US2009318380A1PendingUtilityA1
2',4'-substituted nucleosides as antiviral agents
Est. expiryNov 20, 2027(~1.3 yrs left)· nominal 20-yr term from priority
A61P 31/12A61P 31/18A61P 31/20A61P 35/00A61P 31/14A61P 31/04A61P 31/00C07H 19/16C07H 19/073A61K 31/7064A61K 31/7072A61K 31/7068C07H 19/173A61K 31/7076C07H 19/14C07H 19/06
66
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Claims
Abstract
Embodiments of the invention are to compounds, methods, and compositions for use in the treatment of viral infections. More specifically embodiments of the invention are 2′,4′-substituted nucleoside compounds useful for the treatment of viral infections, such as HIV, HCV, and HBV infections.
Claims
exact text as granted — not AI-modified1 . A compound of the formula:
wherein for structure A or A′
(a) R 2 is independently CH 3 , CH 2 F, CHF 2 , CF 3 , F, CN, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
(b) R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
(c) R 3 is independently OH, H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-10 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-18 acyl) 2 , wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N 3 , CN, one to three halogen (Cl, Br, F, I), NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-4 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 14 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-4 acyl) 2 ;
(d) R 4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH 2 ) p OH, where p is 1-6, including hydroxylmethyl (CH 2 OH), CH 2 F, N 3 , CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino;
(e) R and R 3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof;
(f) Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
wherein for a and b
Z is Nor CR 8 ;
R 5 , R 6 , and R 7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 such as C—CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′ wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkylaryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl;
R 8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO 2 , lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkyl-aryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl; or
base may be selected from a group of formula c
wherein for structure c,
if Z is a participant in a pi bond (double bond), Z is independently selected from N or C-G; or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR 2 , CO, CS, CNR, SO, S(O) 2 , SeO, Se(O) 2 , or C(G) 2 ;
each G is independently selected from the group consisting of H, halogen, OR, SR, NR 2 , NROR, N 3 , COOR, CN, CONR 2 , C(S)NR 2 , C(═NR)NR 2 , and R; and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O) 2 , SeO and Se(O) 2 ;
wherein, if X is a participant in a pi bond (double bond), X is C; or if X is not a participant in a pi bond (double bond), X is CR X or N;
wherein, if R″ is a participant in a pi bond (double bond), R″ is O, S, Se, NR, NOR or NNR 2 ; or if R″ is not a participant in a pi bond (double bond), R″ is OR′, SR′, F, Cl, R, or SeR; and
dashed lines indicate a possible pi or double bond;
each R is independently selected from the group consisting of H, CF 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylalkyl; or
base may be a structure selected from the group consisting of structures d-n
wherein Z, X, and R″ are defined as in structure c;
base may be a structure selected from the group consisting of structures o-ff
wherein G and R are defined as in structure c;
base may be a structure gg
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R″, R, and Z are defined as in structure c;
base may be a structure hh
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G) 2 (if not a participant in a pi bond), wherein R″ and G are defined as in structure c;
base may be a structure ii
wherein R and G are defined as in structure c;
base may be a structure jj
wherein R and G are defined as in structure c; or
base may be a structure kk
wherein for structure kk:
R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Y is selected from the group consisting of a bond, O, and CH 2 ;
Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH 2 group;
V is selected from the group consisting of N and C-G;
Z is selected from the group consisting of N and C-G′;
G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO 3 H, —SO 2 NH 2 , aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
provided that V and Z are not identical;
provided that when V is C—H, Z is N;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo; and
each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure ll
wherein for structure ll:
R is C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Q′ is selected from the group consisting of NH, O, and S;
G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO 3 H, —SO 2 NH 2 , alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure mm
where in for structure mm
Q is as defined for structure kk
A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH;
D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH 2 —(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)=(CX′)—(C=Q)-, or —CH═CH—NH— group where X′ is halo;
each Q is independently selected from the group consisting of O, S, and NH; R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo;
Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group;
and pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable salts of tautomers, salts (acidic or basic addition salts), hydrates, solvates, crystalline forms thereof,
optionally in combination with one or more antiviral, antibacterial, or antiproliferative agents.
2 . A compound of the formula of claim 1 or its pharmaceutically acceptable salt.
3 . A pharmaceutical composition for treating HBV, HCV or HIV that includes a pharmaceutically effective treatment amount of a compound of claim 1 in a pharmaceutically acceptable carrier or diluent.
4 . A compound according to claim 1 , wherein the compound is represented by formula A.
5 . A compound according to claim 1 wherein the compound is
6 . A method for the treatment of a host infected with HBV, HCV, or HIV that includes administering an effective amount of a compound of the formula:
wherein for structure A or A′
(a) R 2 is independently CH 3 , CH 2 F, CHF 2 , CF 3 , F, CN, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
(b) R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
(c) R 3 is independently OH, H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-10 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-18 acyl) 2 , wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N 3 , CN, one to three halogen (Cl, Br, F, I), NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-4 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-4 acyl) 2 ;
(d) R 4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH 2 ) p OH, where p is 1-6, including hydroxylmethyl (CH 2 OH), CH 2 F, N 3 , CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino;
(e) R and R 3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof,
(f) Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
wherein for a and b
Z is Nor CR 8 ;
R 5 , R 6 , and R 7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 such as C—CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkyl-aryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl;
R 8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO 2 , lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkyl-aryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl; or
base may be selected from a group of formula c
wherein for structure c,
if Z is a participant in a pi bond (double bond), Z is independently selected from N or C-G; or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR 2 , CO, CS, CNR, SO, S(O) 2 , SeO, Se(O) 2 , or C(G) 2 ;
each G is independently selected from the group consisting of H, halogen, OR, SR, NR 2 , NROR, N 3 , COOR, CN, CONR 2 , C(S)NR 2 , C(═NR)NR 2 , and R; and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O) 2 , SeO and Se(O) 2 ;
wherein, if X is a participant in a pi bond (double bond), X is C; or if X is not a participant in a pi bond (double bond), X is CR X or N;
wherein, if R″ is a participant in a pi bond (double bond), R″ is O, S, Se, NR, NOR or NNR 2 ; or if R″ is not a participant in a pi bond (double bond), R″ is OR, SR, F, Cl, R, or SeR; and dashed lines indicate a possible pi or double bond;
each R is independently selected from the group consisting of H, CF 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylalkyl; or
base may be a structure selected from the group consisting of structures d-n
wherein Z, X, and R″ are defined as in structure c;
base may be a structure selected from the group consisting of structures o-ff
wherein G and R are defined as in structure c;
base may be a structure gg
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R″, R, and Z are defined as in structure c;
base may be a structure hh
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G) 2 (if not a participant in a pi bond), wherein R″ and G are defined as in structure c;
base may be a structure ii
wherein R and G are defined as in structure c;
base may be a structure jj
wherein R and G are defined as in structure c; or
base may be a structure kk
wherein for structure kk:
R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Y is selected from the group consisting of a bond, O, and CH 2 ;
Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH 2 group;
V is selected from the group consisting of N and C-G;
Z is selected from the group consisting of N and C-G′;
G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO 3 H, —SO 2 NH 2 , aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
provided that V and Z are not identical;
provided that when V is C—H, Z is N;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo; and
each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure ll
wherein for structure ll:
R is C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Q′ is selected from the group consisting of NH, O, and S;
G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO 3 H, —SO 2 NH 2 , alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure mm
where in for structure mm
Q is as defined for structure kk
A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH;
D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH 2 —(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)=(CX′)—(C=Q)-, or —CH═CH—NH— group where X′ is halo;
each Q is independently selected from the group consisting of O, S, and NH; R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo;
Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group;
and pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable salts of tautomers, salts (acidic or basic addition salts), hydrates, solvates, crystalline forms thereof,
optionally in combination with one or more antiviral, antibacterial, or antiproliferative agents.
7 . A use of the compound represented by formula A or A′ in the manufacture of a medicament for the treatment and/or prophylaxis of any condition the result of an infection by HBV, HCV, or HIV:
wherein for structure A or A′
(a) R 2 is independently CH 3 , CH 2 F, CHF 2 , CF 3 , F, CN, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
(b) R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
(c) R 3 is independently OH, H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-10 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-18 acyl) 2 , wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N 3 , CN, one to three halogen (Cl, Br, F, I), NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-4 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-4 acyl) 2 ;
(d) R 4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH 2 ) p OH, where p is 1-6, including hydroxylmethyl (CH 2 OH), CH 2 F, N 3 , CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino;
(e) R and R 3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof;
(f) Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
wherein for a and b
Z is N or CR 8 ;
R 5 , R 6 , and R 7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 such as C—CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkyl-aryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl;
R 8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO 2 , lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkyl-aryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl; or
base may be selected from a group of formula c
wherein for structure c,
if Z is a participant in a pi bond (double bond), Z is independently selected from N or C-G; or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR 2 , CO, CS, CNR, SO, S(O) 2 , SeO, Se(O) 2 , or C(G) 2 ;
each G is independently selected from the group consisting of H, halogen, OR, SR, NR 2 , NROR, N 3 , COOR, CN, CONR 2 , C(S)NR 2 , C(═NR)NR 2 , and R; and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O) 2 , SeO and Se(O) 2 ;
wherein, if X is a participant in a pi bond (double bond), X is C; or if X is not a participant in a pi bond (double bond), X is CR X or N;
wherein, if R″ is a participant in a pi bond (double bond), R″ is O, S, Se, NR, NOR or NNR 2 ; or if R″ is not a participant in a pi bond (double bond), R″ is OR, SR, F, Cl, R, or SeR; and dashed lines (---) indicate a possible pi or double bond;
each R is independently selected from the group consisting of H, CF 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylalkyl; or
base may be a structure selected from the group consisting of structures d-n
wherein Z, X, and R″ are defined as in structure c;
base may be a structure selected from the group consisting of structures o-ff
wherein G and R are defined as in structure c;
base may be a structure gg
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R″, R, and Z are defined as in structure c;
base may be a structure hh
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G) 2 (if not a participant in a pi bond), wherein R″ and G are defined as in structure c;
base may be a structure ii
wherein R and G are defined as in structure c;
base may be a structure jj
wherein R and G are defined as in structure c; or
base may be a structure kk
wherein for structure kk:
R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Y is selected from the group consisting of a bond, O, and CH 2 ;
Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH 2 group;
V is selected from the group consisting of N and C-G;
Z is selected from the group consisting of N and C-G′;
G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO 3 H, —SO 2 NH 2 , aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
provided that V and Z are not identical;
provided that when V is C—H, Z is N;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo; and
each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure ll
wherein for structure ll:
R is C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Q′ is selected from the group consisting of NH, O, and S;
G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO 3 H, —SO 2 NH 2 , alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure mm
where in for structure mm
Q is as defined for structure kk
A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH;
D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH 2 —(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)=(CX′)—(C=Q)-, or —CH═CH—NH— group where X′ is halo;
each Q is independently selected from the group consisting of O, S, and NH; R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo;
Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group;
and pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable salts of tautomers, salts (acidic or basic addition salts), hydrates, solvates, crystalline forms thereof;
optionally in combination with one or more antiviral, antibacterial, or antiproliferative agents.
8 . A method of making a medicament that comprises combining a pharmaceutically effective carrier with a compound of the formula:
wherein for structure A or A′
(a) R 2 is independently CH 3 , CH 2 F, CHF 2 , CF 3 , F, CN, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
(b) R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
(c) R 3 is independently OH, H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-10 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-18 acyl) 2 , wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N 3 , CN, one to three halogen (Cl, Br, F, I), NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-4 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-4 acyl) 2 ;
(d) R 4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH 2 ) p OH, where p is 1-6, including hydroxylmethyl (CH 2 OH), CH 2 F, N 3 , CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino;
(e) R and R 3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof;
(f) Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
wherein for a and b
Z is N or CR 8 ;
R 5 , R 6 , and R 7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 , lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 such as C—CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′ wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkyl-aryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl;
R 8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 , NO 2 , lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkyl-aryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl; or
base may be selected from a group of formula c
wherein for structure c,
if Z is a participant in a pi bond (double bond), Z is independently selected from N or C-G; or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR 2 , CO, CS, CNR, SO, S(O) 2 , SeO, Se(O) 2 , or C(G) 2 ;
each G is independently selected from the group consisting of H, halogen, OR, SR, NR 2 , NROR, N 3 , COOR, CN, CONR 2 , C(S)NR 2 , C(═NR)NR 2 , and R; and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O) 2 , SeO and Se(O) 2 ;
wherein, if X is a participant in a pi bond (double bond), X is C; or if X is not a participant in a pi bond (double bond), X is CR X or N;
wherein, if R″ is a participant in a pi bond (double bond), R″ is O, S, Se, NR, NOR or NNR 2 ; or if R″ is not a participant in a pi bond (double bond), R″ is OR, SR, F, Cl, R, or SeR; and dashed lines (---) indicate a possible pi or double bond;
each R is independently selected from the group consisting of H, CF 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylalkyl; or
base may be a structure selected from the group consisting of structures d-n
wherein Z, X, and R″ are defined as in structure c;
base may be a structure selected from the group consisting of structures o-ff
wherein G and R are defined as in structure c;
base may be a structure gg
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R″, R, and Z are defined as in structure c;
base may be a structure hh
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G) 2 (if not a participant in a pi bond), wherein R″ and G are defined as in structure c;
base may be a structure ii
wherein R and G are defined as in structure c;
base may be a structure jj
wherein R and G are defined as in structure c; or
base may be a structure kk
wherein for structure kk:
R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Y is selected from the group consisting of a bond, O, and CH 2 ;
Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH 2 group;
V is selected from the group consisting of N and C-G;
Z is selected from the group consisting of N and C-G′;
G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO 3 H, —SO 2 NH 2 , aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
provided that V and Z are not identical;
provided that when V is C—H, Z is N;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo; and
each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure ll
wherein for structure ll:
R is C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Q′ is selected from the group consisting of NH, O, and S;
G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO 3 H, —SO 2 NH 2 , alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure mm
where in for structure mm
Q is as defined for structure kk
A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH;
D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH 2 —(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)=(CX′)—(C=Q)-, or —CH═CH—NH— group where X′ is halo;
each Q is independently selected from the group consisting of O, S, and NH; R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo;
Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group;
and pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable salts of tautomers, salts (acidic or basic addition salts), hydrates, solvates, crystalline forms thereof;
optionally in combination with one or more antiviral, antibacterial, or antiproliferative agents.
8 . A compound selected from among the following compounds:
9 . A process, which comprises:
(1) deoxygenating the 2′-C-position of a compound represented by 1 or 1′
to obtain a compound represented by 2 or 2′
and
(2) derivatizing the compound represented by 2 or 2′ to obtain a compound represented by A or A′
wherein for structures 1, 1′, 2, 2′, A, and A′
(a) R 2 is independently CH 3 , CH 2 F, CHF 2 , CF 3 , F, CN, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
(b) R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
(c) R 3 is independently OH, H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-10 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-18 acyl) 2 , wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N 3 , CN, one to three halogen (Cl, Br, F, I), NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-4 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 14 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-4 acyl) 2 ;
(d) R 4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH 2 ) p OH, where p is 1-6, including hydroxylmethyl (CH 2 OH), CH 2 F, N 3 , CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino;
(e) R and R3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof,
(f) Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
wherein for a and b
Z is Nor CR 8 ;
R 5 , R 6 , and R 7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′ wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkylaryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl;
R 8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO 2 , lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkyl-aryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl; or
base may be selected from a group of formula c
wherein for structure c,
if Z is a participant in a pi bond (double bond), Z is independently selected from N or C-G; or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR 2 , CO, CS, CNR, SO, S(O) 2 , SeO, Se(O) 2 , or C(G) 2 ;
each G is independently selected from the group consisting of H, halogen, OR, SR, NR 2 , NROR, N 3 , COOR, CN, CONR 2 , C(S)NR 2 , C(═NR)NR 2 , and R; and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O) 2 , SeO and Se(O) 2 ;
wherein, if X is a participant in a pi bond (double bond), X is C; or if X is not a participant in a pi bond (double bond), X is CR X or N;
wherein, if R″ is a participant in a pi bond (double bond), R″ is O, S, Se, NR, NOR or NNR 2 ; or if R″ is not a participant in a pi bond (double bond), R″ is OR, SR, F, Cl, R, or SeR; and dashed lines indicate a possible pi or double bond;
each R is independently selected from the group consisting of H, CF 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylalkyl; or
base may be a structure selected from the group consisting of structures d-n
wherein Z, X, and R″ are defined as in structure c;
base may be a structure selected from the group consisting of structures o-ff
wherein G and R are defined as in structure c;
base may be a structure gg
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R″, R, and Z are defined as in structure c;
base may be a structure hh
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G) 2 (if not a participant in a pi bond), wherein R″ and G are defined as in structure c;
base may be a structure ii
wherein R and G are defined as in structure c;
base may be a structure jj
wherein R and G are defined as in structure c; or
base may be a structure kk
wherein for structure kk:
R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Y is selected from the group consisting of a bond, O, and CH 2 ;
Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH 2 group;
V is selected from the group consisting of N and C-G;
Z is selected from the group consisting of N and C-G′;
G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO 3 H, —SO 2 NH 2 , aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
provided that V and Z are not identical;
provided that when V is C—H, Z is N;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo; and
each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure ll
wherein for structure ll:
R is C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Q′ is selected from the group consisting of NH, O, and S;
G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO 3 H, —SO 2 NH 2 , alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure mm
where in for structure mm
Q is as defined for structure kk
A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH;
D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH 2 —(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)=(CX′)—(C=Q)-, or —CH═CH—NH— group where X′ is halo;
each Q is independently selected from the group consisting of O, S, and NH; R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo;
Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group;
and pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable salts of tautomers, salts (acidic or basic addition salts), hydrates, solvates, crystalline forms thereof,
optionally in combination with one or more antiviral, antibacterial, or antiproliferative agents.
10 . A product or composition obtained by a process, which comprises:
(a) deoxygenating the 2′-C-position of a compound represented by 1 or 1′
to obtain a compound represented by 2 or 2′
and
(b) derivatizing the compound represented by 2 or 2′ to obtain a compound represented by A or A′
wherein for structures 1, 1′, 2, 2′, A, and A′
(a) R 2 is independently CH 3 , CH 2 F, CHF 2 , CF 3 , F, CN, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
(b) R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
(c) R 3 is independently OH, H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-10 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-18 acyl) 2 , wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N 3 , CN, one to three halogen (Cl, Br, F, I), NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-4 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO 2 (C 2-4 alkenyl), OS(O) 2 (C 1-4 acyl), OS(O) 2 (C 1-4 alkyl), OS(O) 2 (C 2-4 alkenyl), NH 2 , NH(C 1-4 alkyl), NH(C 2-4 alkenyl), NH(C 2-4 alkynyl), NH(C 1-4 acyl), N(C 1-4 alkyl) 2 , N(C 1-4 acyl) 2 ;
(d) R 4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH 2 ) p OH, where p is 1-6, including hydroxylmethyl (CH 2 OH), CH 2 F, N 3 , CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino;
(e) R and R 3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof,
(f) Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
wherein for a and b
Z is Nor CR 8 ;
R 5 , R 6 , and R 7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′ wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkylaryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl;
R 8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO 2 , lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR 12 , CH═CHCO 2 H, or CH═CHCO 2 R′, wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C 2 -C 6 , an optionally substituted lower alkenyl of C 2 -C 6 , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C 1-20 alkyl), C(O)(C 1-10 alkyl), or C(O)(lower alkyl), optionally substituted aryl, optionally substituted C 1 -C 4 alkyl-aryloxy, heteroaryl, optionally substituted C 1 -C 4 alkyl-heteroaryl, an optionally substituted alkoxy C 1-20 alkyl, an optionally substituted amino C 1-20 alkyl, an optionally substituted fluoro C 1-20 alkyl; or
base may be selected from a group of formula c
wherein for structure c,
if Z is a participant in a pi bond (double bond), Z is independently selected from N or C-G; or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR 2 , CO, CS, CNR, SO, S(O) 2 , SeO, Se(O) 2 , or C(G) 2 ;
each G is independently selected from the group consisting of H, halogen, OR, SR, NR 2 , NROR, N 3 , COOR, CN, CONR 2 , C(S)NR 2 , C(═NR)NR 2 , and R; and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O) 2 , SeO and Se(O) 2 ;
wherein, if X is a participant in a pi bond (double bond), X is C; or if X is not a participant in a pi bond (double bond), X is CR X or N;
wherein, if R″ is a participant in a pi bond (double bond), R″ is O, S, Se, NR, NOR or NNR 2 ; or if R″ is not a participant in a pi bond (double bond), R″ is OR, SR, F, Cl, R, or SeR; and dashed lines (---) indicate a possible pi or double bond;
each R is independently selected from the group consisting of H, CF 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylalkyl; or
base may be a structure selected from the group consisting of structures d-n
wherein Z, X, and R″ are defined as in structure c;
base may be a structure selected from the group consisting of structures o-ff
wherein G and R are defined as in structure c;
base may be a structure gg
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R″, R, and Z are defined as in structure c;
base may be a structure hh
wherein each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G) 2 (if not a participant in a pi bond), wherein R″ and G are defined as in structure c;
base may be a structure ii
wherein R and G are defined as in structure c;
base may be a structure jj
wherein R and G are defined as in structure c; or
base may be a structure kk
wherein for structure kk:
R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Y is selected from the group consisting of a bond, O, and CH 2 ;
Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH 2 group;
V is selected from the group consisting of N and C-G;
Z is selected from the group consisting of N and C-G′;
G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO 3 H, —SO 2 NH 2 , aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group;
provided that V and Z are not identical;
provided that when V is C—H, Z is N;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo; and
each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure ll
wherein for structure ll:
R is C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
Q′ is selected from the group consisting of NH, O, and S;
G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO 3 H, —SO 2 NH 2 , alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
base may be a structure mm
where in for structure mm
Q is as defined for structure kk
A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH;
D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH 2 —(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)=(CX′)—(C=Q)-, or —CH═CH—NH— group where X′ is halo;
each Q is independently selected from the group consisting of O, S, and NH; R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
X is selected from the group consisting of hydrogen, halo, and OW 2 ;
T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo;
Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group;
and pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable salts of tautomers, salts (acidic or basic addition salts), hydrates, solvates, crystalline forms thereof,
optionally in combination with one or more antiviral, antibacterial, or antiproliferative agents.Join the waitlist — get patent alerts
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