NOVEL COMPOUNDS AND COMPOSITIONS AND METHODS OF USE

• US 20090197825A1
• Filed: 11/26/2008
• Published: 08/06/2009
• Est. Priority Date: 11/27/2007
• Status: Active Grant

• Current Assignee: Ardea Biosciences, Inc (Astrazeneca PLC)
• Original Assignee: Ardea Biosciences, Inc (Astrazeneca PLC)
• Inventors: GIRARDET, Jean-Luc, GUNIC, Esmir, YEH, Li-Tain, QUART, Barry D.
• Granted Patent: US 8,084,483 B2
• Time in Patent Office: Days
• US Class Current: 514/46
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/04 for urolithiasis
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/20 for decreasing, blocking or antagonising the activity of PTH
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 249/12 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 249/14 : Nitrogen atoms
• CPC Class Codes: C07H 19/06 : Pyrimidine radicals
• CPC Class Codes: C07H 19/16 : Purine radicals
• CPC Class Codes: C07H 7/02 : Acyclic radicals

Abstract

Described herein are compounds useful in the modulation of blood uric acid levels, formulations containing them and methods of using them. In some embodiments, the compounds described herein are used in the treatment or prevention of disorders related to aberrant levels of uric acid.

Claims

1. A compound of formula (III), or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof:

wherein

X is CH or N;

W is O, S, S(O), S(O)₂, NH, N (optionally substituted alkyl), NC(O) (optionally substituted alkyl) or CH₂;

R¹ is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted i-propyl, CF₃, CHF₂ or CH₂F;

R³ and R^3′

are independently selected from H and lower alkyl, or R³ and R^3′

together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from N, S and O;

R² is selected from the group consisting of (a), (b), (c) and (d);

wherein

represents a carbon-carbon single bond or a carbon-carbon double bond;

Q and Q′

are independently selected from N and CH;

R^P is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl;

R⁸, R⁹ and R¹⁰ are independently selected from H, F, Cl, Br, CH₃, CF₃, CFH₂, CF₂H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF₃, NH₂ and NHCH₃;

R¹¹ is Cl, Br, I, CH₃, CF₃, methoxy, i-propyl, cyclopropyl, tert-butyl, cyclobutyl or methyl; and

R¹², R¹³, R¹⁴ and R¹⁵ are independently H or methyl.

2. The compound of claim 1, wherein:

X is N.

3. The compound of claim 1, wherein:

W is S or O.

4. The compound of claim 1, wherein:

R² is (a)

5. The compound of claim 4, wherein:

represents a carbon-carbon double bond; and

R^P is cyclopropyl.

6. The compound of claim 1, wherein:

X is N;

W is S; and

R¹ is Cl, Br, I, optionally substituted methyl, CF₃, CHF₂ or CH₂F.

7. The compound of claim 1, wherein:

R³ and R^3′

are not H.

8. The compound of claim 1, wherein:

R³ and R^3′

are H.

9. The compound of claim 1, wherein:

R³ and R^3′

together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from N, S and O.

10. The compound of claim 1, wherein:

R³ and R^3′

together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring.

73. The compound of claim 1, which is a pharmaceutically acceptable salt of a compound of formula (III).

74. The compound of claim 73, wherein the pharmaceutically acceptable salt is a L⁺, Na⁺, K⁺, Mg⁺⁺, Ca⁺⁺ or a protonated amine salt.

77. The pharmaceutical composition of claim 73, wherein:

R^B is SCH₂C(═

O)R^1a;

R^1a is OR^2a and;

R^2a is a pharmaceutically acceptable cation.

11. A compound of formula (II), wherein the compound of formula (II) is a 3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole wherein the substituent at the 3-position is —

R^B, or pharmaceutically acceptable salt, solvate, or tautomer thereof;

wherein,

R^B is —

SCH₂C(═

O)R^1a, SCH₂-tetrazolyl, —

SCH₂C(═

O)NHOH, —

SCH₂C(═

O)O-alkyl-OC(═

O)R^3a, —

SCH₂C(═

O)O-alkyl-OC(═

O)OR^3a, —

SCH₂C(═

O)O-alkyl-OC(═

O)NR^4aR^4b, or —

SCH₂C(Oalkyl)₃;

R^1a is OR^2a, SR^3a, NR^4aR^4b, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, or a combination thereof, wherein

R^2a is substituted C₁-C₄ alkyl, optionally substituted C₅-C₁₀ alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

or

R^2a is a pharmaceutically acceptable cation;

or

R^2a is [C(R^5a)(R^5b)]_mR^5c;

R^3a is hydrogen, optionally substituted C₁-C₁₀ alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;

or

R^3a is [C(R^5a)(R^5b)]_nR^5c;

R^4a is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and

R^4b is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

or

R^4b is [C(R^5a)(R^5b)]_nR^5c, wherein

each R^5a is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionally substituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

each R^5b is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionally substituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

R^5c is hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄alkylamine, optionally substituted -L-di(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein L is a bond, —

C(O)—

, —

S(O), or —

S(O)₂;

y₁ is 0, 1, 2 or 3;

Y is OH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂, OP(O)(OH)₂, OP(O)(OH)(O—

C_1-4 alkyl) or NY²Y³Y⁴;

wherein

Y² and Y³ are each independently hydrogen or methyl;

or

Y² and Y³ are taken together with the nitrogen to which they are attached to form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and

Y⁴ is an electron pair or an oxygen atom;

m is 1, 2, 3, 4;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

and wherein if R^2a is -[C(R^5a)(R^5b)]_mR^5c then at least one of R^5a, R^5b and R^5c is not hydrogen.

24. The compound of claim 11, wherein:

R^1a is OR^2a.

26. The compound of claim 24, wherein:

R^2a is a pharmaceutically acceptable cation.

27. The compound of claim 24, wherein:

R^2a is a pharmaceutically acceptable cation selected from L⁺, Na⁺ K⁺, Mg⁺⁺, Ca⁺⁺ or a protonated amine.

12-23. -23. (canceled)

25. (canceled)

28-67. -67. (canceled)

68. A pharmaceutical composition comprising:

(i) a compound of formula (I);

or

(ii) a compound of formula (II), wherein the compound of formula (II) is a 3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole wherein the substituent at the 3-position is —

R^B;

or

(iii) a compound of formula (III);

or

(iv) a combination thereof;

wherein

X is CH or N;

W is O, S, S(O), S(O)₂, NH, N (optionally substituted alkyl), NC(O) (optionally substituted alkyl) or CH₂;

R¹ is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted i-propyl, CF₃, CHF₂ or CH₂F;

R³ and R^3′

are independently selected from H and lower alkyl, or R³ and R^3′

together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from N, S and O;

R² is selected from the group consisting of (a), (b), (c) and (d);

wherein

represents a carbon-carbon single bond or a carbon-carbon double bond;

Q and Q′

are independently selected from N and CH;

R^P is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl;

R⁸, R⁹ and R¹⁰ are independently selected from H, F, Cl, Br, CH₃, CF₃, CFH₂, CF₂H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF₃, NH₂ and NHCH₃;

R¹¹ is Cl, Br, I, CH₃, CF₃, methoxy, i-propyl, cyclopropyl, tert-butyl, cyclobutyl or methyl; and

R¹², R¹³, R¹⁴ and R¹⁵ are independently H or methyl;

R^B is —

SCH₂C(═

O)R^1a, —

CH₂-tetrazolyl, —

SCH₂C(═

O)NHOH, —

SCH₂C(═

O)O-alkyl-OC(═

O)R^3a, —

SCH₂C(═

O)O-alkyl-OC(═

O)OR^3a, —

SCH₂C(═

O)O-alkyl-OC(═

O)NR^4aR^4b, or —

SCH₂C(Oalkyl)₃;

R^1a is OR^2a, SR^3a, NR^4aR^4b, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, or a combination thereof, wherein

R^2a is substituted C₁-C₄ alkyl, optionally substituted C₅-C₁₀ alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

or

R^2a is a pharmaceutically acceptable cation;

or

R^2a is [C(R^5a)(R^5b)]_mR^5c;

R^3a is hydrogen, optionally substituted C₁-C₁₀ alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;

or

R^3a is [C(R^5a)(R^5b)]_nR^5c;

R^4a is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and

R^4b is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

or

R^4b is —

[C(R^5a)(R^5b)]_nR^5c, wherein

each R^5a is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionally substituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

each R^5b is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionally substituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

R^5c is hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄alkylamine, optionally substituted -L-di(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein L is a bond, —

C(O)—

, —

S(O), or —

S(O)₂;

y₁ is 0, 1, 2 or 3;

Y is OH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂, OP(O)(OH)₂, OP(O)(OH)(O—

C_1-4 alkyl) or NY²Y³Y⁴;

wherein

Y² and Y³ are each independently hydrogen or methyl;

or

Y² and Y³ are taken together with the nitrogen to which they are attached to form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and

Y⁴ is an electron pair or an oxygen atom;

m is 1, 2, 3, 4;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

and wherein if R^2a is [C(R^5a)(R^5b)]_mR^5c then at least one of R^5a, R^5b and R^5c is not hydrogen;

R⁴ is H, lower alkyl, lower alkenyl or lower alkynyl;

R⁵, R^5′

, R⁶, R^6′

and R⁷ are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, substituted methyl, substituted ethyl, substituted n-propyl, substituted i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, CF₃, CHF₂, CH₂F, NH₂, NHR′

, NR′

R″

, OR′

, SR′

, C(O)R′

, CO₂H, a salt of CO₂H, COOR′

, CONH₂, CONHR′

, CONR′

R″

, SO₃H, a salt of SO₃H, S(O)₂R′

, S(O)₂NH₂, S(O)₂NHR′

, S(O)₂NR′

R″

, aryl or a heterocycle, wherein

R′

is H, C_1-3 alkyl, substituted C_1-3 alkyl wherein said substituents are selected from CF₃, OH, OC_1-3 alkyl, COC_1-3 alkyl, COOH, COOC_1-3 alkyl, NH₂, NHC_1-3 alkyl, N(C_1-3 alkyl)(C_1-3 alkyl), CONHC_1-3 alkyl, aryl or a heterocycle;

R″

is H, C_1-3 alkyl, substituted C_1-3 alkyl wherein said substituents are selected from CF₃, OH, OC_1-3 alkyl, COC_1-3 alkyl, COOH, COOC_1-3 alkyl, NH₂, NHC_1-3 alkyl, N(C_1-3 alkyl)₂, CONHC_1-3 alkyl, aryl or a heterocycle;

or

R′ and

R″

together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring;

or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof; and

(v) optionally one or more pharmaceutically acceptable carriers.

69. The composition of claim 68, further comprising a second agent effective for the treatment of the gout.

70. The composition of claim 69, wherein the second agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, or combinations thereof.

71. The composition of claim 69, wherein the second agent is allopurinol, febuxostat, FYX-051, or combinations thereof.

75. The pharmaceutical composition of claim 68, comprising:

ii) a compound of formula (II);

or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof; and

v) optionally one or more pharmaceutically acceptable carriers.

76. The pharmaceutical composition of claim 75, comprising:

ii) a pharmaceutically acceptable salt of a compound of formula (II);

v) optionally one or more pharmaceutically acceptable carriers.

72. A method of reducing serum uric acid levels in an individual, comprising administering;

(i) a compound of formula (I);

or

(ii) a compound of formula (II), wherein the compound of formula (II) is a 3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole wherein the substituent at the 3-position is —

R^B;

or

(iii) a compound of formula (III);

or

(iv) a combination thereof;

wherein

X is CH or N;

W is O, S, S(O), S(O)₂, NH, N (optionally substituted alkyl), NC(O) (optionally substituted alkyl) or CH₂;

R¹ is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted i-propyl, CF₃, CHF₂ or CH₂F;

R³ and R^3′

are independently selected from H and lower alkyl, or R³ and R^3′

together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from N, S and O;

R² is selected from the group consisting of (a), (bi), (c) and (d);

wherein

represents a carbon-carbon single bond or a carbon-carbon double bond;

Q and Q′

are independently selected from N and CH;

R^P is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl;

R⁸, R⁹ and R¹⁰ are independently selected from H, F, Cl, Br, CH₃, CF₃, CFH₂, CF₂H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF₃, NH₂ and NHCH₃;

R¹¹ is Cl, Br, I, CH₃, CF₃, methoxy, i-propyl, cyclopropyl, tert-butyl, cyclobutyl or methyl; and

R¹², R¹³, R¹⁴ and R¹⁵ are independently H or methyl;

R^B is —

SCH₂C(═

O)R^1a, —

SCH₂-tetrazolyl, —

SCH₂C(═

O)NHOH, —

SCH₂C(═

O)O-alkyl-OC(═

O)R^3a, —

SCH₂C(═

O)O-alkyl-OC(═

O)OR^3a, —

SCH₂C(═

O)O-alkyl-OC(═

O)NR^4aR^4b, or —

SCH₂C(Oalkyl)₃;

R^1a is OR^2a, SR^3a, NR^4aR^4b, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, or a combination thereof, wherein

R^2a is substituted C₁-C₄ alkyl, optionally substituted C₅-C₁₀ alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

or

R^2a is a pharmaceutically acceptable cation;

or

R^1a is [C(R^5a)(R^5b)]_mR^5c;

R^3a is hydrogen, optionally substituted C₁-C₁₀ alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;

or

R^3a is [C(R^5a)(R^5b)]_nR^5c;

R^4a is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and

R^4b is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

or

R^4b is [C(R^5a)(R^5b)]_nR^5c, wherein

each R^5a is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionally substituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

each R^5b is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄ alkylamine, optionally substituted -L-di-(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

R^5c is hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄alkylamine, optionally substituted -L-di(C₁-C₄)alkylamine, optionally substituted -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein L is a bond, —

C(O)—

, —

S(O), or —

S(O)₂;

y₁ is 0, 1, 2 or 3;

Y is OH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂, OP(O)(OH)₂, OP(O)(OH)(O—

C_1-4 alkyl) or NY²Y³Y⁴;

wherein

Y² and Y³ are each independently hydrogen or methyl;

or

Y² and Y³ are taken together with the nitrogen to which they are attached to form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and

Y⁴ is an electron pair or an oxygen atom;

m is 1, 2, 3, 4;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

and wherein if R^2a is -[C(R^5a)(R^5b)]_mR^5c then at least one of R^5a, R^5b and R^5c is not hydrogen;

R⁴ is H, lower alkyl, lower alkenyl or lower alkynyl;

R⁵, R^5′

, R⁶, R^6′

and R⁷ are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, substituted methyl, substituted ethyl, substituted n-propyl, substituted i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, CF₃, CHF₂, CH₂F, NH₂, NHR′

, NR′

R″

, OR′

, SR′

, C(O)R′

, CO₂H, a salt of CO₂H, COOR′

, CONH₂, CONHR′

, CONR′

R″

, SO₃H, a salt of SO₃H, S(O)₂R′

, S(O)₂NH₂, S(O)₂NHR′

, S(O)₂NR′

R″

, aryl or a heterocycle, wherein

R′

is H, C_1-3 alkyl substituted C_1-3 alkyl wherein said substituents are selected from CF₃, OH, OC_1-3 alkyl, COC_1-3 alkyl, COOH, COOC_1-3 alkyl, NH₂, NHC_1-3 alkyl, N(C_1-3 alkyl)(C_1-3 alkyl), CONHC_1-3 alkyl, aryl or a heterocycle;

R″

is H, C_1-3 alkyl substituted C_1-3 alkyl wherein said substituents are selected from CF₃, OH, OC_1-3 alkyl, COC_1-3 alkyl, COOH, COOC_1-3 alkyl, NH₂, NHC_1-3 alkyl, N(C_1-3 alkyl)₂, CONHC_1-3 alkyl, aryl or a heterocycle;

or

R′ and

R″

together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring;

or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof.