Antiviral phosphonate analogs

• US 20050215513A1
• Filed: 04/26/2004
• Published: 09/29/2005
• Est. Priority Date: 04/25/2003
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: MacKman, Richard L., Watkins, William J., Cho, Aesop, Fardis, Maria, Markevitch, David Y., Chong, Lee S., Kim, Choung U., Boojamra, Constantine G., Ray, Adrian S., Prasad, Vidya K., Lee, Christopher P., Chen, Xiaowu, Swaminathan, Sundaramoorthi, Kirschberg, Thorsten, Chen, James M., Huang, Alan X., Oare, David A., Hirschmann, Ralph F., Jin, Haolun, Sherlock, Rosemarie, Zhang, Jennifer R., Lee, William A., Cannizzaro, Carina, Pyun, Hyung-Jung
• Granted Patent: US 7,429,565 B2
• Time in Patent Office: Days
• US Class Current: 514/47
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 475/00 Heterocyclic compounds containing pteridine ring systems
• CPC Class Codes: C07F 9/4075 Esters with hydroxyalkyl compounds
• CPC Class Codes: C07F 9/5728 condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/58 Pyridine rings
• CPC Class Codes: C07F 9/60 Quinoline or hydrogenated quinoline ring systems
• CPC Class Codes: C07F 9/65031 having the nitrogen atoms in the positions 1 and 2
• CPC Class Codes: C07F 9/650905 having the nitrogen atoms in the positions 1 and 2
• CPC Class Codes: C07F 9/653 : Five-membered rings
• CPC Class Codes: C07F 9/6539 : Five-membered rings
• CPC Class Codes: C07F 9/65515 : the oxygen atom being part of a five-membered ring
• CPC Class Codes: C07F 9/655354 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6561 : containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• CPC Class Codes: C07F 9/65616 : containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: C07H 15/00 : Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
• CPC Class Codes: C07H 17/00 : Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
• CPC Class Codes: C07H 19/056 : Triazole or tetrazole radicals
• CPC Class Codes: C07H 19/10 : with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 : with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention is related to phosphorus substituted compounds with antiviral activity, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

Claims

1. A conjugate comprising an antiviral compound linked to one or more phosphonate groups;

or a pharmaceutically acceptable salt or solvate thereof.

2. The conjugate of claim 1, or a pharmaceutically acceptable salt or solvate thereof, that is a compound of any one of formulae 501-569 substituted with one or more groups A⁰, wherein:

A⁰ is A¹, A² or W³ with the proviso that the conjugate includes at least one A¹;

Y¹ is independently O, S, N(R^x), N(O)(R^x), N(OR^x), N(O)(OR^x), or N(N(R^x)(R^x));

Y² is independently a bond, O, N(R^x), N(O)(R^x), N(OR^x), N(O)(OR^x), N(N(R^x)(R^x)), —

S(O)_M2—

, or —

S(O)_M2—

S(O)_M2—

; and

when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^x is independently H, R¹, R², W³, a protecting group, or the formula;

wherein;

R^y is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independently substituted with 0 to 3 R³ groups or taken together at a carbon atom, two R² groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R³ groups;

R³ is R^3a, R^3b, R^3c or R^3d, provided that when R³ is bound to a heteroatom, then R³ is R^3c or R^3d;

R^3a is F, Cl, Br, I, —

CN, N₃ or —

NO₂;

R^3b is Y¹;

R^3c is —

R^x, —

N(R^x)(R^x), —

SR^x, —

S(O)R^x, —

S(O)₂R^x, —

S(O)(OR^x), —

S(O)₂(OR^x), —

OC(Y¹)R^x, —

OC(Y¹)OR^x, —

OC(Y¹)(N(R^x)(R^x)), —

SC(Y¹)R^x, —

SC(Y¹)OR^x, —

SC(Y¹)(N(R^x)(R^x)), —

N(R^x)C(Y¹)R^x, —

N(R^x)C(Y¹)OR^x, or —

N(R^x)C(Y¹)(N(R^x)(R^x));

R^3d is —

C(Y¹)R^x, —

C(Y¹)OR^x or —

C(Y¹)(N(R^x)(R^x));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —

C(Y¹)R⁵, —

C(Y¹)W⁵, —

SO_M2R⁵, or —

SO_M2W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substituted with 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

X¹⁴⁹ is thymine, adenine, uracil, a 5-halouracil, a 5-alkyluracil, guanine, cytosine, a 5-halo cytosine, 5-alkyl cytosine, or 2,6-diaminopurine;

X₁₅₀ is OH, C₁, NH₂, H, Me, or MeO;

X₁₅₁ is H, NH₂, or NH-alkyl;

X₁₅₂ and X₁₅₃ are independently H, alkyl, or cyclopropyl;

X₁₅₄ is a halo;

X₁₅₅ is alkoxy, aryloxy, halo-substituted alkoxy, alkenyloxy, or arylalkoxy;

X₁₅₆ is alkyl; and

X¹⁵⁷ is thymine, adenine, guanine, cytosine, uracil, inosine, or diaminopurine.

3. The conjugate of claim 2, or a pharmaceutically acceptable salt or solvate thereof, which has the formula:

[DRUG]-(A⁰)_nn

wherein;

DRUG is a compound of any one of formulae 501-561; and

nn is 1, 2, or 3.

4. The conjugate of claim 2 which has any one of formulae 1-108 wherein:

A⁰ is A¹;

X⁵¹ is H, α

-Br, or β

-Br;

X⁵² is C₁-C₆ alkyl or C₇-C₁₀ arylalkyl group;

X⁵³ is H, alkyl or substituted alkyl;

X⁵⁴ is CH or N;

X⁵⁵ is thymine, adenine, uracil, a 5-halouracil, a 5-alkyluracil, guanine, cytosine, a 5-halo cytosine, a 5-alkyl cytosine, or 2,6-diaminopurine;

X⁵⁶ is H, Me, Et, or i-Pr;

X⁵⁷ is H or F;

X⁵⁸ is OH, C₁, NH₂, H, Me, or MeO;

X⁵⁹ is H or NH₂;

X⁶⁰ is OH, C₁, NH₂, or H;

X⁶ is H, NH₂, or NH-alkyl;

X⁶² and X⁶³ are independently H, alkyl, or cyclopropyl;

X⁶⁴ is H, N₃, NH₂, or NHAc;

X⁶⁵ is a halo;

X⁶⁶ is alkoxy, aryloxy, halo-substituted alkoxy, alkenyloxy, arylalkoxy;

X⁶⁷ is O or NH;

X⁶⁸ is H, acetate, benzyl, benzyloxycarbonyl, or an amino protecting group;

X⁶⁹ is H or alkyl;

X⁷⁰ is H;

alkyl;

alkyl substituted with cycloalkyl containing three to about six carbon atoms that is optionally substituted with one or more alkyl;

alkenyl;

alkenyl substituted with cycloalkyl containing three to about six carbon atoms that is optionally substituted with one or more alkyl;

hydroxyl-substituted alkyl;

alkoxy-substituted alkyl;

acyloxy-substituted alkyl;

aryl;

substituted aryl;

arylalkyl;

or (substituted aryl)alkyl;

X⁷¹ and X⁷² are each independently hydrogen, alkyl, phenyl, or substituted phenyl;

X⁷³ is alkoxy, substituted alkyl, alkylamido amino, monoalkylamino, dialkylamino, azido, chloro, hydroxy, 1-morpholino, 1-pyrrolidino, and alkylthio;

X⁷⁴ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

X⁷⁵ and X⁷⁶ attached to nitrogen or carbon in X⁷⁴ wherein X⁷⁵ is H, halo, nitro, C₁-C₆alkyl, C₁-C₆alkoxy, (fluoro-substituted)C₁-C₆alkyl, (fluoro-substituted)C₁-C₆alkoxy, C₂-C₈alkoxyalkyl, (fluoro-substituted)C₂-C₈alkoxyalkyl, N(R^a)(R^b), (CH₂)_1-3N(R^a)(R^b), (CH₂)_0-3R^c, or O(CH₂)_0-3R^c; and

X⁷⁶ is H, halo, nitro, C_1-6alkyl, C_1-6alkoxy, (fluoro-substituted)C_1-6 alkyl, (fluoro-substituted)C_1-6 alkoxy, C_2-8alkoxyalkyl, (fluoro-substituted)C_2-8alkoxyalkyl, N(R^a)(R^b), (CH₂)_1-3N(R^a)(R b), (CH₂)_0-3R^e, O(CH₂)_0-3R^c, (CH₂)_0-3R^d, O(CH₂)_0-3R^d, C(═

O)CH₂C(═

O)R^e, or R^f, R^a and R^b are each independently H, C₁-C₆ alkyl, or (fluoro-substituted)C₁-C₆ alkyl;

Re is aryl, or substituted aryl;

Rd is heterocycle, or substituted heterocycle;

Re is heteroaryl or substituted heteroaryl;

R^f is X¹²⁰-NH(CH₂)_1-3X¹²¹, wherein X¹²⁰ is a 5- or 6-membered monocyclic heterocycle which is saturated or unsaturated and which contains carbon atoms and from 1 to 3 nitrogen atoms and which is unsubstituted or substituted with one or more substituents selected from halo, cyano, OH, (CH₂)_1-4OH, oxo, N(R^a)(R^b), C₁-C₆ alkyl, fluorinated C₁-C₆ alkyl, C₁-C₆ alkoxy, fluorinated C₁-C₆ alkoxy, (CH₂)_0-4CO₂R^a, (CH₂)_0-4C(═

O)N(R^a)(R^b), (CH₂)_0-4SO₂R^a, (CH₂)_1-4N(R^a)(R^b), (CH₂)_0-4N(R^a)C(═

O)R^b, (CH₂)_0-4SO₂N(R^a)(R^b), (CH₂)_1-4N(R^a)SO₂R^b, C₂-C₈ alkoxyalkyl, and (fluoro-substituted)C₂-C₈ alkoxyalkyl; and

X¹²¹ is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is unsubstituted or substituted with one or more substituents selected from halo, cyano, OH, (CH₂)_1-4OH, oxo, N(R^a)(R^b), C₁-C₆ alkyl, fluorinated C₁-C₆ alkyl, C₁-C₆ alkoxy, fluorinated C₁-C₆ alkoxy, (CH₂)_0-4CO₂R^a, (CH₂)_0-4C(═

O)N(R^a)(R b), (CH₂)_0-4 SO₂R^a, (CH₂)_1-4N(R^a)(R b), (CH₂)_0-4N(R^a)C(═

O)R^b, (CH₂)_0-4SO₂N(R^a)(R b), (CH₂),4N(R^a)SO₂R^b, C₂-C₈ alkoxyalkyl, and (fluoro-substituted)C₂-C₈ alkoxyalkyl;

X⁷⁷ is H or C_1-6 alkyl;

X⁷⁸ is OH, protected hydroxyl, or N(R^a)(R^b);

X⁷⁹ is a attached to nitrogen or carbon in X⁷⁴; and

X⁷⁹ is H, halo, nitro, oxo, C_1-6alkyl, C_3-7cycloalkyl, C_3-7cycloalkoxy, C_1-6alkoxy, (fluoro-substituted)C_1-6 alkyl, (fluoro-substituted)C_1-6 alkoxy, C_2-8 alkoxyalkyl, (fluoro-substituted)C_2-8 alkoxyalkyl, N(R^a)(R^b), (CH₂)_1-4N(R^a)(R^b), C(═

O)N(R^a)(R b), (CH₂)_1-4C(═

O)N(R^a)(R^b), N(R^a)C(═

O)R^b, (CH₂)_1-4N(R^a)C(═

O)R^b, SO₂R^a (CH₂)_1-4SO₂R^a, SO₂N(R^a)(R^b), (CH₂)_1-4SO₂N(R^a)(R^b), (CH₂)_1-4N(R^a)SO₂R b, (CH₂)_0-3R^c, or (CH₂)_0-3R^g;

X⁸⁰ is (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 nitrogen atoms, 0 to 2 sulfur atoms, and at least 1 carbon atom, or (ii) an 8- to 10-membered fused bicyclic heterocycle containing from 1 to 4 nitrogen atoms, 0 to 2 sulfur atoms, and carbon atoms, wherein the ring of the heterocycle attached to the central dione moiety is a 5- or 6 membered heteroaromatic ring containing at least one nitrogen or sulfur atom and the other ring of the heterocycle is a saturated or unsaturated ring;

wherein X⁸⁰ is attached to the central propenone moiety via a carbon atom and at least one nitrogen or sulfur atom in X⁸⁰ is adjacent to the point of attachment;

X⁸¹ is attached to nitrogen or carbon in X⁸⁰, and is independently selected from H, halo, OH, (CH₂)_1-4OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, (fluoro-substituted)C₁-C₆ alkyl, (fluoro-substituted)C₁-C₆ alkoxy, C₁-C₈ alkoxyalkyl, (fluoro-substituted)C₁-C₈ alkoxyalkyl, N(R^a)(R^b), (CH₂)_1-4N(R^a)(R^b), C(═

O)N(R^a)(R^b), (CH₂)_1-4C(═

O)N(R^a)(R^b), N(R^a)C(═

O)R b, (CH₂)_1-4 N(R^a)C(═

O)R^b, SO₂R^a, (CH₂)_1-4SO₂R^a, SO₂N(R^a)(R^b), (CH₂)_1-4SO₂N(R^a)(R b), (CH₂)_1-4 N(R^a)SO₂R b, and (CH₂)_0-3R^b;

R^g is a 5- or 6-membered monocyclic heterocycle which is saturated or unsaturated and which contains one or more carbon atoms and from 1 to 4 nitrogen atoms, the heterocycle being unsubstituted or substituted with one or more substituents selected from halo, cyano, OH, (CH₂)_1-4 OH, oxo, N(R^a)(R^b), C₁-C₆alkyl, (fluoro-substituted)C₁-C₆alkyl, C₁-C₆alkoxy, (fluoro-substituted)C₁-C₆ alkoxy, (CH₂)_0-4CO₂R^a, (CH₂)_0-4C(═

O)N(R^a)(R^b), (CH₂)_0-4SO₂R^a, (CH₂)_1-4 N(R^a)(R^b), (CH₂)_0-4N(R^a)C(═

O)R^b, (CH₂)_0-4SO₂N(R^a)(R^b), (CH₂)_1-4N(R^a)SO₂R^b, C₂-C₈alkoxyalkyl, (fluoro-substituted)C₂-C₈alkoxyalkyl, phenyl and benzyl;

x⁸² is OH, F, or cyano;

X⁸³ is N or CH;

X⁸⁴ is cis H or trans H;

X⁸⁵ is C₈-C₁₆ alkyl which can optionally contain one to five oxygen atoms in the chain;

X⁸⁶ is H, methyl, hydroxymethyl, or fluoromethyl;

X⁸⁷ and X⁸⁸ are each independently H or C_1-4 alkyl, which alkyl is optionally substituted with OH, amino, C_1-4 alkoxy, C_1-4 alkylthio, or one to three halogen atoms;

X⁸⁹ is —

O—

or —

S(O)_n—

, where n is 0, 1, or 2;

X⁹⁰ is H, methyl, hydroxymethyl, or fluoromethyl;

X⁹ is H hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, bromovinyl, —

C(O)O(alkyl), —

O(acyl), alkoxy, alkenyloxy, chloro, bromo, fluoro, iodo, NO₂, NH₂, —

NH(lower alkyl), —

NH(acyl), —

N(lower alkyl)₂, —

N(acyl)₂;

X⁹² is H, C_2-4alkenyl, C_2-4alkynyl, or C_1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;

one of X⁹³ and X⁹⁴ is hydroxy or C_1-4 alkoxy and the other of X⁹³ and X⁹⁴ is selected from the group consisting of H;

hydroxy;

halo;

C_1-4 alkyl optionally substituted with 1 to 3 fluorine atoms;

C_1-10 alkoxy, optionally substituted with C_1-3 alkoxy or 1 to 3 fluorine atoms;

C_2-6 alkenyloxy;

C_1-4alkylthio;

C_1-8 alkylcarbonyloxy;

aryloxycarbonyl;

azido;

amino;

C_1-4 alkylamino; and

di(C_1-4 alkyl)amino;

or

X⁹³ is H, C_2-4 alkenyl, C_2-4 alkynyl, or C_1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms, and one of X⁹² and X⁹⁴ is hydroxy or C_1-4alkoxy and the other of X⁹² and X⁹⁴ is selected from the group consisting of H;

hydroxy;

halo;

C_1-4 alkyl optionally substituted with 1 to 3 fluorine atoms;

C_1-10 alkoxy, optionally substituted with C_1-3 alkoxy or 1 to 3 fluorine atoms;

C_2-6 alkenyloxy;

C_1-4alkylthio;

C_1-8 alkylcarbonyloxy;

aryloxycarbonyl;

azido;

amino;

C_1-4 alkylamino; and

di(C_1-4 alkyl)amino;

or

X⁹² and X⁹³ together with the carbon atom to which they are attached form a 3- to 6 membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC_0-4 alkyl;

X⁹⁵ is H, OH, SH, NH₂, C_1-4 alkylamino, di(C_1-4alkyl)amino, C_3-6cycloalkylamino, halo, C_1-4alkyl, C_1-4 alkoxy, or CF₃;

or X⁹² and X⁹⁵ can optionally together be a bond linking the two carbons to which they are attached;

X⁹⁶ is H, methyl, hydroxymethyl, or fluoromethyl;

X⁹⁷ is selected from the group consisting of

U, G, and J are each independently CH or N;

D is N, CH, C—

CN, C—

NO₂, C-C_1-3 alkyl, C—

NHCONH₂, C—

CONT₁₁T₁₁, C—

CSN T₁₁T₁₁, C—

COOT₁₁, C—

C(═

NH)NH₂, C-hydroxy, C—

C_1-3 alkoxy, C-amino, C—

C_1-4 alkylamino, C-di(C_1-4 alkyl)amino, C-halogen, C-(1,3-oxazol-2-yl), C-(1,3 thiazol-2-yl), or C-(imidazol-2-yl);

wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C_1-3 alkoxy;

E is N or CT₅;

W^a is O or S;

T₁ is H, C_2-4alkenyl, C_2-4alkynyl, or C_1-4alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of T₂ and T₃ is hydroxy or C_1-4 alkoxy and the other of T₂ and T₃ is selected from the group consisting of H;

hydroxy;

halo;

C_1-4 alkyl optionally substituted with 1 to 3 fluorine atoms;

C₁₀ alkoxy, optionally substituted with C_1-3 alkoxy or 1 to 3 fluorine atoms;

C_2-6 alkenyloxy;

C_1-4alkylthio;

C_1-8 alkylcarbonyloxy;

aryloxycarbonyl;

azido;

amino;

C_1-4 alkylamino; and

di(C_1-4 alkyl)amino;

or

T₂ is H, C_2-4alkenyl, C_2-4alkynyl, or C_1-4alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of T, and T₃ is hydroxy or C_1-4alkoxy and the other of T, and T₃ is selected from the group consisting of H;

hydroxy;

halo;

C_1-4 alkyl optionally substituted with 1 to 3 fluorine atoms;

C_1-10 alkoxy, optionally substituted with C_1-3 alkoxy or 1 to 3 fluorine atoms;

C_2-6 alkenyloxy;

C_1-4alkylthio;

C_1-8 alkylcarbonyloxy;

aryloxycarbonyl;

azido;

amino;

C_1-4 alkylamino; and

di(C_1-4 alkyl)amino;

or

T₁ and T₂ together with the carbon atom to which they are attached form a 3- to 6 membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC_0-4 alkyl;

T₄ and T₆ are each independently H, OH, SH, NH₂, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_3-6 cycloalkylamino, halo, C_1-4 alkyl, C_1-4 alkoxy, or CF₃;

T₅ is H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-4alkylamino, CF₃, or halogen;

T₁₄ is H, CF₃, C_1-4 alkyl, amino, C_1-4alkylamino, C_3-6cycloalkylamino, or di(C_1-4alkyl)amino;

T₇ is H, amino, C_1-4alkylamino, C_3-6 cycloalkylamino, or di(C_1-4alkyl)amino;

each T₁₁ is independently H or C_1-6 alkyl;

T₈ is H, halo, CN, carboxy, C_1-4 alkyloxycarbonyl, N₃, amino, C_1-4 alkylamino, di(C_1-4 alkyl)amino, hydroxy, C_1-6 alkoxy, C_1-6 alkylthio, C_1-6 alkylsulfonyl, or (C_1-4 alkyl)_0-2 aminomethyl;

X⁹⁸ is methoxy, ethoxy, vinyl, ethyl, methyl, cyclopropyl, N-methylamino, or N-formylamino;

X⁹⁹ is methyl, chloro, or trifluoromethyl;

X¹⁰⁰ is H, methyl, ethyl, cyclopropyl, vinyl, or trifluoromethyl;

X¹⁰¹ is H, methyl, ethyl, cyclopropyl, chloro, vinyl, allyl, 3-methyl-1-buten-yl;

X¹⁰² is thymine, adenine, guanine, cytosine, uracil, inosine, or diaminopurine;

X¹⁰³ is OH, OR, NR₂, CN, NO₂, F, Cl, Br, or I;

X¹⁰⁴ is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O⁶-methylguanine, N⁶-methyladenine, O⁴-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, or pyrazolo[3,4-d]pyrimidine;

X¹⁰⁵ is selected from O, C(R^y)₂, OC(R^y)₂, NR and S;

X¹⁰⁶ is selected from O, C(R^y)₂, C═

C(R^y)₂, NR and S;

X¹⁰⁷ is selected from adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O⁶-methylguanine, N⁶-methyladenine, O⁴-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, and pyrazolo[3,4-D]pyrimidine;

X¹⁰⁸ is independently selected from H, OH, OR, NR₂, CN, NO₂, SH, SR, F, Cl, Br, and I;

X¹⁰⁹ is selected from H, C₁-C₈alkyl, substituted C₁-C₈alkyl, C₁-C₈alkenyl, substituted C₁-C₈alkenyl, C₁-C₈alkynyl, and substituted C₁-C₈alkynyl,

X¹¹⁰ is independently O, CR₂, NR, ⁺N(O)(R), N(OR), ^+N(O)(OR), N—

NR₂, S, S—

S, S(O), or S(O)₂;

X¹¹¹ is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O⁶-methylguanine, N⁶-methyladenine, O⁴-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, or pyrazolo[3,4-D]pyrimidine;

X¹¹² is independently selected from H, OH, OR, NR₂, CN, NO₂, SH, SR, F, Cl, Br, and I;

X¹¹³ is F;

X¹¹⁴ is independently H, F, Cl, Br, I, OH, R, —

C(═

Y¹)R, —

C(═

Y¹)OR, —

C(═

Y¹)N(R)₂, —

N(R)₂, —

⁺N(R)₃, —

SR, —

S(O)R, —

S(O)₂R, —

S(O)(OR), —

S(O)₂(OR), —

OC(═

Y¹)R, —

OC(═

Y¹)OR, —

OC(═

Y¹)(N(R)₂), —

SC(═

Y¹)R, —

SC(═

Y¹)OR, —

SC(═

Y¹)(N(R)₂), —

N(R)C(═

Y¹)R, —

N(R)C(═

Y¹)OR, or —

N(R)C(═

YI)N(R)₂, amino (—

NH₂), ammonium (—

NH₃⁺), alkylamino, dialkylamino, trialkylammonium, C₁-C₈alkyl, carboxy, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, 4-dialkylaminopyridinium, hydroxyl-substituted C₁-C₈alkyl, C₁-C₈alkylthiol, alkylsulfonyl, arylsulfonyl, arylsulfinyl (—

SOAr), arylthio, —

SO₂NR₂, —

SOR, —

C(═

O)OR, —

C(═

O)NR₂, 5-7 membered ring lactam, 5-7 membered ring lactone, cyano, azido, nitro, C₁-C₈alkoxy, substituted C₁-C₈alkyl, C₁-C₈alkenyl, substituted C₁-C₈alkenyl, C₁-C₈alkynyl, substituted C₁-C₈ alkynyl, aryl, substituted aryl, heterocycle, substituted heterocycle, polyethyleneoxy, a protecting group, or W³;

or when taken together, two R^ys form a carbocyclic ring of 3 to 7 carbon atoms;

X¹¹⁵ is independently selected from H, OH, OR, NR₂, CN, NO₂, SH, SR, F, Cl, Br, and I;

X¹¹⁶ is selected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈ alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, and C₁-C₈ substituted alkynyl.

28. The conjugate of claim 2 wherein each A³ is of the formula:

31. The conjugate of claim 2 wherein each A³ is of the formula:

35. The conjugate of claim 2 wherein each A³ is of the formula:

38. The conjugate of claim 2 wherein each A³ is of the formula:

42. The conjugate of claim 2 wherein each A³ is of the formula:

46. The conjugate of claim 2 wherein each A³ is of the formula:

52. The conjugate of claim 2 wherein each A³ is of the formula:

63. The conjugate of claim 3 wherein A⁰ is of the formula:

64. The conjugate of claim 1 which has the formula:

90. The conjugate as described in claim 1, which is isolated and purified.

105. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a conjugate, or a pharmaceutically acceptable salt or solvate thereof, as described in claim 1.

106. A unit dosage form comprising a conjugate, or a pharmaceutically acceptable salt or solvate thereof, as described in claim 1;

and a pharmaceutically acceptable excipient.

107. A method for promoting an anti-viral effect in vitro or in vivo comprising contacting a sample in need of such treatment with a conjugate claim 1, or a pharmaceutically acceptable salt or solvate thereof.

109. A method of inhibiting a viral infection in an animal, comprising administering an effective amount of a conjugate claim 1, or a pharmaceutically acceptable salt or solvate thereof, to the animal.

116. The conjugate of claim 1 having the following formula:

155. A method for the treatment or prevention of the symptoms or effects of a viral infection in an infected animal comprising administering to said animal a pharmaceutical composition or formulation comprising an effective amount of a conjugate of claim 116, or a pharmaceutically acceptable salt or solvate thereof.

172. A pharmaceutical composition comprising a therapeutically effective amount of a conjugate of claim 116, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

180. A method of inhibiting RNA-dependent RNA polymerase comprising administering to a mammal in need of such treatment a therapeutically effective amount of a conjugate of claim 116, or a pharmaceutically acceptable salt or solvate thereof.

188. The conjugate of claim 1 having the following formula:

215. A method for the treatment or prevention of the symptoms or effects of a viral infection in an infected animal comprising administering to said animal a pharmaceutical composition or formulation comprising an effective amount of a conjugate of claim 188.

231. A pharmaceutical composition comprising a therapeutically effective amount of a conjugate of claim 188, or a pharmaceutically acceptable salt or solvate thereof;

and a pharmaceutically acceptable excipient.

246. The conjugate of claim 1 that has the following formula:

268. The conjugate of claim 1 having the following formula:

269. A method for the treatment or prevention of the symptoms or effects of a viral infection in an infected animal comprising administering to said animal a pharmaceutical composition or formulation comprising an effective amount of a conjugate of claim 246 or a pharmaceutically acceptable salt or solvate thereof.

286. A pharmaceutical composition comprising a therapeutically effective amount of a conjugate of claim 246 or a pharmaceutically acceptable salt or solvate thereof;

and a pharmaceutically acceptable excipient.

5-27. -27. (canceled)

29-30. -30. (canceled)

32-34. -34. (canceled)

36-37. -37. (canceled)

39-41. -41. (canceled)

43-45. -45. (canceled)

47-51. -51. (canceled)

53-62. -62. (canceled)

65-89. -89. (canceled)

91-102. -102. (canceled)

103. A compound of the formula MBF.

104. A compound of claim 103 selected from Table 100.

108. (canceled)

110-115. -115. (canceled)

117-152. -152. (canceled)

153. A conjugate having the following formula:

154. (canceled)

156-171. -171. (canceled)

173-179. -179. (canceled)

181-187. -187. (canceled)

189-214. -214. (canceled)

216-230. -230. (canceled)

232-245. -245. (canceled)

247-267. -267. (canceled)

270-285. -285. (canceled)

287-299. -299. (canceled)