HIV-1 protease inhibitors and uses thereof
Compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof are disclosed. The compounds HIV- 1 protease and, as a result, are useful in the treatment of HIV infection.
1 . A compound of formula (I):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
X 1 -X 4 are each independently alkylene;
n is an integer from 0 to 4;
R 1 is alkoxy, hydroxyalkyl, halo or heterocyclylalkyloxy;
R 2 is alkyl,
R 11 is —SO 2 R 3 ; and
R 3 is heterocyclyl.
2 . The compound of claim 1 , wherein the compounds of the formula (I) are of the formula (Ia)-(Ih):
or a pharmaceutically acceptable salt or solvate thereof.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein
X 1 , X 2 , X 3 , and X 4 are —CH 2 —;
X 1 is —CH 2 —; X 2 is —CH 2 —; X 3 is —CH 2 CH 2 —, and X 4 is —CH 2 —;
X 1 is —CH 2 —; X 2 is —CH 2 CH 2 —; X 3 is —CH 2 —, and X 4 is —CH 2 —; or
X 1 is —CH 2 CH 2 —; X 2 is —CH 2 —; X 3 is —CH 2 —, and X 4 is —CH 2 .
4 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 to 3 or 2 to 3.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 is halo or alkoxy.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1, 2 or 3, wherein each R 1 is fluoro.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 6 -C 8 heteroaryl.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is substituted C 6 -C 8 heteroaryl having the formula:
wherein R 5 is C 1 -C 6 alkylamino; and X 6 is S, O or NR 6 , wherein R 6 is H, alkyl, cycloalkyl or alkylaryl.
9 . The compound of claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is —NHCH 3 , —NHCH(CH 3 ) 2 , -NHcyclopropyl, —NHCH 2 CH(CH 3 ) 2 , and —NHC(CH 3 ) 3 .
10 . The compound of claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein X 6 is S.
11 . The compound of claim 1 , wherein the compound has the formula:
or a pharmaceutically acceptable salt or solvate thereof.
12 . The compound of claim 1 , wherein the compound has the formula:
or a pharmaceutically acceptable salt or solvate thereof.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has at least one of: an HIV-1 protease inhibition constant (K i ) of from about 1 μM to about 100 nM;
an antiviral activity in vitro against a wild-type laboratory strain, HIV- 1LAI with half-maximal inhibitory concentration (IC 50 ) of from about 1 μM to about 100 nM;
an antiviral activity in vitro against a darunavir-resistant HIV-1 variant with half-maximal inhibitory concentration (IC 50 ) of from about 1 μM to about 100 nM; and
an antiviral activity in vitro against a wild-type laboratory strain, HIV- 1LAI and an antiviral activity in vitro against a darunavir-resistant HIV-1 variant with half-maximal inhibitory concentration (IC 50 ) of from about 1 μM to about 100 nM.
14 . The compound of claim 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein the darunavir-resistant HIV-1 variant is selected from DRV R P20, DRV R P30, and DRV R P51.
15 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
16 . A method for treating an HIV infection comprising administering a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof.