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US 2014/0194349 A1Published application
HIV Protease Inhibiting Compounds
AssigneeAbbVie Inc.
InventorsDavid A. DeGoey, Charles A. Flentge, William J. Flosi, David J. Grampovnik, Dale J. Kempf, Larry L. Klein, Ming C. Yeung, John T. Randolph, Xiu C. Wang, Su Yu
Life of this patent
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Abstract
A compound of the formula is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
Claims16
A compound having formula (II)
- or a pharmaceutically acceptable salt form or a stereoisomer thereof, wherein:
- RA is selected from the group consisting of —N(H)C(O)R8, —O(Ra),—N(Rb)S(O)2Ra, —N(Rb)alkylN(Rb)S(O)2Ra, —N(Rb)alkylN(Rb)C(O)ORa, and -alkylS(O)2Ra;
- R1 is alkyl;
- R2 is alkyl;
- R3 is arylalkyl, wherein the aryl moiety of the arylalkyl is independently substituted with R3a;
- R3a is heteroaryl selected from the group consisting of thiazolyl, and pyridyl, wherein each R3a is substituted with 0 or 1 substituents independently selected from the group consisting of alkyl and alkoxy;
- R4 is H and R5 is OR16, or R5 is H and R4 is OR16, or R4 and R5 are —OR16;
- R16 is hydrogen or R15;
- R6 is arylalkyl, wherein the aryl moiety of the arylalkyl is independently substituted with 0 or 1 substituents independently selected from the group consisting of R6a;
- R6a is pyridyl;
- R7 is —N(Rb)C(O)ORa, alkyl or tetrahydrofuranyl, wherein the alkyl is independently substituted with 0 or 1 substituents independently selected from the group consisting of —ORa, —OC(O)Ra, —SRa, —SORa, —SO2Ra, —N(Ra)C(O)NRaRb, —C(O)NRaRb, —C(O)ORa and R7a;
- R7a is heteroaryl selected from the group consisting of thiazolyl and pyridyl;
- R8 is —ORa, —N(Rb)C(O)ORa, -alkylORa, -alkylOC(O)Ra, or —O-alkylC(O)Ra;
- R15 is —P(O)(OH)2, or -alkyl-O—P(O)(OH)2;
- Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, aryl and pyridyl, wherein each Ra and Rb, at each occurrence, is independently substituted with 0 or 1 substituent independently selected from the group consisting of alkyl and Rc;
- and
- R1 is aryl or pyridyl.
14 more elements
A process of preparing a compound of formula (XVIII)
- wherein
- X1 is CH or N;
- X2 is CH or N;
- X3 is CH or N;
- provided only one of X1, X2, X3 is N and the other two are CH;
- R112 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl heterocyle, aryl or heteroaryl;
- wherein each R112 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, —ORa′, —SRa′, —SORa′, —SO2Ra′, —NRa′Rb′, —N(Rb)C(O)Ra′—N(Rb)C(O)ORa′, —N(Rb′)C(═N)NRa′Rb′, —N(Rb)C(O)NRa′Rb′, —C(O)NRa′Rb′, —C(O)ORa′ and R112a;
- R112a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;
- wherein each R112a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH2, —N(H)(alkyl), —N(alkyl)2, —SH, —S(alkyl), —SO2(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH2, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)2, —C(O)OH, —C(O)Oalkyl, —C(O)NH2, —C(O)N(H)(alkyl), —C(O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(O)NH2, -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)2, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH2, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)2;
- R111 is C1-C6 alkyl or phenylmethyl;
- and
- Ra′ and Rb′ are each independently selected from the group consisting of hydrogen and alkyl.
- wherein the process comprises the steps of:
- (a) contacting a compound of formula (i)
- with potassium tert-butoxide and n-butyl lithium in a first solvent;
- (b) contacting a first base with ketonitrile of formula (ii)
- wherein P1 and P2 are nitrogen protecting group and P1 and P2 can be the same or different, in the first solvent;
- (c) contacting the product of step (b) with the product of step (a) to provide a compound of formula (iii)
- (d) contacting the compound of formula (iii) with a first reducing agent and an acid in a second solvent;
- (e) contacting the product of step (d) in the second solvent with a second reducing agent, to provide a compound of formula (iv);
- (f) contacting the compound of formula (iv) with a hydrogen source and a catalyst in a third solvent to provide a compound of formula (v);
- and
- (g) contacting the compound of formula (v) with a compound of formula (vi),
- a coupling reagent and a second base in a fourth solvent to provide the compound of formula (XVIII).
21 more elements
Dependencies are inferred from the claim text.