201515311806-A
Country	US
Kind code	B2
Filing date	May 15, 2015
Priority date	May 16, 2014
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Purdue Research Foundation
• Mitsuya Hiroaki
• Nat Univ Corp Kumamoto Univ

Inventors

• Ghosh Arun K
• Kalapala Venkateswara Rao
• Mitsuya Hiroaki

Classifications

• A61P31/18

  for HIV · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D493/08 Primary

  Bridged systems · CPC title