Combined modalities for nucleosides and/or NADPH oxidase (NOX) inhibitors as myeloid-specific antiviral agents

A method of treating HIV, comprising administering one or more compounds of Formula (A) or Formula (B) to a patient in need of treatment thereof, wherein Formula (A) and Formula (B) are shown below:

• or a pharmaceutically acceptable salt thereof, wherein:
• Y is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl,
• R is selected from the group consisting of H, substituted or unsubstituted C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, aryl, heteroaryl, heterocyclic, alkylaryl, arylalkyl, hydroxyl, nitro, cyano, cyanoalkyl, azido, azidoalkyl, formyl, hydrazino, OR′, SR′, COOR′, COR′, OCOR′, NHCOR′, N(COR′)COR′, SCOR′, OCOOR′, and NHCOOR′,
• wherein each R′ is independently H, a C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate,
• R1 is and R1A are, independently, H, CH3, CH2F, CHF2, or CF3, wherein, when R1 is Me, the carbon to which it is attached may be wholly or partially R or S or any mixture thereof, or R1 and R1A can combine to form a C3-7 cycloalkyl ring;
• R2 is substituted or unsubstituted C2-8 alkynyl;
• R4 is P(O)R6R7, wherein, when chirality exists at the phosphorous center of R4, it may be wholly or partially Rp or Sp or any mixture thereof,
• R5 is O, CH2, S, Se, CHF, CF2, or C═CH2,
• R3 is H, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, CN or N3 when R5 is O, and
• R3 is selected from the group consisting of H, CN, substituted or unsubstituted (C1-8)alkyl, substituted or unsubstituted (C2-8)alkenyl, substituted or unsubstituted (C2-8)alkynyl, O—(C1-8) alkyl and N3 when R5 is CH2, CHF, CF2, or C═CH2,
• R8 and R8′ are independently selected from the group consisting of H, C(O)(C1-8)alkyl, C(O)(C1-8)branched alkyl, C(O)NH(C1-8)alkyl, C(O)NH(C1-8)branched alkyl, C(O)aryl C(O)(C1-8) alkyl-aryl, C(O)NH(C1-8)alkyl-aryl C(O)O(C1-8)alkyl, C(O)O(C1-8)branched alkyl, and C(O)O(C1-8)alkyl-aryl, or OR8 as it appears in Formulas A is an ester derived from an alpha amino acid,
• R6 and R7 are independently selected from the group consisting of:
• (a) OR15 where R15 is aryl, wherein aryl is optionally substituted with zero to three substituents independently selected from the group consisting of (CH2)0-6CO2R16 and (CH2)0-6 CON(R16)2;
• where R16 is independently H, substituted or unsubstituted C1-20 alkyl, the carbon chain derived from a fatty alcohol or C1-20 alkyl substituted with a C1-6 alkyl, C1-6 alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10 cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;
• wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a C1-6 alkyl, alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10 cycloalkyl, or cycloalkyl;
• (b) the ester of a D- or L-amino acid where R17 is restricted to those occurring in natural L-amino acids, and
• R18 is H, C1-20 alkyl, the carbon chain derived from a fatty alcohol or C1-20 alkyl optionally substituted with a C1-6 alkyl, alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10 cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;
• wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a C1-6 alkyl, alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10 cycloalkyl, or cycloalkyl;
• Base is selected from the group consisting of:
• X1 is CH, C—(C1-6)alkyl, C—(C2-6)alkenyl, C—(C2-6)alkynyl, C—(C3-7)cycloalkyl, C—(C1-6) haloalkyl, C—(C1-6)hydroxyalkyl, C—OR22, C—N(R22)2, C-halo, C—CN or N,
• R22 is independently H, (C1-10)alkyl, (C1-10)haloalkyl or (C3-7)cycloalkyl,
• R9 is OH, NH2, halo, O(C1-10)alkyl, O(C3-7)cycloalkyl, NH(C1-10)alkyl, N((C1-10)alkyl)2, NH(C3-7)cycloalkyl, NH(CO)(C1-20)alkyl, NH(CO)O(C1-20)alkyl, NHOH, NHO(CO)(C1-20)alkyl, or NHO(CO)NH(C1-20)alkyl,
• R10 is H, F or CH3 and
• X2 is H, F, Cl, Br, I, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, C—(C3-7)cycloalkyl, C—(C1-6) haloalkyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, (C1-6)hydroxyalkyl, OR22, N(R22)2, NHC(O)OR22, NHC(O)N(R22)2, NHC(O)R22, CN or NH2;
• or Base is
• wherein:
• each R′, R″, and R″′ are independently selected from the group consisting of H, OH, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, C3-6 cycloalkyl, Br-vinyl, —O—C1-6 alkyl, O—C2-6 alkenyl, O—C2-6 alkynyl, O-aryl, O-aralkyl, —O-acyl, O—C3-6 cycloalkyl, NH2, NHC1-6 alkyl, N-di-C1-6-alkyl, NH-acyl, N-aryl, N-aralkyl, NHC3-6 cycloalkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2C1-6 alkyl, CONHC1-6 alkyl, CON-di-C1-6 alkyl, OH, CF3, CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCO2H, (CH2)mCN, (CH2)mNO2, and (CH2)mCONH2;
• m is 0 or 1;
• X2 is H, straight chained, branched or cyclic optionally substituted alkyl, CH3, CF3, C(Y3)3, 2-Br-ethyl, CH2F, CH2Cl, CH2CF3, CF2CF3, C(Y3)2C(Y3)3, CH2OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR1BB, COO-alkyl, COO-aryl, CO—Oalkoxyalkyl, CONH2, CONHR1B, CON(R1B)2, chloro, bromo, fluoro, iodo, CN, N3, OH, OR1B, NH2, NHR1B, NR1B2,
• each X3 is independently a straight chained, branched or cyclic optionally substituted alkyl, CH3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, CF3, C(Y3)3, 2-Br-ethyl, CH2F, CH2Cl, CH2CF3, CF2CF3, C(Y3)2C(Y3)3, optionally substituted C2-6 alkenyl, C2-6 haloalkenyl, Br-vinyl, optionally substituted alkynyl, C2-6 haloalkynyl, N3, CN, —C(O)OH, —C(O)OR1B, —C(O)O(C1-6 alkyl), —C(O)NH2, —C(O)NHR1B, —C(O)NH(C1-6 alkyl), —C(O)N(R1B)2, —C(O)N(C1-6 alkyl)2, OH, OR1B, —O(acyl), —O(C1-6 acyl), —O(alkyl), —O(C1-6 alkyl), —O(C2-6 alkenyl), —O(C2-6 alkynyl), —O(aralkyl), —O(cycloalkyl), chloro, bromo, fluoro, iodo, NH2, —NH(C1-6 alkyl), —NHR1B, —NR1B2, —NH(acyl), —N(C1-6 alkyl)2, —NH(alkenyl), —NH(alkynyl), —NH(aralkyl), —NH(cycloalkyl), or —N(acyl)2;
• each Y2 is independently O, S, Se, NH, or NR1B;
• each Y3 is independently H, F, Cl, Br, or I;
• and
• each R1B is independently hydrogen, acyl, alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 cycloalkyl;
• wherein, in each occurrence, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, are optionally substituted with from 1-3 substituents selected from the group consisting of halogen, hydroxyl, nitrile, amino, alkylamino, arylamino, alkoxy, thioalkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, deuterated analogs thereof, and pharmaceutically-acceptable salts thereof.