Phospho-indoles as HIV inhibitors
3-phosphoindole compounds for the treatment of retroviral infections, and particularly for HIV, are described. Also included are compositions comprising the 3-phosphoindole derivatives alone or in combination with one or more other anti-retroviral agents, processes for their preparation, and methods of manufacturing a medicament incorporating these compounds.
1. A compound of Formula (B):
or a pharmaceutically acceptable salt, prodrug, N-oxide, quaternary amine, stereochemical isomer or tautomer thereof, wherein:
Y is O-alkyl;
W is O;
R 1 is selected from the group consisting of H, R 2 , C(═O)R 2 , C(═O)—O—R 2 , C(═O)—S—R 2 , C(═O)—NH—R 2 , C(═O)—NR 2 R 2 , C(═O)—NH-A-(amino acid residue), A-(amino acid residue)-R 2 , S(O) n —R 3 , S(O) 2 —NR 2 R 2 , any of which may optionally be substituted by one or more C 1-6 alkyl, OH, alkoxy, aryl, halo, CN, NO 2 , or NR 2 R 2 ;
each R 2 is independently H; OH; halogen; optionally substituted, branched or unbranched alkyl; optionally substituted, branched or unbranched alkenyl;optionally substituted, branched or unbranched alkynyl; 3-14 membered carbocycle; alkylheterocycle; acyl; carboxamido; carbamoyl; alkoxy; optionally substituted aryl; optionally substituted aralkyl; optionally substituted alkylaryl; O-alkyl; O-alkenyl; O-alkynyl; O-alkaryl; O-aralkyl; O-carbocycle; O-heterocycle; O-aryl; CF 3 ; CN; S(O) n —R 3 ; N(R 3 )(R 3 ); NH—S(O) n —R 3 ; NHC(═W)-aryl; NHC(═W)-alkyl; NHC(═W)-heterocycle; CH 2 —S(O) n —R 3 ; C(═W)R 3 ; C(═W)NR 3 R 3 ; C(alkyl) 2 -S(O) n R 3 ; CH(alkyl)-S(O) n R 3 ; C(alkyl) 2 -NH 2 ; CH(alkyl)-N(alkyl)R 3 ; CR 3 R 2 —NR 3 R 3 ; CH 2 N(alkyl)R 3 ;CH(alkyl)-NHR 3 ; C(alkyl) 2 -NHR 3 ; C(alkyl) 2 -N(alkyl)R 3 ; CH 2 —C(═W)H; CH 2 —C(═W)alkyl; CR 3 R 3 —C(═W)R 3 ; A-R 3 ; C(R 3 ) 2 —C(═W)R 3 ; CH 2 —C(═W)H; CH 2 —C(═W)alkenyl; CH(alkenyl)-C(═W)H; A-S(O)R 3 ; CH(NH)—S(O) n R 3 ; or A-N(NH)R 3 ; wherein said optional substitution comprises one or more of: a substituted or unsubstituted heterocycle; C(═W)O-aryl; C(═W)O-alkyl; C(═W)NH 2 ; C(═W)NH-alkyl; C(═W)NH-aryl; C(═W)N-di-alkyl; C(═W)N(alkyl)-aryl; α-amino acid; α-amino ester; α-amino-carboxamide; β-amino acid; β-amino ester; or β-amino-carboxamide;
each R 3 is independently H; OH; C 1-6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; alkoxy; CF 3 ; CN; amino; NR 2 R 2 ; O-alkyl; O-alkenyl; O-alkynyl; C(R 2 )(R 2 )—S(O) n NH 2 ; C(R 2 )(R 2 )—S(O) n CF 3 ; C(R 2 )(R 2 )—NH 2 ; A-heterocycle; C(R 2 )(R 2 )—NR 2 R 2 ; C(R 2 )(R 2 )—C(═W)R 2 ; aryl; carbocycle; heterocycle; cycloalkyl; alkaryl; alkylheterocycle; aralkyl; or heterocycle-alkyl; any of which may be unsubstituted or substituted with one or more of the following taken in any combination: halo; OH; OR 2 ; SR 2 ; COOH; carboxylic acid ester; C(═W)R 2 ; C(═W)OR 2 ; C(═W)OR 3 ; C(═W)SR 2 ; A-C(═W)NH 2 ; C(═W)NR 2 R 3 ; NR 2 R 2 ; NR 2 R 3 ; NR 2 —S(O) n R 3 ; NR 2 —C(═W)—C 1-6 alkyl; S(O) n R 3 ; C 1-6 alkoxy; C 1-6 thioether; amino acid residue; NH-A-(amino acid residue); C(═W)NH-A-(amino acid residue); and wherein when said optional substitution comprises a substituted heterocycle, then substitution is selected from the group consisting of: C(═W)O-aryl; C(═W)O-alkyl; C(═W)NH 2 ; C(═W)NH-aryl; C(═W)NH-alkyl; C(═W)N-di-alkyl; C(═W)N(alkyl)-aryl; α-amino acid; α-amino ester; α-amino-carboxamide; β-amino acid; β-amino ester; β-amino-carboxamide; halo; or cyano, taken alone or in any combination;
each n is independently 0, 1 or 2;
A is a disubstituted spacer selected from the group consisting of: C 1-6 alkylene, branched or unbranched, and optionally having one or more heteroatoms, aryl, cycloalkyl or heterocyclyl functions in or attached to the chain; C 2-12 alkenylene, branched or unbranced, and optionally having one or more heteroatoms, aryl, cycloalkyl or heterocyclyl functions in or attached to the chain; C 2-12 alkynylene, branched or unbranced, and optionally having one or more heteroatoms, aryl, cycloalkyl or heterocyclyl functions in or attached to the chain; optionally substituted arylene; O-alkylene, branched or unbranched, and optionally having one or more heteroatoms, aryl, cycloalkyl or heterocyclyl functions in or attached to the chain; aralkylene, branched or unbranched, and optionally having one or more heteroatoms, aryl, cycloalkyl or heterocyclyl functions in or attached to the chain; optionally substituted cycloalkyl; and optionally substituted heterocycle; wherein “A” may be joined by any desired linkage or any combination of desired linkages;
R 6′ and R 7′ are each independently H;
R 4′ and R 5′ are each independently Cl, F, Br, I, methyl, ethyl or CF 3 ;
Z is —C(═O)NH 2 ; and
R 2″ , R 3″ , R 4″ , R 5″ , and R 6″ are each independently selected from the group consisting of hydrogen, halogen, NO 2 , CN, OR 2 , SR 2 , NH 2 , NR 2 R 3 , N(R 2 )—C(═W)—C 1-4 alkyl, N(R 2 )—SO 2 —C 1-4 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, CF 3 , CR 2 R 2 —S(O) n —R 3 , CR 2 R 2 NR 2 R 3 , C—OH, CR 2 R 2 —C(═W)R 2 , acyl, C(═W)R 2 , C(═W)OR 2 , C(═W)SR 2 , C(═W)—NR 2 R 3 , C(═W)NH(CH 2 ) p -(amino acid residue), amino residue, and A-(amino acid residue), any of which optionally may be substituted.
2. The compound of claim 1 wherein
each R 2″ , R 4″ , and R 6″ is independently hydrogen, and
each R 3″ and R 5″ is independently halogen; NO 2 ; CN; OR 2 ; NH—CO—C 1-4 alkyl; oxime; hydrazine; —N(OH)C 1-6 alkyl; C 1-6 alkoxy; OH; NR 2 R 3 ; or C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl optionally substituted with one or more of —OH, —SR, —CN, —C(═W)H, —C(═W)OH, halogen, NR 2 R 3 , —C 1-6 thioether, or —C 1-6 alkoxy.
3. The compound of claim 1 that is:
4. A pharmaceutical composition comprising an effective anti-HIV treatment amount of a compound of any of claims 1 - 3 , or its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, N-oxide or quaternary amine, optionally with a pharmaceutically acceptable carrier or diluent.
5. A pharmaceutical composition comprising an effective anti-HIV treatment amount of a compound of any of claims 1 - 3 , or its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, N-oxide or quaternary amine, in combination with at least one other anti-HIV agent, optionally with a pharmaceutically acceptable carrier or diluent.
6. The pharmaceutical composition of claim 5 wherein the other anti-HIV agent is a reverse transcriptase inhibitor.
7. The pharmaceutical composition of claim 6 wherein the reverse transcriptase inhibitor induces a mutation lysine 103→ asparagine and/or tyrosine 181→ cysteine in HIV reverse transcriptase.
8. A method for the treatment of an HIV-infection in a host comprising administering to said host an anti-HIV effective treatment amount of a compound of any of claims 1 - 3 , or its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, N-oxide or quaternary amine, optionally with a pharmaceutically acceptable carrier or diluent.
9. The method of claim 8 wherein the host is human.
10. A method for the treatment of an HIV-infection in a host comprising administering to said host an anti-HIV effective treatment amount of a compound of any of claims 1 - 3 , or its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, N-oxide or quaternary amine, in combination and/or alternation with at least one other anti-HIV agent, optionally with a pharmaceutically acceptable carrier or diluent.
11. The method of claim 10 wherein the host is human.
12. The method of claim 10 wherein the other anti-HIV agent is a reverse transcriptase inhibitor.
13. The method of claim 12 wherein the reverse transcriptase inhibitor induces a mutation lysine 103→ asparagine and/or tyrosine 181→ cysteine in HIV reverse transcriptase.
14. A method for the treatment of an HIV-infection in a host, wherein the HIV has a mutation at lysine 103→ asparagine and/or tyrosine 181→ cysteine in HIV reverse transcriptase, comprising administering to said host an effective anti-HIV treatment amount of a compound according to any of claims 1 - 3 , or its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, N-oxide or quaternary amine, optionally with a pharmaceutically acceptable carrier or diluent.
15. The method of claim 14 wherein the host is a human.
16. A method for the treatment of an HIV-infection in a host, wherein the HIV has a mutation at lysine 103→ asparagine and/or tyrosine 181→ cysteine in HIV reverse transcriptase, comprising administering to said host an effective anti-HIV treatment amount of a compound according to any of claims 1 - 3 , or its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, N-oxide or quaternary amine, in combination and/or alternation with at least one other anti-HIV agent, optionally with a pharmaceutically acceptable carrier or diluent.
17. The method of claim 16 wherein the host is a human.
18. A method for the treatment of an HIV-infection in a host wherein the HIV is resistant to one or more reverse transcriptase inhibitor(s), comprising administering to said host an anti-HIV effective treatment amount of a compound of any of claims 1 - 3 , or its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, N-oxide or quaternary amine, optionally with a pharmaceutically acceptable carrier or diluent.
19. The method of claim 18 wherein the host is a human.
20. A method for the treatment of an HIV-infection in a host wherein the HIV is resistant to one or more reverse transcriptase inhibitor(s), comprising administering to said host an anti-HIV effective treatment amount of a compound of any of claims 1 - 3 , or its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, N-oxide or quaternary amine, in combination and/or alternation with at least one other anti-HIV agent, optionally with a pharmaceutically acceptable carrier or diluent.
21. The method of claim 20 wherein the host is a human.
22. A method for salvage therapy in the treatment of an anti-HIV infection in a host comprising administering to said host an anti-HIV effective treatment amount of a compound of any of claims 1 - 3 , or its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, N-oxide or quaternary amine, optionally with a pharmaceutically acceptable carrier or diluent.
23. The method of claim 22 wherein the host is a human.
24. A method for salvage therapy in the treatment of an anti-HIV infection in a host comprising administering to said host an anti-HIV effective treatment amount of a compound of any of claims 1 - 3 , or its pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, N-oxide or quaternary amine, in combination and/or alternation with at least one other anti-HIV agent, optionally with a pharmaceutically acceptable carrier or diluent.
25. The method of claim 24 wherein the host is a human.