UA102826C2 - Triazole derivatives and use thereof as a medicament - Google Patents

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.

Description

1. Application of a compound having the structure:

M-Mm ra ra o

Vg Mat or its pharmaceutically acceptable salt as a medicinal product. 2. Use according to item 1, in which the compound is a sodium salt. 3. Application according to item 1 or item 2 in the treatment of gout. 4. Application according to item I or item 2 in the treatment of gout in combination with allopurinol, febuxostat or EU X-051. 5. Application according to item 1 or item 2 in the treatment of hyperuricemia. 6. Application according to item 1 or item 2 to reduce the serum level of uric acid. 7. Application according to any of paragraphs 1-3, 5 or 6 in combination with allopurinol. 8. Application according to any of paragraphs 1-3, 5 or 6 in combination with febuxostat. 9. A pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound having the structure:

M--M ra ra o

Vg M a to i 5 or its pharmaceutically acceptable salt. 10. Pharmaceutical composition according to item 9, in which the compound is a sodium salt. 11. Pharmaceutical composition according to item 9 or item 10, which is intended for oral use in the form of individual units. 12. The pharmaceutical composition according to item 9, which additionally contains a second drug effective in the treatment of gout. 13. Pharmaceutical composition according to item 12, in which the second drug is an inhibitor of OKAT 1, an inhibitor of xanthine oxidase, xanthine dehydrogenase or an inhibitor of xanthine oxidoreductase. 14. Pharmaceutical composition according to item 12, in which the second drug is selected from allopurinol, febuxostat, EU X-051 or their combinations. 15. Pharmaceutically acceptable salt of a compound having the structure:

M--M ra ra o

Vg M a

AND

16. Pharmaceutically acceptable salt according to item 15, which is a sodium salt.

Related applications

This application claims priority to prior application US Mo 60/990,574 entitled "NEW

COMPOSITIONS AND METHODS OF THEIR USE", submitted on November 27, 2007, and the previous application

US Patent No. 61/094,388, entitled "COMPOUNDS, COMPOSITIONS AND METHODS THEREOF," filed Sep. 4, 2008, which are incorporated herein by reference in their entirety.

Level of knowledge

Uric acid is the result of xanthine oxidation. Disorders of uric acid metabolism include, but are not limited to, polycythemia, myeloid metaplasia, gout, recurrent gout attacks, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lesche-Nyhan syndrome, Kelly-Sigmaller syndrome (hypoxanthineguanine phosphoribosyltransferase deficiency) , kidney disease, kidney stones, kidney failure, inflammation of the joints, arthritis, urolithiasis, saturnism, hyperparathyroidism, psoriasis or sarcoidosis.

The essence of the invention

The present invention provides methods for reducing uric acid levels in one or more tissues or organs, blood, serum, urine, or combinations thereof in an individual in need of uric acid reduction, which include administering to such an individual a uric acid-lowering amount of a compound of the formula ( I), formula (I) or formula (II) or its metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug.

The present invention also provides methods for reducing uric acid production, increasing uric acid excretion, or both in an individual, comprising administering to such an individual a compound of formula (I), formula (II), or formula (II), or a metabolite, a pharmaceutically acceptable salt thereof , solvate, polymorph, ester, tautomer, or prodrug.

The present invention also provides methods of treating an individual suffering from a condition characterized by abnormal tissue levels of uric acid comprising administering to such an individual an effective amount of a compound of formula (I), formula (II) or formula (II) or a metabolite, a pharmaceutically acceptable salt thereof , solvate, polymorph, ester, tautomer, or prodrug. In certain embodiments, the condition is characterized by low tissue levels of uric acid. In further or additional embodiments, the condition is characterized by high tissue levels of uric acid. In further or additional embodiments, the disorder is characterized by excess uric acid production, low uric acid excretion, tumor lysis, blood disorders, or a combination thereof. In further or additional embodiments, the blood disorder is polycythemia or myeloid metaplasia. In further or additional embodiments, the individual in need of lowering the serum uric acid level suffers from gout, recurrent gout attacks, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lesche-Nyhan syndrome, Kelly-Sigmiller syndrome ( hypoxanthineguanine phosphoribosyltransferase deficiency), kidney disease, kidney stones, kidney failure, inflammation of the joints, arthritis, urolithiasis, saturnism, hyperparathyroidism, psoriasis or sarcoidosis. In certain preferred embodiments, the condition is gout. In certain embodiments, the condition is joint inflammation that causes uric acid crystals to deposit in the joints. In further or additional embodiments, uric acid crystals are deposited in the joint fluid (synovial fluid) or in the lining of the joint (synovial lining).

The present invention also provides methods of treating or preventing hyperuricemia in an individual, which include administering to such an individual an effective amount of a compound of formula (I), formula (II) or formula (II) or a metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer thereof or pro-drugs, wherein said amount is effective in reducing uric acid levels.

The present invention also provides methods of treating or preventing a condition characterized by abnormal tissue levels of uric acid in an individual at increased risk of developing the condition, which comprise administering to such an individual an effective amount of a compound of formula (I), formula (I) or formula (II) or its metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug. In further or additional embodiments, the condition is polycythemia, myeloid metaplasia, gout, recurrent gout attacks, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lechet syndrome

Nyhan, Kelly-Sigmailler syndrome (hypoxanthineguanine phosphoribosyltransferase deficiency), kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, saturnism, hyperparathyroidism, psoriasis, or sarcoidosis. In certain preferred embodiments, the condition is gout. In certain embodiments, the condition is inflammation of the joints caused by the deposition of uric acid crystals in the joints. In further or additional embodiments, uric acid crystals are deposited in the joint fluid (synovial fluid) or in the lining of the joint (synovial lining).

The present invention also provides methods of treatment or prevention of polycythemia, myeloid metaplasia, gout, recurrent gout attacks, gouty arthritis, hyperuricemia, hypertension,

cardiovascular disease, coronary heart disease, Lesche-Nyhan syndrome, Kelly syndrome

Sigmiller's disease, kidney disease, kidney stones, kidney failure, arthritis, arthritis, urolithiasis, saturnism, hyperparathyroidism, psoriasis or sarcoidosis in an individual, comprising administering to such an individual an effective amount of a compound of formula (I), formula (II) or formula (II) or its metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug. In preferred embodiments, the present invention provides methods of treating gout comprising administering to an individual an effective amount of a compound of formula (1), formula (I) or formula (I) or a metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or pro - medicines

The present invention also provides methods of preventing the formation or reduction of gouty joint deposits in an individual, which comprise administering to such an individual an effective amount of a compound of formula (I), formula (II) or formula (I) or a metabolite, pharmaceutically acceptable salt, solvate, polymorph thereof , ester, tautomer or prodrug.

The present invention also provides methods of reducing uric acid levels in one or more tissues or organs, blood, serum, urine, or combinations thereof in an individual, comprising administering to such an individual an amount of a compound of formula (I), formula (II) or formula (II) capable of reducing uric acid levels. of formula (II) or its metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug, wherein this reduction in uric acid levels results in amelioration of hypertension or cardiovascular events.

The present invention also offers methods of treating hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency in an individual, which include administering to such an individual a compound of formula (I), formula (II) or formula (II) or its metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester , tautomer or prodrug.

In certain embodiments, the methods described above additionally include the administration of a second drug effective in the treatment of the relevant condition. In further or additional embodiments, this second drug is effective in reducing tissue levels of uric acid. In further or additional embodiments, this second drug is a non-steroidal anti-inflammatory drug (NSAID), colchicine, corticosteroid, adrenocorticotropic hormone (ACTH), probenecid, sulfinpyrazone, allopurinol, febuxostat, EUH-051 (4-(5-pyridin-4-yl- 1H-P2,4|)griazol-3-yl)pyridine-2-carbonitrile) or their combinations.

In certain embodiments, the methods described above additionally include the administration of a second drug effective in the treatment of the relevant condition. In certain embodiments, this second drug is an OVAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase inhibitor, a xanthine oxidoreductase inhibitor, or combinations thereof. In further or additional embodiments, this second drug is a non-steroidal anti-inflammatory drug (NSAID), colchicine, corticosteroid, adrenocorticotropic hormone (ACTH), probenecid, sulfinpyrazone, allopurinol, febuxostat, EUH-051 (4-(5-pyridin-4-yl- 1H-I(1,2,4)griazol-3-yl)upyridin-2-carbonitrile) or their combinations.

Described herein, in certain embodiments, is a method of treating a disorder characterized by abnormal levels of uric acid in the blood and/or urine. In certain embodiments, this method includes the administration of (a) a compound described herein and (B) an OVAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase inhibitor, a xanthine oxidoreductase inhibitor, or combinations thereof. In certain embodiments, this method includes administration of allopurinol, febuxostat, EUH-051 (4-(5-pyridin-4-yl-1H-

1,2,4)griazol-3-yl)pyridine-2-carbonitrile) or their combinations.

In certain embodiments, the methods described above include administration of a compound of formula (1). In further or additional embodiments, the methods described herein include administration of a pharmaceutically acceptable salt of a compound of formula (I). In further or additional embodiments, the methods described herein include administration of a solvate of a compound of formula (I). In further or additional embodiments, the methods described herein include the introduction of a polymorph of the compound of formula (IM. In further or additional embodiments, the methods described herein include the introduction of an ester of the compound of formula (I). In further or additional embodiments, the methods described herein include the introduction of a tautomer of the compound of formula (I). In further or additional embodiments, the methods described herein include administration of a prodrug of a compound of formula (I). In further or additional embodiments, the methods described herein include administration of a metabolite of a compound of formula (I). In further or additional embodiments, this metabolite has structure selected from:

ko v v nose vo di v

H-M OVO alone hmm va v

M Se ii

IN! M ti da "d v m U -N ro "V! 7 V

In further or additional embodiments, this metabolite has a structure selected from: - Mk sne and este

On che choi

Z sk "eh y " "Yuh dH not soon, 2 and and zooon.

In certain embodiments, the methods described herein include administration of a compound of formula (II). In further or additional embodiments, the methods described herein include administration of a pharmaceutically acceptable salt of a compound of formula (I). In further or additional embodiments, the methods described herein include administration of a solvate of a compound of formula (II). In further or additional embodiments, the methods described herein include the introduction of a polymorph of the compound of formula (II). In further or additional embodiments, the methods described herein include the introduction of an ester of the compound of formula (I). In further or additional embodiments, the methods described herein include the introduction of a tautomer of the compound of formula (II). In further or additional embodiments, the methods described herein include administration of a prodrug of a compound of formula (I). In further or additional embodiments, the methods described herein include administration of a metabolite of a compound of formula (II).

In certain embodiments, the methods described herein include administration of a compound of formula (I). In further or additional embodiments, the methods described herein include administration of a pharmaceutically acceptable salt of a compound of formula (II). In further or additional embodiments, the methods described herein include administration of a solvate of a compound of formula (III). In further or additional embodiments, the methods described herein include administration of a polymorph of a compound of formula (IP). In further or additional embodiments, the methods described herein include the administration of an ester of a compound of formula (II). In further or additional embodiments, the methods described herein include the introduction of a tautomer of a compound of formula (IP). In further or additional embodiments, the methods described herein include administration of a prodrug of a compound of formula (I). In further or additional embodiments, the methods described herein include administration of a metabolite of a compound of formula (PP).

In certain embodiments, the individual is a mammal. In further or additional embodiments, the mammal is a human. In certain embodiments, the individual has a disorder characterized by abnormally high levels of uric acid in the individual's body. In further or additional embodiments, such a disorder is characterized by excess uric acid production, low uric acid excretion, tumor lysis, or a blood disorder. In further or additional embodiments, the blood disorder is polycythemia or myeloid metaplasia. In further or additional embodiments, the individual in need of lowering the serum uric acid level suffers from gout, recurrent gout attacks, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, syndrome

Lesche-Nyhan syndrome, Kelly-Sigmailler syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, saturnism, hyperparathyroidism, psoriasis, or sarcoidosis.

In further or additional embodiments, uric acid levels are reduced by at least about 5595. In further or additional embodiments, uric acid levels are reduced by at least about 10 95. In further or additional embodiments, uric acid levels are reduced by at least about 15 95. In further or additional embodiments, uric acid levels are reduced by at least about 15 95. in additional embodiments, uric acid levels are reduced by at least about 20 95. In further or additional embodiments, uric acid levels are reduced by at least about 25 95. In further or additional embodiments, uric acid levels are reduced by at least about 3095. In further or additional embodiments, uric acid levels are reduced by at least about 40 95. In further or additional embodiments, uric acid levels are reduced by at least about 50 95. In further or additional embodiments, uric acid levels are reduced by at least about 6 0 95. In further or additional embodiments, uric acid levels are reduced by at least about 75 95. In further or additional embodiments, blood uric acid levels are reduced by at least about 0.5 mg/dL. In further or additional embodiments, blood uric acid levels are reduced by at least about 1 mg/dL. In further or additional embodiments, blood uric acid levels are reduced by at least about 1.5 mg/dL. In further or additional embodiments, blood uric acid levels are reduced by at least about 2 mg/dL. In further or additional embodiments, blood uric acid levels are reduced by at least about 2.5 mg/dL.

In further or additional embodiments, the tissue or organ is blood, serum, or plasma.

The present invention also relates to pharmaceutical compositions containing an effective amount of a compound described herein or its metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug. In certain embodiments, such pharmaceutical compositions additionally contain a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical compositions described herein contain adjuvants, excipients, preservatives, absorption delaying agents, fillers, binders, adsorbents, buffers, disintegrating agents, solubilizing agents, other carriers, other inert ingredients, or their combinations In certain embodiments, the pharmaceutical composition is in a form suitable for oral administration. In further or additional variants of implementation, the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, drug with delayed release, solution, suspension, for parenteral injection - as a sterile solution, suspension or emulsion, for local administration - as an ointment or cream or for rectal administration -- as a suppository. In further or additional embodiments, the pharmaceutical composition is in a dosage form intended for single administration of precise doses. In further or additional embodiments, the amount of the compound of formula (I) ranges from about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments, the amount of the compound of formula (I) ranges from about 0.5 to about 50 mg/kg/day. In further or additional embodiments, the amount of the compound of formula (I) is from about 0.001 to about 7 g/day. In further or additional embodiments, the amount of the compound of formula (I) is from 0.002 to about 6 g/day. In further or additional embodiments, the amount of the compound of formula (I) is from about 0.005 to about 5 g/day. In further or additional embodiments, the amount of the compound of formula (I) is from about 0.01 to about 5 g/day. In further or additional embodiments, the amount of the compound of formula (I) is from about 0.02 to about 5 g/day. In further or additional embodiments, the amount of the compound of formula (I) is from about 0.05 to about 2.5 g/day. In further or additional embodiments, the amount of the compound of formula (I) is from about 0.1 to about 1 g/day. In further or additional embodiments, dose levels below the lower end of the above range are more than sufficient. In further or additional embodiments, dose levels higher than the upper limit of the above range are required. In further or additional embodiments, the compound of formula (I) is administered as a single dose once daily. In further or additional embodiments, the compound of formula (I) is administered in multiple doses, more than once a day. In further or additional embodiments, the compound of formula (I) is administered twice a day. In further or additional embodiments, the compound of formula (I) is administered three times a day.

In further or additional embodiments, the compound of formula (I) is administered four times a day. In further or additional embodiments, the compound of formula (I) is administered more than four times a day. In certain embodiments, such a pharmaceutical composition is intended for administration to a mammal. In further or additional embodiments, the mammal is a human. In further or additional embodiments, such a pharmaceutical composition additionally contains a pharmaceutical carrier, auxiliary substance and/or adjuvant. In further or additional embodiments, such a pharmaceutical composition additionally contains at least one therapeutic drug.

In certain embodiments, pharmaceutical compositions are used to reduce uric acid levels. In further or additional embodiments, pharmaceutical compositions are used to alleviate hypertension or cardiovascular events.

In certain embodiments, the pharmaceutical compositions contain a compound of formula (I), formula (II) or formula (III) thereof or a metabolite thereof, a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug; and iii) optionally, one or more pharmaceutically acceptable carriers.

In further or additional embodiments, the amount of the compound of formula (I), formula (II) or formula (II) is sufficient to reduce uric acid levels.

In further or additional embodiments, pharmaceutical compositions contain a compound of formula (I), formula (II) or formula (II) or its metabolite, a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug; ii) SHVAT 1 inhibitor, xanthine oxidase inhibitor, xanthine dehydrogenase inhibitor, xanthine oxidoreductase inhibitor or their combinations; and iii) optionally, one or more pharmaceutically acceptable carriers.

In further or additional embodiments, pharmaceutical compositions contain: its compound of formula (I), formula (II) or formula (III) or its metabolite, a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug; ii) allopurinol, febuxostat, EMH-051 (4-(5-pyridin-4-yl-1H-(11,2,4|)griazol-3-yl)pyridine-2-carbonitrile) or their combinations; and iii) optionally, one or more pharmaceutically acceptable carriers.

The present invention also offers pharmaceutical compositions suitable for the treatment of edema and hypertension, which also maintain uric acid levels at pre-treatment levels or cause a decrease in uric acid levels, which contain: i) an antihypertensive drug; ii) maintaining or lowering the level of uric acid, the amount of the compound of formula (I), formula (II) or formula (III) or its metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug; and iii) optionally, one or more pharmaceutically acceptable carriers.

The present invention also provides pharmaceutical compositions suitable for the treatment of cancer, which also maintain uric acid levels at pre-treatment levels or cause a decrease in uric acid levels, which contain: i) an anti-cancer drug; ii) maintaining or lowering the level of uric acid, the amount of the compound of formula (I), formula (II) or formula (III) or its metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug; and iii) optionally, one or more pharmaceutically acceptable carriers.

The present invention also offers pharmaceutical compositions suitable for mitigating the side effects of chemotherapy in an oncological patient, which contain: i) maintaining or lowering the level of uric acid, the amount of the compound of formula (I), formula (II) or formula (III) or its metabolite, a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug; and iii) optionally, one or more optionally acceptable carriers; where the indicated side effects are associated with increased levels of uric acid.

In certain embodiments, pharmaceutical compositions contain a metabolite of a compound of formula (I), formula (II) or formula (PP).

In certain embodiments, this metabolite has a structure selected from

Ko v no nor Vo x-M 3 ve da Be ve x-M vi" Shi: ve?

Zh o Zh I

Dn pish and do sia "V k M ozh vit V"

And. E t i ve v o. x 2

In certain embodiments, this metabolite has a structure selected from:

: - - Mk ps me VM V8N

Av on SHCI re o

OS Oh nm. yes we are oh she sooN, ' and "ooon,

According to one aspect of the present invention, there is provided a compound of formula (I) or its metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug:

KZ vk ra o. -x M ak i

And. ' re M Shi: | formula re () and the point re where:

X-cesSNabo M,

MU is 0, 5, 5(0), 5(0)2, МН, M (optionally substituted alkyl),

MS(O) (optionally substituted alkyl) or CH5g;

BA is Н, СИ, ВГ, И, МНе, methyl, ethyl, p-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted p-propyl, optionally substituted II-propyl, СЕз, СНЕ» or СНоЕ ;

BZ and E" are independently selected from H and lower alkyl, or BZ and KU, together with the carbon atom to which they are attached, form a 4-, 5- or b-membered ring, which optionally contains 1 or 2 heteroatoms selected from M , Bi 0;

B" is H, lower alkyl, lower alkenyl or lower alkynyl;

B", VU, NE, Ve and K" are independently selected from H, E, SI, Bg, I, methyl, ethyl, p-propyl, i-propyl, substituted methyl, substituted ethyl, substituted p-propyl, substituted i- propyl, cyclopropyl, cyclobutyl, cyclopentyl, SEz, СНЕ», СНеЕ, МНг, МНЕА», MAV», ОВ, ЗА, С(О)Б', СОН, СОН salts,

SOOV', SOMN»:, SOMN", SOMA B", 5OzZN, salts of 5OzZN, 5(O)28", 5(O)2MNeg, 5(O)2MNA, 5(O)2MAK", of an aryl or heterocycle, where

E: is H, C.s. alkyl, substituted C.-s. alkyl, where the indicated substitutions are selected from C.s.e., OH, OSi-s. alkyl,

SOS from alkyl, COOH, COOS. from alkyl, МНе, МНС: -from alkyl, M(Сч-from alkyl) (С:и-from alkyl), SOMNO: from alkyl, aryl or heterocycle;

E" is H, C.sub.3 alkyl, substituted C'.sub.3 alkyl, where the specified substitutions are selected from SEz, OH, OS: from alkyl,

SOS from alkyl, COOH, COOS. from alkyl, МНе, МНС: -from alkyl, M(Сч-from alkyl) (Ci-from alkyl), SOMNEO: from alkyl, aryl or heterocycle; or

KE Her AK", together with the nitrogen atom to which they are attached, form a 4-, 5- or b-membered heterocyclic ring;

IN? is selected from the group consisting of (a), (b), (c) and (9):

IN? dent - Oh a rib | in di | . re vO- | riv drya-- -- In i -- with 2 a B: 2 -y in? c-rV in? Kk ee ve eR dz rrnfya

Ca) (c) (c) (a where: y-ya-5 represents a carbon-carbon single bond or a carbon-carbon double bond

O and 0" are independently chosen from M and CH;

B is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl;

AV, W i KE? are independently selected from Н, Е, СИ, Ви, CH3, СЕ3, СЕНг, СЕН, ethyl, i-propyl, cyclopropyl, methoxy, ОН, ОСЕ3, МН» and МНСОН3;

B" is Cl, Bi, I, CH", CE3, methoxy, i-propyl, cyclopropyl, (eg-butyl, cyclobutyl or methyl; and

B"2, BZ, IN ITS Ex is independently H or methyl.

In certain embodiments, X is SEX or M, where Ex is H, lower alkyl, or substituted lower alkyl.

In certain embodiments, B: is (a). In further or additional variants of implementation with: there is (br).

In further or additional variants of implementation of HB: there is (c). In further or additional variants of the implementation of the VZ: there is (4).

In further or additional embodiments, the HVR is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In further or additional implementation options, No, B? and B" is N.

In further or additional variants of the implementation of B? is (a) and BP is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In further or additional embodiments, B: is (a), B" is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and No, B?" and VZ is N.

In certain embodiments, X is M. In further or additional embodiments, X is CH. In further or additional embodiments, X is C-lower alkyl. In certain variants of implementation of UU/ is O. In further or additional variants of implementation of MU is 5. In certain variants of implementation of B" is Si,

Bg, I, methyl, ethyl, n-propyl or i-propyl. In certain embodiments, NU, B, and B" are N. In further or additional embodiments, X is M; MU is O or 5; B! is Si, Bg, or I, and VU, B, and Ve are N. In certain embodiments, YAN"? is SI, Bg or I. In certain embodiments, НА is H. In further or additional embodiments, B? is Si, Bg or I, and B? is H. In further or additional embodiments, B" is SON, salt СО2Н or СОН". In further or additional variants of implementation of B" is

SON, a salt of SON or SOORN and ER is N. In further or additional embodiments, B: is Si, Bg or

And, A" is SON, a salt of SON or COOR: and is not H. In further or additional embodiments, P: is Si,

Vie is SON, a salt of SON and is N. In further or additional embodiments, X is M, MU is O or 5,

IN! is SI, Bg or I, BZ is H, B" is H, B: is SI, Bg or I, is not H and B" is SON, CO»-H salt or SOOBB'.

In certain embodiments, the compound of formula (I) is 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-A4H-I, 2,4-triazol-3-ylthioacetamido)-3-chlorobenzoin acid or its metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug:

ЖАД Я and тва Я , o che 7

In certain embodiments, the compound of formula (I) is the metabolite 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-Y, 2,4-triazol-3-ylthioacetamido)-3- chlorobenzoic acid.

In further or additional embodiments, this metabolite has a structure selected from:

Pho; ovo no ra NOM. And NM.

A: both sleep A and ve "sleep,

In one aspect of the present invention, there is provided a compound of formula (II) or its metabolite, pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug: x-mM VZ

Ххх о m мы ше

I re On formula (PP)

where:

X-cesSNabo M,

MU is 0, 5, 5(0), 5(0)2, МН, M (optionally substituted alkyl),

MS(O) (optionally substituted alkyl) or CH5g;

A' is Н, СИ, ВГ, И, МН», methyl, ethyl, p-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted p-propyl, optionally substituted I-propyl, СЕз, СНЕ» or СНоЕ;

BZ and E7 are independently selected from H and lower alkyl, or KZ and KU, together with the carbon atom to which they are attached, form a 4-, 5- or b-membered ring, which optionally contains 1 or 2 heteroatoms selected from M, Bi;

B: is selected from the group containing (a), (B), (c) and (4): zvalltch advance a ro A i ta do | Re to to I --d8 dIo-. | -Z dv vi -8 di se 2-X i: o she: heh z 12

With a | К в и и К к в в в д (c) (c) (c) (9) where: --i- represents a carbon-carbon single bond or a carbon-carbon double bond;

O and 0" are independently chosen from M and CH;

BP is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl;

AV, W i KE? are independently selected from Н, Е, СИ, Ви, CH3, СЕ3, СЕНг, СЕН, ethyl, i-propyl, cyclopropyl, methoxy, ОН, ОСЕ3, МН» and МНСОН3;

B" is Cl, Be, I, CH3, CE3, methoxy, i-propyl, cyclopropyl, (eg-butyl, cyclobutyl or methyl; and

B, BZ, B1a and B15 are independently H or methyl.

In certain embodiments, X is M. In other embodiments, MU is 5 or 0. eta | - thank you! KR and;

In one aspect of the present invention HB? is (a)! - In one aspect, t-k represents a carbon-carbon double bond. In certain embodiments, the BP is cyclopropyl.

In certain embodiments, X is M; MU is 5; and K! is SI, Vg, I. optionally substituted methyl, SEz,

СНЕ»: or СНоЕ.

In certain embodiments, the VZ and the short circuit are not H. In one aspect, the VZ and the short circuit are H.

In certain embodiments, NU and KU, together with the carbon atom to which they are attached, form a 4-, 5-, or b-membered ring, which optionally contains 1 or 2 heteroatoms selected from M, 5 and

A. In certain other embodiments, VZ and KU, together with the carbon atom to which they are attached, form a 4-, 5-, or b-membered ring.

In one aspect, provided herein is a compound of formula (II), wherein the compound of formula (II) is a C-substituted 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole, wherein the substitution in the C3-position is -AB or a pharmaceutically acceptable salt, solvate or tautomer thereof: where

AB is -5CH2C(O)Vya, -5CHNe-tetrazolyl, -5CH2C(-O)MNON, -5CHneC(-O0)O-alkyl-OC(-O)Ka, --

ЗСНгС(О)О-аклы-ОС(-О0)ОКЗа, -ЗХСНгС(-О)О-alkyl-ОС(О)MAА» or - BSNoС(Oalkyl)»z;

And is there Ov2a, 58Za, MAL?" at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, polyethylene glycol, or a combination thereof, where

Ba is substituted C1-C6 alkyl, optionally substituted C5-C0 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or is a pharmaceutically acceptable cation; or if there is -С(ВХАЬ) that; dza is hydrogen, optionally substituted C1-C:0 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; or

Aza is С(В5а) (Ве) pes;

Va is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; and

IN? is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; or des -IS(Bzau(ve) p de; each Ka is independently hydrogen, halogen, cyano, nitro, at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, polyethylene glycol, -I -OH, -I -5H, -I-MH". substituted -I -C1-C3 alkyl, optionally substituted -Y - b4-Co alkyl, optionally substituted 1-C2-C5 alkenyl, optionally substituted 1-b2-C5 alkynyl, optionally substituted 1-C2-C5 heteroalkyl, optionally substituted -І-б3-С7 cycloalkyl, optionally substituted I -С3з-С7 cycloalkenyl, optionally substituted -І -С3з-С7 heterocycloalkyl, optionally substituted -І -С1-С4 haloalkyl, optionally substituted -І -

Ci-C4 alkoxy, optionally substituted -I-Ci-C4 alkylamine, optionally substituted -I -di-(C1-

Sal)alkylamine, optionally substituted -Y-C5-C7 aryl, optionally substituted -1I-C5-C7 heteroaryl, c and cs

Each KZ is independently hydrogen, halogen, cyano, nitro, at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, polyethylene glycol, -I -OH, -I -5H, -I -MH", substituted -I -C1-C3 alkyl, optionally substituted -Y - b4-C0 alkyl, optionally substituted 1-C2-C5 alkenyl, optionally substituted 1-B2-C5 alkynyl, optionally substituted 1-C2-C5 heteroalkyl, optionally substituted -Y -b3-C7 cycloalkyl, optionally substituted I -C3z-C7 cycloalkenyl, optionally substituted -I -C3z-C7 heterocycloalkyl, optionally substituted -I -C1-C4 haloalkyl, optionally substituted -I -

Ci-C4 alkoxy, optionally substituted -I-Ci-C4 alkylamine, optionally substituted -I -di-(C1-

Sal)alkylamine, optionally substituted -Y-C5-C7 aryl, optionally substituted -1I-C5-C7 heteroaryl, poi ! F

I'm broken

Ve is hydrogen, halogen, cyano, nitro, at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, polyethylene glycol, -I -OH, -I-5H, -I-MNe, substituted -1Y-Si -C3 alkyl, optionally substituted -1-C4-C0 alkyl, optionally substituted 1-C2-C5 alkenyl, optionally substituted 1-C2-C6 alkynyl, optionally substituted I-C2-C5 heteroalkyl, optionally substituted -Y-C3z-C7 cycloalkyl , optionally substituted 1-C3z-C7 cycloalkenyl, optionally substituted /--Y-03-C7 heterocycloalkyl, optionally substituted -I -C1-C4 haloalkyl, optionally substituted -I -

Ci-C4 alkoxy, optionally substituted -I-Ci-C4 alkylamine, optionally substituted -I -di-(C1-

Cl)alkylamine, optionally substituted -I/-C5-C7 aryl, optionally substituted --I-C5-C7 heteroaryl. ; ay! F - Art of the eye in

In shk and or:

where G. is a bond, -С(О)-, -5(0) or -5(0)2; ut is 0,1,2 or 3;

In is OH, OMe, COOH, 5OZN, О5О0zH, О5(0)2MH», P(IOHON)g, OR(IOHON)», OR(IOHONHO-C: 4 alkyl) or MU2gUZUuya: where ug and "3, each independently is hydrogen or methyl; or UZ: and UZ are taken together with the nitrogen atom to which they are attached to form a 5- or b-membered ring which optionally contains an oxygen atom or a second nitrogen atom; and

U" is an electron pair or an oxygen atom; is 1, 2, 3 or 4; is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; where, when ha is -IS(Hza)( V»»)|piVese, then at least one of INza, Ve» and

To: is not hydrogen.

In certain embodiments, B is at least one amino acid. In certain embodiments, the HB is a peptide. In certain embodiments, is not a lipid. In certain embodiments, B is a phospholipid. In certain embodiments, B'g is a glycoside. In certain embodiments, B": is a nucleoside. In certain embodiments, B": is a nucleotide. In certain embodiments, B": is polyethylene glycol.

In certain embodiments, B": is a combination of one or more groups selected from at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, and polyethylene glycol. In certain embodiments, one or more HB groups are covalently linked In certain embodiments, one or more B": groups form a conjugate.

In certain embodiments, Ka is OMKZ2a,

In certain embodiments, B22 is substituted C:1-Ca4 alkyl or optionally substituted C5-

Hundred alkyl. In certain embodiments, Na is a pharmaceutically acceptable cation. In certain embodiments, Ne is a pharmaceutically acceptable cation selected from Hy, Ma", K", Md", Ca- and a protonated amine.

In certain embodiments, Ne is -IS(8a)(Be)|n As; t is 1, 2, Z, 4; and where at least one of Va,

AR and where: is not hydrogen. In certain embodiments, B: is hydrogen, B? is hydrogen, and B: is not hydrogen.

In certain embodiments, Ne is at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, or polyethylene glycol.

In certain embodiments, No is 5NHa. In certain embodiments, Na is optionally substituted C1-C10 alkyl.

In certain embodiments, Nza is -IS(Nza)(A5eAc,

In certain embodiments, He: is hydrogen, Be is hydrogen, and HB: is not hydrogen. In certain embodiments, Be is at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, or polyethylene glycol.

In certain embodiments, B" is MIALadE,

In certain embodiments, B": is hydrogen. In certain embodiments, B" is hydrogen. is optionally substituted alkyl. In certain embodiments, B" is -IS(B22)(B"») As,

In certain embodiments, the implementation of Is not hydrogen, BP? is hydrogen and Ve is not hydrogen. In certain embodiments, Still is at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, or polyethylene glycol.

In certain variants of implementation of BB are -5С20Н2С(-0О)ВЯ, -5СНео-tetrazolyl, -5С0Н2С(-О)МНОН, -

ЗСНгО(-О)О-alkyl-ОС(О)НЗа, -БСН2С(-0)О-alkyl-ХОС(-О0)О Na, -5СН2хС(-0)О-alkyl-ОС(-О)MAaВ or - ZSNegb (Oalkyl)»z;

AB is OB2a, MAV, at least one amino acid, peptide or glycoside;

Ba is substituted C1-C6 alkyl, optionally substituted C5-C0 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or dgag is a pharmaceutically acceptable cation;

Dza is hydrogen, optionally substituted C1-C:10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;

Va is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; and

IN? is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

In certain variants of the implementation of the VU is -5С20Н2С(-0)Н". In certain variants of the implementation of the VU is -

ZSNgF(-O) - at least one amino acid. In certain embodiments, the BB is -"5CH2C(-0O)-lysine. In certain embodiments, the WU is ib-5CH2C(-O)-glycoside. In certain variants of the implementation of the BB there are -

ЗСН2ОС(-Ф)О-glucuronide. In certain embodiments, the WU is -"5CH-tetrazolyl. In certain embodiments, the BB is -5CH2C(-O)MNON. In certain variants of implementation of BB is -BSN2C(-0)O-alkyl-OS(-O) VZA,

In certain variants of the implementation of -"5СН2С(-0)0О-СН"-ОС(-О)В8ЗА, In certain variants of the implementation of BB iv-

ЗСНгО(-0)0-СН(СН3)-ОС(-О)ВХ, In certain variants of the implementation of BB, there is -5СН2С(-0)0-СН»-ОС(-О)О ВХ,

In certain variants of the implementation of B? is - 5СН»С(-0)0О-СН(СНзи)-ОС(-0)ОВА. In one aspect of the present invention, BB is -50H»C(Oalkyl)z.

In one aspect, EC is OH2a, in another aspect, Ka is MALadeV,

One aspect of the present invention provides a method for reducing uric acid levels in one or more tissues or organs, blood, serum, urine, or combinations thereof in an individual in need of uric acid reduction, which comprises administering to the individual an amount capable of reducing uric acid levels: () compounds of formula (I); or (i) compounds of formula (II); Or (iii) compounds of formula (II); or (im) their combinations.

In one aspect of the present invention, lowering uric acid levels leads to attenuation of hypertension or cardiovascular events.

In one aspect, the method comprises administering one or more metabolites of a compound of formula (I).

In one aspect, the compound of formula (I) is 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthioacetamido)-3-chlorobenzoic acid or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer, or prodrug thereof.

In one aspect, the compound of formula (II) is 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid or a pharmaceutically acceptable metabolite thereof salt, solvate, ester, tautomer, or prodrug.

In certain embodiments, the proposed method includes administering to an individual a compound of the formula (IP) or its metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer, or prodrug.

In certain embodiments, the proposed method includes administering to an individual a compound of formula (II), where the compound of formula (II) is 3,5-disubstituted-4-(4-He-naphthalen-1-yl)-4H-1,2,4- triazole, wherein the substitution in the 3-position is BP and the substitution in the 5-position is -B", or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer, or prodrug thereof.

In certain variants of implementation, the proposed method includes administration to an individual of a compound of formula (I), where the compound of formula (II) is 3-substituted-4-(4-dcyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole, where the substitution in the C-position is -NU, or its metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer, or prodrug.

In certain embodiments, the proposed method includes administering to an individual a compound of formula (I), or its metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer, or prodrug.

In one aspect of the present invention, a method of treating or preventing a condition in an individual characterized by abnormal levels of uric acid in tissues or organs is proposed, which includes administering to the individual an effective amount of: () compounds of formula (I); or (i) compounds of formula (II); or (ii) compounds of formula (II); or (im) their combinations.

In certain embodiments, the condition is gout, recurrent gout attacks, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lechet syndrome

Nyhan, Kelly-Sigmailler syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, saturnism, hyperparathyroidism, psoriasis or sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPAT) deficiency, or a combination thereof.

In one aspect of the invention, the condition is gout. In certain embodiments, the proposed method additionally includes administration of an additional drug effective in the treatment of gout. In certain embodiments, this additional drug is allopurinol, febuxostat, EUH-051 (4-(5-pyridin-4-yl-1H-(1,2,Agriazol-3-yl)pyridin-2-carbonitrile) or combinations thereof.

In one aspect of the present invention, a method of treating or preventing cancer is proposed, which also maintains uric acid levels at pretreatment levels or causes a decrease in uric acid levels, which includes the administration of: a) an effective amount of an anticancer drug; p) able to maintain or reduce the level of uric acid amount () compound of formula (I); or (i) compounds of formula (II); or (ii) compounds of formula (II); or (im) their combinations.

In one aspect of the present invention, a pharmaceutical composition is proposed, which contains: () a compound of formula (I); or (i) a compound of formula (II); or (ii) a compound of formula (II); or (im) a combination of (her), (her) and (her); and (m) optionally, one or more pharmaceutically acceptable carriers.

In certain embodiments, this pharmaceutical composition additionally contains allopurinol, febuxostat, EMUH-051 (4-(5-pyridin-4-yl-1H-11,2,4)triazol-3-ylpyridine-2-carbonitrile) or combinations thereof.

In this description, the groups and their substitutions are chosen by a person skilled in the art in such a way as to provide stable substances and compounds.

A brief description of the drawings

Distinctive features of this invention are detailed in the appended claims. For a better understanding of the features and advantages of this invention, the following detailed description of illustrative embodiments embodying the principles of the invention includes reference to the accompanying drawings, in which:

In Fig. 1 shows the levels of uric acid in serum (mg/dL) 0, 3, 7 and 14 days after administration of 4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2 ,4-triazol-3-ylthioacetamido)-3-chlorobenzoic acid in the form of potassium salt for humans in doses of 300 mg, 400 mg or 500 mg 2 times a day.

In Fig. 2 shows the levels of uric acid in serum (pmol/l) 0, 3, 7 and 14 days after administration of 4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2 ,4-triazol-3-ylthioacetamido)-3-chlorobenzoic acid in the form of potassium salt for humans in doses of 300 mg, 400 mg or 500 mg 2 times a day.

In Fig. From the presented changes in serum uric acid levels (mg/dL) 3, 7 and 14 days after administration of 4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2, 4-triazol-3-ylthioacetamido)-3-chlorobenzoic acid in the form of potassium salt for humans in doses of 300 mg, 400 mg or 500 mg 2 times a day.

In Fig. 4 shows changes in serum uric acid levels (μmol/l) 3, 7 and 14 days after administration of 4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2, 4-triazol-3-ylthio)dacetamido)-3-chlorobenzoic acid in the form of potassium salt for humans in doses of 300 mg, 400 mg or 500 mg 2 times a day.

In Fig. 5 shows the changes in the levels of uric acid in the serum (μmol/l) by days of treatment after administration of 4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol- 3-ylthioacetamido)-3-chlorobenzoic acid in the form of potassium salt for humans in doses of 300 mg, 400 mg or 500 mg 2 times a day.

In Fig. 6 shows an increase in the daily excretion of uric acid after oral administration of a solution of 4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid.

Detailed description of the invention

Distinctive features of this invention are detailed in the appended claims.

The following detailed description of illustrative embodiments embodying the principles of the invention is intended for a better understanding of the features and advantages of this invention.

In the following, preferred embodiments of the present invention will be shown and described, but it should be apparent to those skilled in the art that they are provided by way of example only. Numerous variations, changes and substitutions are possible without departing from the spirit and scope of the invention. It should be understood that in the implementation of the present invention, various alternatives to the implementation options described here are possible. This should be understood in the following sense

Claims (1)

the claim defines its scope and that it covers all methods and structures within the scope of this claim, as well as their equivalents. The section headings used herein are for organizational purposes only and are not intended to limit the disclosure of the subject matter of the invention. Chemical terminology Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by those skilled in the art to which the claimed subject matter belongs. In the event that there are multiple definitions for terms, those given in this section take precedence. It should be understood that the foregoing general description and the following detailed description are illustrative and explanatory only and do not limit any of the claimed objects of the invention. In this application, the use of the singular includes the plural unless specifically indicated otherwise. It should be noted that, as used in the description and claims, the singular forms include the plural unless the context clearly indicates otherwise. It should also be noted that the use of "or" means "and/or" unless otherwise indicated. Moreover, the use of the term "including" as well as other forms such as "include", "includes" and "included" are not limiting. Definitions of standard chemical terms can be found in reference books, including Sageu apa Ziparegu "AOMAMSEO OVOSAMIS SNEMI5TAM 4 EO." Volume A (2000) and Volume B (2001), Riepyt Rgev5, Mem UoZhK. When not indicated otherwise, conventional methods of mass spectroscopy, NMR, HPLC, IR and UV/Visual spectroscopy and pharmacology are used, within the knowledge of specialists in this field. When no specific definitions are given, the nomenclature used here is the standard definitions. Standard methods can be used for chemical synthesis, chemical analysis, pharmaceuticals, drug formulation and delivery, and for the treatment of individuals. Reactions and purification methods can be carried out, for example, using appropriate kits according to the manufacturer's instructions, or as they are commonly performed in the art or as described herein. In general, the techniques and procedures used may be performed by conventional methods well known in the art and described in various general and more specialized sources cited and discussed herein. In this description, the groups and their substitutions are chosen by a person skilled in the art in such a way as to provide stable substances and compounds. When substitution groups are denoted by conventional chemical formulas written from left to right, they equally cover chemically identical substitutions, which results from writing the structure from right to left. As a non-limiting example, -СНгО- is equivalent to -ОСН»-. Unless otherwise indicated, the use of general chemical terms such as, without limitation, "alkyl", "amine", "aryl" are equivalent to their optionally substituted forms. For example, "alkyl" as used herein includes optionally substituted alkyl. In certain embodiments, the compounds disclosed herein possess one or more stereocenters. In certain embodiments, the stereocenter is in the AB configuration, the 5 configuration, or a combination of configurations. In certain embodiments, the compounds presented herein have one or more double bonds. the compounds presented herein possess one or more double bonds, where each double bond exists in the E (Mapv) or 7 (cm) configuration or has a combination of configurations. When referring to one particular stereoisomer, regioisomer, diastereomer, enantiomer, or epimer, it should be understood to include all possible stereoisomers, regioisomers, diastereomers, enantiomers, or epimers and mixtures thereof. Therefore, the compounds presented herein include all individual configurational stereoisomeric, regioisomeric, diastereomeric, enantiomeric or epimeric forms, as well as their respective mixtures. Methods for inverting or leaving unchanged a particular stereocenter and methods for separating mixtures of stereoisomers can be found, for example, in the encyclopedia of EPIRB. (united), MOSE 5 EMSUSIGOREOIA OE RVASTISAI OVSAMIS SNEMIZTAU 5.vir.TN EO., Gopdtap 5siepiyis apa TesNnpisa! THIS. Evzekh, 1991, 809-816; and Neieg, Assoc. SKet. Rev. 1990, 23, 128. The terms "fragment", "chemical moiety", "group" and "chemical group", as used herein, refer to a specific segment or functional group of a molecule. Chemical moieties are often referred to as chemical structural units incorporated into or attached to a molecule. The term "reactant" as used herein refers to the nucleophile or electrophile used to form covalent bonds. The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties, when the atoms connected by this bond are considered as part of a larger substructure. The term "optional" or "optionally" means that the event or circumstance described below may or may not occur, and that this description includes both instances when the specified event or circumstance occurs and instances when it does not. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl", as defined below. In addition, an optionally substituted group may be unsubstituted (e.g., -CHnCHbz), fully substituted (e.g., -Ce»Ce3), monosubstituted (e.g., -CHNaCNoE), or substituted at any level between fully substituted and monosubstituted (e.g., -"СНаСНЕ", -СНоСЕ3, -СЕ2СН3, -СЕНСНЕ, etc.). Those skilled in the art will appreciate with respect to any group containing one or more substituents that no substitutions or patterns of substitution have been specifically introduced into such groups (eg, substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including facultatively substituted allelic groups, potentially ai ipijpisht), which is spatially impractical and/or synthetically infeasible. Therefore, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically up to about 500 daltons (except where macromolecular substituents are expressly referred to, e.g. polypeptides, polysaccharides, polyethylene glycols, DNA, RNA, etc.). As these designations are used herein, C-Cx includes C1-C2, C1-Cz... Cb1-Cx. By way of example only, a group designated as "Si-Ce" means that there are from one to four carbon atoms in a given structural unit, that is, groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms, as well as C1-C2 and C1-C3 boundaries. So, just as an example, "Ci-Cg alkyl means that there are from 1 to 4 carbon atoms in the allelic group, that is, the given allelic group is chosen between methyl, ethyl, propyl, isho -propyl, p-butyl, i-butyl, zes-butyl and i-butyl. Whenever a numeric interval such as "1 to 10" occurs here, it means that it refers to every integer in that interval; for example "from 1 to 10 carbon atoms" means that this group can have 1 carbon atom, 2 carbon atoms, C carbon atoms, 4 carbon atoms, 5 carbon atoms, b carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 atoms carbon or 10 carbon atoms. The term "lower" as used herein in combination with alkyl, alkenyl, or alkynyl (ie, "lower alkyl," "lower alkenyl," or "lower alkynyl") refers to optionally substituted with a straight chain or optionally substituted with a branched chain saturated hydrocarbon monoradical having from one to about six carbon atoms, preferably from one to three carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2 -methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-Tpentyl, 4-methyl-1-repyl, 2-methyl-2-pentyl, 3-methyl -2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, s-butyl , 1-butyl, p-pentyl, isopentyl, neopentyl, iep-amyl and hexyl. The term "hydrocarbon", as used herein alone or in combination, refers to a compound or chemical group that contains only carbon and hydrogen atoms. The terms "heteroatom" or "hetero", as used herein alone or in combination, refer to any atom other than carbon and hydrogen. Heteroatoms may be independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same or different. The term "alkyl", as used herein alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, preferably from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2 - methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, C -methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-BSu!, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, t-butyl, t-butyl, p-pentyl, isopentyl, neopentyl, t-amyl and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. In all cases where a numerical interval such as "Ci-Ce alkyl or "Ci-Ce alkyl appears, it means that this alkyl group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although this definition also covers the use of the term "alkyl" without an indicated numerical interval. The term "alkylene", as used herein alone or in combination, refers to a diradical derived from the above-defined monoradical, alkyl. Examples include, but are not limited to, methylene (-СНе-), ethylene (-СНаСНе»-), propylene (-СНаСНоСН»-), isopropylene (-СН(СНг)СН5-) and the like. The term "alkenyl" as used herein alone or in combination refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monoradical having one or more carbon-carbon double bonds and having from two to about ten atoms carbon, preferably from two to about six carbon atoms. This group can be in the siz or igap5 conformation with respect to the double bond(s) and includes both isomers. Examples include, but are not limited to, ethenyl (-CH-CHg), 1-propenyl (-CHgCH-CH5", isopropenyl |-C(CH3)-CH3", butenyl, 1,3-butadienyl, and the like. In all cases where a numerical interval such as "C2-C6 alkenyl" or "C2-C6 alkenyl" appears, it means that this alkenyl group may contain 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also covers the use of the term "alkenyl" without an indicated numerical interval. The term "alkenylene", as used herein alone or in combination, refers to a diradical derived from an alkenyl monoradical as defined above. Examples include, but are not limited to, ethenylene (-CH-CH-), isomers of propenylene (eg, -CHgCH-CH- and -C(CH3)-CH-), and the like. The term "alkynyl" as used herein alone or in combination refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from two to about ten atoms carbon, preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiinyl, and the like. In all cases where a numerical interval such as "C2-C8 alkynyl" or "C2-C8 alkynyl" appears, it means that this alkynyl group can contain 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although such a definition also covers the use of the term "alkynyl" without an indicated numerical interval. The term "alkynylene", as used herein alone or in combination, refers to a diradical derived from an alkynyl monoradical as defined above. Examples include, but are not limited to, ethynylene (-SES-), propargylene (-CH2-SES-), and the like. The term "aliphatic", as used herein alone or in combination, refers to an optionally substituted, straight or branched chain, non-cyclic, saturated, partially unsaturated or fully unsaturated non-aromatic hydrocarbon. Therefore, this collective term includes groups such as alkyl, alkenyl and alkynyl. The terms "heteroalkyl," "heteroalkenyl," and "heteroalkynyl," as used herein alone or in combination, refer to optionally substituted alkyl, alkenyl, and alkynyl structures, respectively, as described above, in which one or more backbone carbon atoms (and associated with them hydrogen atoms, as appropriate), are each independently substituted by a heteroatom (ie, an atom other than carbon, such as oxygen, nitrogen, sulfur, silicon, phosphorus, tin, or combinations thereof) or a heteroatomic group, such as -0-0-, -5-5-, -0-5-, - 5-0-, -М-М-, -М-АМ-, -М-М-МН-, -Р(О)2 -, -О-Р(О)е-, - Р(О)2-О-, -5(0)-, -5(0)2-, -ZPNe-, etc. The terms "haloalkyl", "haloalkenyl" and "haloalkynyl", as used herein alone or in combination, refer to optionally substituted alkyl, alkenyl and alkynyl groups, respectively, as described above, in which one or more hydrogen atoms are substituted for fluorine atoms , chlorine, bromine or iodine or a combination thereof. In certain embodiments, two or more hydrogen atoms can be replaced by halogen atoms that are the same (eg, difluoromethyl); in other embodiments, two or more hydrogen atoms may be replaced by halogen atoms that are not the same (eg, 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of haloalkyl groups are fluoromethyl and bromomethyl. A non-limiting example of a haloalkenyl group is bromothenyl. A non-limiting example of a haloalkynyl group is chloroethynyl. The term "perhalo," as used herein alone or in combination, refers to groups in which all of the hydrogen atoms are replaced by fluorine, chlorine, bromine, iodine, or combinations thereof. Thus, by way of non-limiting example, the term "perhaloalkyl" refers to an alkyl group, as defined herein, in which all hydrogen atoms are replaced by fluorine, chlorine, bromine, iodine, or combinations thereof. A non-limiting example of a perhaloalkyl group is bromo-, chloro-, fluoromethyl. A non-limiting example of a perhaloalkenyl group is trichloroethenyl. A non-limiting example of a perhaloalkynyl group is tribromopropynyl. The term "carbon chain", as used herein alone or in combination, refers to any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl group that is linear, cyclic, or any combination thereof. When that chain is part of a linker, and that linker contains one or more rings as part of the core framework, then for purposes of estimating chain length, "chain" includes only those carbon atoms that make up the bottom or top of that ring, not both, but when the top and bottom of the ring(s) are not equivalent in length, the shortest distance should be used to determine the length of the chain. When a chain contains heteroatoms as part of the framework, these atoms are not counted as part of the carbon chain length. The terms "cycle," "cyclic," "ring," and "non-membered ring," as used herein alone or in combination, refer to any covalently closed structure, including acyclic, heterocyclic, aromatic, heteroaromatic, and polycyclic fused or non-articulated ring systems as described herein. Rings can be optionally substituted. Rings can form part of an articulated ring system. The term "n-ch-lens ring" refers to the number of framework atoms that make up the ring. So, just as an example, cyclohexane, pyridine, pyran, and pyrimidine are 6-membered rings, and cyclopentane, pyrrole, tetrahydrofuran, and thiophene are 5-membered rings. The term "membered", as used herein alone or in combination, refers to cyclic structures in which two or more rings share one or more bonds. The term "cycloalkyl", as used herein alone or in combination, refers to an optionally substituted, saturated, hydrocarbon monoradical ring containing from three to about fifteen ring carbon atoms or from three to about ten ring carbon atoms, although it may include additional, non-ring carbon atoms as substitutions (for example, methylcyclopropyl). In all cases where a numerical interval such as "cycloalkylC3-Ce" or "cycloalkylC3-e" appears, it means that this cycloalkyl group may contain 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, i.e. is cyclopropyl, cyclobutyl, cyclopentyl or cycloheptyl, although such a definition also covers the use of the term "cycloalkyl" without an indicated numerical interval. This term includes articulated, non-articulated, bridging and spiro radicals. A membered cycloalkyl may contain from two to four membered rings, where the connecting ring is a cycloalkyl ring and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. Examples include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, decalinyl, and bicyclo(2.2.11 heptyl and adamantyl ring systems. Exemplary examples include, but are not limited to, the following structures: ex.) p.s" cO.SYA.SOYU. CO. etc. The term "cycloalkenyl", as used herein alone or in combination, refers to an optionally substituted, hydrocarbon, non-aromatic, monoradical ring having one or more carbon-carbon double bonds and from three to about twenty ring carbon atoms or from three to approximately ten ring carbon atoms. This term includes fused, non-fused, bridged and spiro radicals. A fused cycloalkenyl may contain from two to four fused rings, where the connecting ring is a cycloalkenyl ring and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. Jointed ring systems can be connected through a bond that is either a carbon-carbon single bond or a carbon-carbon double bond. Examples of cycloalkenyls include, but are not limited to, cyclohexenyl, cyclopentadienyl, and bicyclo(2.2.1|hept-2-ene ring systems. Illustrative examples include, but are not limited to, the following structures: sho 03.0. 3.pa, СО se Du СХ Total. The terms "alicyclyl" or "alicyclic," as used herein alone or in combination, refer to optionally substituted, saturated, partially unsaturated, or fully unsaturated, non-aromatic hydrocarbon ring systems containing from three to about twenty ring carbon atoms or from three to about ten ring carbon atoms. Thus, these collective terms include cycloalkyl and cycloalkenyl groups. The terms "nonaromatic heterocyclyl" and "heteroalicyclyl," as used herein alone or in combination, refer to optionally substituted, saturated, partially unsaturated, or fully unsaturated, nonaromatic, ring monoradicals that contain from three to about twenty ring atoms, where one or more e of these ring atoms is an atom other than carbon independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. In embodiments where two or more heteroatoms are present in the ring, these two or more heteroatoms may be the same or different. These terms include articulated, non-articulated, bridging and spiro radicals. A fused non-aromatic heterocyclic radical may contain from two to four fused rings, where the connecting ring is a non-aromatic heterocycle and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. The articulated ring systems can be connected through a single bond or a double bond, as well as through bonds such as carbon-carbon, carbon-heteroatom or heteroatom-heteroatom. These terms also include radicals having from three to about twelve framework ring atoms, as well as those having from three to ten framework ring atoms. The attachment of a non-aromatic heterocyclic subunit to its parent molecule can be carried out through a heteroatom or a carbon atom. Similarly, additional substitution can be carried out through a heteroatom or a carbon atom. As a non-limiting example, an ap imidazolidine nonaromatic heterocycle can be attached to the parent molecule through its M atoms (imidazolidin-1-yl or imidazolidin-3-yl)y or through any of its carbon atoms (imidazolidin-2-yl, imidazolidine -4-yl or imidazolidin-5-yl. In certain embodiments, non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups, such as, for example, oxo and thio moieties. Examples include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl . , 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolanil, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicycloI3.1.O)hexanyl, 3-azabicycloI|4.1.0)heptanyl, ZH-indolyl and quinolizinyl. Exemplary examples of heterocycloalkyl groups, also called non-aromatic heterocycles, include: A.O OO OO z i vok SYA MO d Kin vm I ky from pool M M M shchi i i o. only CHO, . ; ; M 5 tv Z. bu onyv. re ad (in not in vu ny, sh- S. etc. These terms also include all ring forms of hydrocarbons, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. The term "aromatic" as used herein refers to a planar, cyclic or polycyclic, ring structure having a delocalized n-electron system that contains 4n--21t electrons, where n is an integer. Aromatic rings can be formed by five, six, seven, eight, nine or more than nine atoms. Aromatic compounds may be optionally substituted and may be monocyclic or fused ring polycyclic structures. The term aromatic compound includes both all rings containing carbon (eg, phenyl) and those rings that contain one or more heteroatoms (eg, pyridine). The term "aryl," as used herein alone or in combination, refers to an optionally substituted, aromatic, hydrocarbon radical having from six to about twenty ring carbon atoms and includes fused and unfused aryl rings. A membered aryl ring radical contains from two to four membered rings, where the ring of attachment is an aryl ring and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. Moreover, the term aryl includes articulated and non-articulated rings containing from six to about twelve ring carbon atoms, as well as those containing from six to about ten ring carbon atoms. A non-limiting example of a monocyclic aryl group is phenyl; the articulated ring aryl group includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and an unbranched bi-aryl group includes biphenyl. The term "arylene", as used herein alone or in combination, refers to a diradical derived from the above-described aryl monoradical. Examples include, but are not limited to, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, and the like. The term "heteroaryl," as used herein alone or in combination, refers to optionally substituted, aromatic monoradicals containing from about five to about twenty framework ring atoms, wherein one or more of said ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but not limited to these atoms and provided that the ring of the specified group does not contain two adjacent O or 5 atoms. In those variants of implementation, when two or more are present in the ring heteroatoms, these two or more heteroatoms may be the same or different. The term heteroaryl includes optionally substituted, fused and unfused, heteroaryl radicals having at least one heteroatom. The term heteroaryl also includes articulated and unarticulated heteroaryls having from five to about twelve framework ring atoms, as well as those having from five to about ten framework ring atoms. Bonding to a heteroaryl group can be through a carbon atom or a heteroatom. Thus, as a non-limiting example, an imidazole group can be attached to the parent molecule through any of its carbon atoms (imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl) or its nitrogen atoms (imidazol- 1-yl or imidazol-3-yl). Similarly, a heteroaryl group may be further substituted through any or all of its carbon atoms and/or any or all of its heteroatoms. A fused heteroaryl radical may contain from two to four fused rings, where the ring of attachment is a heteroaromatic ring and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. A non-limiting example of a monocyclic heteroaryl group is pyridyl; articulated ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl; and an unbranched bi-heteroaryl group includes bipyridinyl. Further examples of hetero aryls include, but are not limited to, furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isoizazolidindolyl, , pyridyl, pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, thiadiazolyl, etc., and their oxides such as for example, pyridyl-M-oxide. Exemplary examples of heteroaryl groups include the following structures: Kum, Zm, "v, M, o i 47 Pedeneneneo i i I : ; vdeOpeoshih ve Y: M M M ! 09.00 S Y and M. M, M, hv, te, etc. The term "heteroarylene", as used herein alone or in combination, refers to a diradical derived from a heteroaryl monoradical as defined above. Examples include, but are not limited to, pyridinyl and pyrimidinyl. The term "heterocyclyl", as used herein alone or in combination, refers to heteroalicyclyl and heteroaryl groups together. In this description, when the number of carbon atoms in a heterocycle (for example, a C.-Cv heterocycle) is indicated, at least one non-carbon atom (heteroatom) must be present in the ring. Designations such as "C.1-Ce heterocycle" refer only to the number of carbon atoms in the ring and not to the total number of atoms in the ring. Designations such as "4-6-ene heterocycle" refer to the total number of atoms contained in a ring (ie, a four-membered, five-membered, or six-membered ring in which at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining 2-4 atoms are either carbon atoms or heteroatoms.) When heterocycles have two or more heteroatoms , these two or more heteroatoms may be the same or different. Heterocycles may be optionally substituted. Nonaromatic heterocyclic groups include groups having only three ring atoms, while aromatic heterocyclic groups must have at least five ring atoms. Bonding ( i.e., attachment to the parent molecule or subsequent substitution) with a heterocycle may be via a heteroatom or a carbon atom. The term "carbocyclyl" as used herein is a separate o or in combination refers to jointly alicyclyl and aryl groups; that is, all carbon, covalently closed, ring structures that may be saturated, partially unsaturated, fully unsaturated, or aromatic. Carbocyclic rings can be formed by three, four, five, six, seven, eight, nine or more than nine carbon atoms. Carbocycles can be optionally substituted. This term is intended to differentiate carbocyclic rings from heterocyclic ones, in which the ring framework contains at least one atom other than carbon. The terms "halogen," "halo," or "halide," as used herein alone or in combination, refer to fluorine, chlorine, bromine, and iodine. The term "hydroxy", as used herein alone or in combination, refers to the monoradical - He The term "cyano", as used herein alone or in combination, refers to the -CM monoradical. The term "cyanomethyl", as used herein alone or in combination, refers to the monoradical -CH 2 CM. The term "nitro", as used here alone or in combination, refers to the monoradical - MO". The term "oxy", as used herein alone or in combination, refers to the diradical -O-. The term "oxo", as used herein alone or in combination, refers to the -0 diradical. The term "carbonyl", as used herein alone or in combination, refers to the diradical -C(-9)-, which may also be written as -C(0)-. The terms "carboxy" or "carboxyl," as used herein alone or in combination, refer to the structure -C(FOOH), which may also be written as -COOH. "Alkoxy", as used herein alone or in combination, refers to an alkyl ester radical, -O-alkyl, including -O-aliphatic and -O-carbocyclyl groups, where the alkyl, aliphatic and carbocyclyl groups may be optionally substituted and where the terms alkyl , the alliratic compound and the carbocyclyl are as defined herein. Non-limiting examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, s-butoxy, t-butoxy, and the like. The term "sulfinyl", as used herein alone or in combination, refers to the diradical - 5(-0).-. The term "sulfonyl", as used herein alone or in combination, refers to the diradical - З(2О) 2г-. The terms "sulfonamide", "sulfonamido" and "sulfonamidyl", as used herein alone or in combination, refer to the diradical groups -5(-:0)2-MH- and -MH-5(-0) 2-. The terms "sulfamide," "sulfamido," and "sulfamidyl," as used herein alone or in combination, refer to the diradical groups -МН-5(-0)2-МН-. It should be understood that in cases where two or more radicals are used in succession, in order to define a substitution attached to a structure, the radical named first is considered terminal and the radical named last is considered attached to the structure in question. So, for example, an arylalkyl radical is an alkyl group attached to this structure. As used herein, "3,5-disubstituted 4-(4-He-naphthalen-1-yl)-4H-1,2,4-triazole" refers to: 1 2 "at 5'M, more As used herein, "3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole" refers to: and 2 A Za, Ve a The term "natural" as used herein refers to a group or compound that is present in nature or produced by nature. The term "unnatural" or "unnatural" as used herein refers to a group or compound that is not present in nature and is not produced by nature. An "unnatural" or "unnatural" group or compound is typically produced by human intervention. An "unnatural" or "unnatural" group or compound is artificial. The term "amino acid" as used herein refers to a group or compound that contains an amino group, a carboxyl group, a hydrogen atom and a characteristic B group (or side chain). The term "amino acid" includes α-amino acids, DV-amino acids, β-amino acids and γ-amino acids. (a- Amino acid contains an amino group, a carboxyl group, a hydrogen atom and a characteristic group B, which is connected to a co-carbon atom. The term "amino acid" includes naturally occurring amino acids, unnatural amino acids, amino acid analogs, amino acid mimics, and the like. In one aspect, the term "amino acid" refers to one of the twenty naturally occurring amino acids (ie, α-amino acids), as shown below. Amino acids contain an amino group, a carboxyl group, a hydrogen atom, and a characteristic KE group (or side chain), all of which are bonded to an α-carbon atom. As a result of finding three different groups on one α-carbon atom, amino acids contain a chiral center and, respectively, can exist as either of the two optically active enantiomers, O and Her. Amino acids of natural origin occur as their I -derivatives. T toshve Son non nys nal tooon nako eoon nim SeoOon wk son nim Teron nm ne ssoon voron nam oon Sptusipe dala Mate setspe Ivsyuyusiiv 0 begppa teevopile Suvcte Maopse ooo neon oon SON is in S ta na yan nm beans mA sok NM ON nMm' ssoOon nyam son mmvige Aegoisele Avrayesaiv Sisiagpvka Aaragadite Sidatipe on meh ra son nm Soon nm boyunN NM UN nya soon n Reetuaiie 0 Tugovilv Tpiriyuriaya Nivikytyu Esve In another aspect, an amino acid is an "unnatural amino acid," an "unnatural amino acid," an "amino acid analog," Amino acid imitator". The terms "unnatural amino acid," "unnatural amino acid," "amino acid analog," "amino acid mimetic," and the like, as used herein, refer to an amino acid that is not one of the 20 naturally occurring amino acids. These terms refer to amino acids in which the fundamental amino acid molecule has been modified in some way. Such modifications include, but are not limited to, side chain variations, substitutions or changes in the amino-CH-carboxyl framework, O enantiomers, combinations thereof, etc. These terms also include, but are not limited to, amino acids that occur in nature but are not naturally incorporated into a growing polypeptide chain, such as M-acetylglucosaminyl-I - serine, M-acetylglucosaminyl-I-threonine, O-phosphotyrosine, etc. In addition, these terms include, but are not limited to, amino acids that do not occur in nature, but can be obtained synthetically or by modification of naturally occurring or unnatural amino acids. Illustrative examples of side chain variations include, but are not limited to, O-i-butyl-serine, hydroxyproline, 4-chlorophenylalanine, homoserine, methionine sulfoxide, thienylalanine, and the like. sleigh and Oh Sov | Te " ni seon m son ni en nm ss nm son "m soon OVShu vela Nudtohurgoyne 4Omohorzeapuvialiche nezhpovegle 0/ Matiopipe zukohiia e-epuye aivplee Illustrative examples of framework changes include, but are not limited to, B-amino acids such as rD-alanine, homoproline, alkylation of the amino group, substitution on the α-carbon atom, thiocarboxylic compounds, etc. Ha | and how I over oon ku osyun nu sosok na sleep neon run 0 Motorenivye 00 Atipo aso faith zoryu 0 Tpissafbozhy Peptide can be natural and unnatural and consists of amino acids bound together. The terms "native peptide", "native polypeptide", "native protein" and the like, as used herein, refer to a polymer of naturally occurring amino acid residues linked by covalent peptide bonds and include amino acid chains of any length , including full-length proteins. The terms "unnatural peptide", "peptide mimic", "peptide analogue" and the like, as used herein, refer to a polymer of amino acid residues of any length, including full-length proteins, where one or more of those amino acids is an unnatural amino acid and/or where one or more of those amino acids are chemically attached , other than natural peptide bonds. Illustrative examples of linking groups that can be used as an alternative to a natural peptide bond include, but are not limited to, ethylene (-СНо-СНе-), ethynylene (-«СН-СН-), ketomethylene (-С(- 0)СНе- or -СН2С(-0)-), aminomethylene (- СНо-МН- or -МН-СН»-), methylene ether (-СН»-О- or -0-СнНе-), thioether (- СНе-5- or -5-СНе-), thioamide (-С(-53)МН- or -МН-С(-5)-), ester (-С(-0)0- or О-С( O)-), tetrazole, thiazole, etc. A "nucleoside" is a glycosylamine that consists of a nucleic acid base (often simply called a base) linked to a ribose or deoxyribose sugar. The nucleoside may be a natural nucleoside or an unnatural nucleoside. The term "native nucleotide" as used herein refers to a nucleic acid linked to a ribose or deoxyribose sugar. Examples of such nucleosides include cytidine, uridine, adenosine, guanosine, thymidine, and inosine. H, more about Sem nya in ke kn, cho no i no NO no and NO. in su - sh- | The terms "unnatural nucleoside," "nucleoside analog," and the like, as used herein, refer to a nucleoside that is not one of these six nucleosides. These terms refer to nucleosides in which the fundamental nucleoside molecule has been modified in some way. Such modifications include, but are not limited to, base modifications, sugar modifications, changes in base-sugar linkages, use of other means of stereochemistry; their combinations, etc. The terms "nucleotide", "polynucleotide", "oligonucleotide", "nucleic acid", "nucleic acid polymer", etc. as used herein refer to deoxyribonucleotides, deoxyribonucleosides, ribonucleosides, or ribonucleotides and polymers thereof in single- or double-stranded form, including, but not limited to, (i) analogs of natural nucleotides that have similar binding properties to a reference nucleic acid and are metabolized in a manner similar to natural nucleotides; (ii) oligonucleotide analogs, including, but not limited to, PNA (peptidonucleic acid), DNA analogs used in antisense technology (phosphorothioates, phosphoroamidates, etc.). The term "lipid" as used herein refers to any fat-soluble (lipophilic) naturally occurring molecule such as fats, oils, waxes, cholesterol, sterols, fat-soluble vitamins (such as vitamins A, O, E, and K), monoglycerides, diglycerides, phospholipids, fatty acids, fatty acid esters, etc. Lipids can be natural or unnatural. In one aspect, the lipid is a fatty acid. Fatty acids are saturated and unsaturated. Saturated fatty acids include, but are not limited to, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid. Unsaturated fatty acids include, but are not limited to, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid. A "phospholipid" is a type of lipid that is amphipathic. Phospholipids are a class of lipids and contain a glycerol backbone where two of the hydroxy groups of the glycerol backbone are esterified with a fatty acid (saturated, unsaturated, natural, unnatural) and the third hydroxy group is used to form a phosphate ester with phosphoric acid. The phosphate part of the resulting phosphatidic acid is further esterified with ethanolamine, choline or serine. Phospholipids are natural or unnatural. Natural phospholipids include, but are not limited to, plasmalogen, cardiolipin, dipalmitoylphosphatidylcholine, glycerophospholipid, glycerophosphoric acid, lecithin, lysophosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol(Z3,4)-bisphosphate, phosphatidylinositol/(Z,4,5)-triphosphate, phosphatidylinositol(Z,5)-bisphosphate, phosphatidylinositol (4,5)-bisphosphate, phosphatidylinositol-3-phosphate, phosphatidylinositol 4-phosphate, phosphatidylinositol phosphate, phosphatidylmyo-inositol mannosides, phosphatidylserine, platelet activation factor, sphingomyelin, sphingosyl phosphatide. "Unnatural phospholipids" contain a diglyceride, a phosphate group, and a simple organic molecule such as choline, but are made naturally. "Glycoside" as used herein refers to a group containing any hydrophilic sugar (eg, sucrose, maltose, glucose, glucuronic acid, etc.). A glycoside is a group of any sugar linked through a glycosidic bond. Glycosides include natural glycosides and unnatural glycosides. Glycosides include an asymmetric carbon(s) and exist in either the I-form or the JO-form. Natural glycosides mainly exist in the U-form. Glycosides include monosaccharides, disaccharides, and polysaccharides. Examples of monosaccharides include, but are not limited to, trioses (e.g., glyceraldehyde, dihydroxyacetone), tetroses (e.g., erythrose, threose, erythrulose), pentoses (e.g., arabinose, lyxose, ribose, deoxyribose, xylose, ribulose, xylulose), hexoses (allose , altrose, galactose, glucose, gulose, idose, mannose, talose, fructose, psicose, sorbose, tagatose), heptose (mannoheptulose, sedoheptulose); octoses (for example, octolose, 2-keto-3-deoxy-manno-octonate), nonoses (for example, sialose). Disaccharides include, but are not limited to, sucrose, lactose, maltose, trehalose, cellobiose, coyibiose, nigerose, isomaltose, B,B-trehalose, sophorose, laminaribiosis, gentiobiose, turanose, maltulose, palatinose, gentiobiulose, manobiose, melibiose, melibiulose, rutinose , rutinulosis, xylobiosis. Polysaccharides include glycans. Aza-sugars are also covered by the term "glycoside". The term "polyethylene glycol" refers to linear or branched polymeric polyester polyols. Pharmaceutical terminology The terms "patient," "subject," or "individual" are used interchangeably. They apply to individuals suffering from disorders and the like, including mammals and non-mammalians. None of these terms require that the individual be under the care and/or supervision of a physician. Mammals are any member of the class of mammals, including but not limited to humans, primates such as chimpanzees and other species of great apes and non-great apes; farm animals, such as cattle, horses, sheep, goats, pigs; pets such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, etc. Non-mammalian examples include, but are not limited to, birds, fish, and the like. In certain embodiments of the methods and compositions provided herein, the subject is a mammal. In preferred embodiments, the individual is a human. The terms "treat," "treatment," and other grammatical equivalents, as used herein, include weakening, alleviating, or alleviating a disease or condition or one or more of its symptoms, preventing additional symptoms, alleviating or preventing underlying metabolic causes at the root of the symptoms, such as stopping the progression of the disease or condition, ameliorating the disease or condition, causing regression of the disease or condition, eliminating the condition causing the disease or condition, or stopping the symptoms of the disease or condition, and also include prevention. These terms also include achieving therapeutic benefit and/or prophylactic benefit. Therapeutic benefit refers to the eradication or attenuation of the underlying disorder being treated. In addition, therapeutic benefit is achieved by eradicating or alleviating one or more physiological symptoms associated with the underlying disorder, such that the individual experiences improvement even though he may remain afflicted with the underlying disorder. For prophylactic purposes, the compositions of the present invention are administered to an individual at risk of developing a particular disease, or when the individual reports one or more physiological symptoms of the disease, although the disease has not yet been diagnosed. The terms "administer," "administer," and the like, as used herein, refer to methods that may be used to ensure the delivery of compounds or compositions to the desired site of their biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art are familiar with the methods of administration that can be used with the compounds and methods described herein. In preferred embodiments, the compounds and compositions described herein are administered orally. The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount," as used herein, refer to a sufficient amount of at least one agent or compound to be administered that will attenuate to some extent one or more symptoms of the disease or condition being treated. . The result may be a reduction and/or amelioration of the signs, symptoms or causes of the disease or any other change in the biological system. For example, an "effective amount" for therapeutic applications is that amount of a composition that contains a compound described herein necessary to provide a clinically significant reduction in disease. The specific "effective" amount may vary from one individual to another. A specific "effective" amount can be determined on a case-by-case basis using methods such as dose-escalation studies. The term "acceptable" as used herein, with respect to a drug, composition or ingredient, means the absence of any persistent adverse effect on the general health of the individual being treated. The term "pharmaceutically acceptable" as used herein refers to a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of the compounds described herein and is relatively non-toxic, that is, the material can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it may be contained. The term "pro-drug," as used herein, refers to a prodrug that, upon administration to an individual and subsequent absorption, is converted to an active or more active form by a process such as metabolic conversion. Therefore, this term covers any derivative of a compound which, when administered to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or a pharmaceutically active metabolite or residue thereof. Certain prodrugs contain a chemical group that makes them less active and/or imparts solubility or some other property to the drug. When this chemical group is removed and/or modified, the active drug is formed. Pro-drugs are often useful because they can be easier to administer than the parent drug in certain situations. They may, for example, be bioavailable when administered orally, whereas the parent drug is not. Particular preference is given to those derivatives or prodrugs that increase the bioavailability of the compounds of this invention when such compounds are administered to an individual (eg, by allowing the orally administered compound to be more readily absorbed into the bloodstream) or enhance the delivery of the parent compound to some biological compartment (eg, the brain or the lymphatic system). The term "pharmaceutically acceptable salt" as used herein refers to salts that retain the biological effectiveness of the free acids and bases of a particular compound and that are not biologically or otherwise undesirable. The compounds described herein may contain acidic or basic groups and therefore may react with any of a number of inorganic or organic bases and inorganic or organic acids to form a pharmaceutically acceptable salt. Such salts can be prepared either during the final isolation and purification of the compounds of this invention or by separate reaction of the purified compound in the form of its free base with a suitable organic or inorganic acid and the subsequent separation of the resulting salt. The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component such as, without limitation, carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, auxiliary substances, etc. The term "carrier" as used herein refers to relatively non-toxic chemical compounds or agents that facilitate the incorporation of the compound into cells or tissues. The terms "pharmaceutical combination", "administering additional therapy", "administering additional therapeutic drug" and the like, as used herein, refer to pharmaceutical therapy resulting from the mixing or combination of more than one active ingredient and includes both fixed and and unfixed combinations of active ingredients. The term "fixed combination" means that at least one of the compounds described herein and at least one other drug are administered to an individual simultaneously in the form of a single substance or dose. The term "unfixed combination" means that at least one of the compounds described herein and at least one other drug are administered to an individual as separate substances simultaneously or sequentially at various intervals, when such administration provides effective levels of two or more compounds in the body of the individual. These terms are also applied to combined therapy, for example to the introduction of three or more active ingredients. The terms "simultaneous administration", "administration in combination with" or their grammatical equivalents, etc., as used herein, are intended to encompass the administration of selected therapeutic drugs to a single individual and include regimens in which these drugs are administered by the same or different routes input at the same time or at different times. In certain embodiments, the compounds described herein will be administered concurrently with other drugs. These terms cover the administration of two or more drugs to an animal so that both drugs and/or their metabolites are present in that animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions and/or administration in one composition in which both drugs are present. Thus, in certain embodiments, compounds of the present invention and another drug(s) are administered in the same composition. In certain embodiments, the compounds of this invention and another drug(s) are mixed in a single composition. The term "metabolite" as used herein refers to a derivative of a compound that is formed during the metabolism of that compound. The term "active metabolite" as used herein refers to a biologically active derivative of a compound that is formed during the metabolism of that compound. The term "metabolism," as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions) by which a particular substance is changed in the body. Yes, enzymes can cause specific structural changes in a compound. For example, cytochrome P.50 catalyzes a wide range of oxidation and reduction reactions, while uridine diphosphate glucuronyltransferases catalyze the transition of an activated glucuronic acid molecule into aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from Tne Rnaptasoiodis book! Vaviv oi TNegaretsiisv, ZI Edyop, MeStam-NII (1996). Compounds Described here are compounds of formula I, their metabolites, pharmaceutically acceptable salts, solvates, polymorphs, esters, tautomers, or prodrugs: : X-cesSNor M, MU is 0, 5, 5(0), 5(0)2, MH, M(optionally substituted alkyl), MC(O)(optionally substituted alkyl) or CH5g; BA is Н, СИ, ВГ, И, МНе, methyl, ethyl, p-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted p-propyl, optionally substituted II-propyl, СЕз, СНЕ» or СНоЕ ; BZ and E" are independently selected from H and lower alkyl, or BZ and EU, together with the carbon atom to which they are attached, form a 4-, 5- or b-membered ring, which optionally contains 1 or 2 heteroatoms selected from M , Bi; B" is H, lower alkyl, lower alkenyl or lower alkynyl; B", VU, NE, Ve and K" are independently selected from H, E, SI, Vg, I. methyl, ethyl, p-propyl, i-propyl, substituted methyl, substituted ethyl, substituted p-propyl, substituted i- propyl, cyclopropyl, cyclobutyl, cyclopentyl, SEz, СНЕ», СНеЕ, МНг, МНЕА», MAV», ОВ, ЗА, С(О)Б', СОН, salts СОН, СОов, СОМНег, СОМНА», SOMA' В" . .-from alkyl, where the specified substitutions are selected from SEz, OH, OSi-from alkyl, SOS from alkyl, COOH, COOS. from alkyl, МНе, МНС: -from alkyl, M(Сч-from alkyl) (С:и-from alkyl), SOMNO: from alkyl, aryl or heterocycle; E" is H, C.sub.3 alkyl, substituted C'.sub.3 alkyl, where the specified substitutions are selected from SEz, OH, OS: from alkyl, SOS from alkyl, COOH, COOS from alkyl, MNe, MHC. from alkyl, M(C1-C alkyl)(C:1-C alkyl), SOMNS from alkyl, aryl or heterocycle; or KE Her AK", together with the nitrogen atom to which they are attached, form a 4-, 5- or b-membered heterocyclic ring; B? is selected from the group containing (a), (B), (c) and ( 9): penyu de sh em r vya | - 83 eru» i | -U dv i -V. dy -h sche zak a ze ze z v vih t 9 Ve ve Kk ve pz dy (in) (B) (o) (9) where: en represents a carbon-carbon single bond or a carbon-carbon double bond; O and O" are independently selected from M and CH; B is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl; AV, W i KE? are independently selected from Н, Е, СИ, Ви, CH3, СЕ3, СЕНг, СЕН, ethyl, i-propyl, cyclopropyl, methoxy, ОН, ОСЕ3, МН» and МНСОН3; B" is Cl, Be, I, CH3, CE3, methoxy, i-propyl, cyclopropyl, (eg-butyl, cyclobutyl, or methyl; and B, B3, B1a, and B15 are independently H or methyl. In certain In embodiments, B: is (a).In further or additional embodiments, B? is (5). In further or additional embodiments, MV? is (c). In further or additional embodiments, B: is (a). In further or additional embodiments, Ne is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In further or additional implementation options, NU, B? There are VEIA H. In further or additional embodiments, B: is (a) and BP is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In further or additional embodiments, B: is (a), B is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and NU, B? and Bc is H. In certain embodiments, X is M. In further or additional embodiments, X is CH. In further or additional embodiments, X is C-lower alkyl. In certain embodiments, M/ is an OO. In further or additional embodiments, MU is 5. In certain embodiments, B" is Ci, Bg, I. methyl, ethyl, p-propyl, or i-propyl. In certain embodiments, BZ and B" are N. In further or additional embodiments, X is M; M/ is O or 5; EW! is SI, Vg or I, and VZ and B? is H. In certain embodiments, But is CI, W, or I. In certain embodiments, N is N. In further or additional embodiments, But is Ci, Bg, or I, and Wb is H. In further or additional embodiments, , B" is SON, a salt of CO2H, or COOB'. In further or additional embodiments, B" is SON, a salt of CO2H, or COOB', and B" is H. In further or additional embodiments, B? is CI, B" is SON, a SON salt, and Ne is H. In further or additional embodiments, X is M, MU is O or 5, HB! is Si, Vg or I, VU is H, B" is H, NA? is SI, Vg or I, VU is H and B" is SON, a salt of SON or COOH. In certain embodiments, the compound of formula (I) is a metabolite of the compound of formula (I). In further or additional embodiments, this metabolite has a structure selected from: vv and sa | In certain embodiments, the compound of formula (I) is 4-(2-(5-bromo-4-(1-cyclopropylnaphthalene-4- yl)-4H-1,2,4-triazol-3-ylthio)dacetamido)-3-chlorobenzoic acid or its metabolite, a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or pro-drug: in certain embodiments, the compound of formula (I) is the metabolite 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthioacetamido)-Z- In further or additional embodiments, this metabolite has a structure selected from: , In one aspect, provided herein is a compound of formula (II), wherein said compound of formula (II) is a 3,5-disubstituted-4-(4-BU-naphthalen-1-yl)-4H-1,2,4-triazole, where the substitution in the 3-position is -AU and the substitution in the 5-position is -P", or a pharmaceutically acceptable salt, solvate or tautomer thereof: where ВАЯ is Н, СИ, ВИ, И, МН", methyl, ethyl, p-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted p-propyl, optionally substituted I-propyl, CEz, SNE" or SNeoE; AB is -5СН2С(-0)ВТя, -5СНеоtetrazolyl, -5СН2С(-О)МНОН, -5СН2С(-0)О-alkyl-ОС(-О)На, - ССНо(-0)О-alkyl-ЮС( -О0)ОНза, -БСН2ОС(-0)О-alkyl-ОС(-О)МааВ or - BSНоС(Оalkyl)з; WU is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl; Va is OrBha, 58Za, MAlad?", at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, polyethylene glycol, or a combination thereof, where: dga is substituted C1-C6 alkyl, optionally substituted C5-C0 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or Hga is a pharmaceutically acceptable cation; Vga is -C(vza)(Aoe)pives; or Aza is hydrogen, optionally substituted C:1-C:10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; or does -IS(Vzau( ve) not; Ba is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; and IN? is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; or But it is -IS(В»2)(В58) пе; each Iza, independently, is hydrogen, halogen, cyano, nitro, at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, polyethylene glycol, -I -OH, -I -5H, -I -MH" e, substituted -I -C1-C3 alkyl, optionally substituted -Y - b4-Co alkyl, optionally substituted 1-C2-C5 alkenyl, optionally substituted 1-b2-C5 alkynyl, optionally substituted 1-C2-C5 heteroaryl, optionally substituted -Y-C03-C7 cycloalkyl, optionally substituted I -C33-C7 cycloalkenyl, optionally substituted -I -C33-C7 heterocycloalkyl, optionally substituted -I -C1-C4 haloalkyl, optionally substituted -I - Ci-C4 alkoxy, optionally substituted - 1-C1-C4 alkylamine, optionally substituted -1-di-(C1-Sal)alkylamine, optionally substituted -1-C3-C7 aryl, optionally substituted -11-C5-C7 heteroaryl, zay i and zva LYA: each Be, independently, is hydrogen, halogen, cyano, nitro, at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, polyethylene glycol, -I -OH, -I - 5Н, -И -МН", substituted -I -C1-С3 alkyl, optionally substituted -Й - б4-Со alkyl, optionally substituted 1-С2-С5 alkenyl, optionally substituted 1-б2-С5 alkynyl, optionally substituted I1-С2 -C5 heteroalkyl, optionally substituted -І-б3-С7 cycloalkyl, optionally substituted I -С3з-С7 cycloalkenyl, optionally substituted -І -С3з-С7 heterocycloalkyl, optionally substituted -І -С1-С4 haloalkyl, optionally substituted -І - С- C4 alkoxy, optionally substituted -I-C1-C4 alkylamine, optionally substituted -I-di-(C1-Sal)alkylamine, optionally substituted -Y-C5-C7 aryl, optionally substituted -1I-C5-C7 heteroaryl, zo N ka i, i : F lu i, u i zvo U : Where is hydrogen, halogen, cyano, nitro, at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, polyethylene glycol, -I -OH, -Й-5Н, -И-МНе, substituted -1- C1-C3 alkyl, optionally substituted -1I-C4-Ceo alkyl, optionally substituted 1-C2-C5 alkenyl, optionally substituted 1-C2-C6 alkynyl, optionally substituted I-C2-C5 heteroalkyl, optionally substituted -Y-C3z-C7 cycloalkyl, optionally substituted 1-C3z-C7 cycloalkenyl, optionally substituted /--Y-03-C7 heterocycloalkyl, optionally substituted -I -C1-C4 haloalkyl, optionally substituted -I - Ci-C4 alkoxy, optionally substituted -1I-C1- C4 alkylamine, optionally substituted -I-di (C1-Ca) alkylamine, optionally substituted -I-C5-C7 aryl, optionally substituted -1I-C5-C7 heteroaryl, Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х where Y is a bond, -C(0)-, -550) or -5(0)2; ut is 0,1,2 or 3; M is OH, OMe, COOH, 5OzZN, О50zH, О5(0)2MH», P(IOHON)g, OR(IOHON)», OR(IOHONHO-C: 4 alkyl) or MU2hUZUuya: where Uug and UZ are each independently hydrogen or methyl; or ug and C are taken together with the nitrogen atom to which they are attached to form a five-membered or six-membered ring which optionally contains an oxygen atom or a second nitrogen atom; and y" by an electron pair or an oxygen atom; ie1,2,3 or 4; sings 0,1,2,3,4,5, 6, 7, 8, 9 or 10. In certain embodiments, B" is Bg; and VU is cyclopropyl. In one aspect, a compound of formula (I) is a 3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole, wherein the substitution at the C-position is -B8. In certain embodiments, Vie is at least one amino acid. In certain embodiments, H'z is a peptide. In certain embodiments, Nya is a lipid. In certain embodiments, HB: is a phospholipid. In certain embodiments, B": is a glycoside. In certain embodiments, B": is a nucleoside. In certain embodiments, B"2 is a nucleotide. In certain embodiments, B" is polyethylene glycol. In certain embodiments, Ne is a combination of one or more groups selected from at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, and polyethylene glycol. In certain embodiments, these one or more B'2 groups are covalently linked. In certain embodiments, these one or more B groups form a conjugate. In certain embodiments, HB: is OH2a. In certain embodiments, Nga is substituted C-C alkyl. or optionally substituted alkyl C5-C:1o. In certain embodiments, Na is a pharmaceutically acceptable cation. In certain embodiments, is a pharmaceutically acceptable cation selected from Ii, Ma, Ku, Md, Ca- and a protonated amine. In certain embodiments, he is -IS(B»2a)(B»»)|)piVes; t is 1, 2, 3, 4; | where at least one of Va, AR and where: is not hydrogen. In certain embodiments, Va is hydrogen, B? is hydrogen and Wes is not hydrogen. In certain embodiments, He is at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, or polyethylene glycol. In certain embodiments, Ba is 5I83a. In certain embodiments, Fa is optionally substituted C1-C:0 alkyl. In certain variants of implementation, Заз -(С(Взау(А»е) Ас, In certain embodiments, BA is hydrogen, B" is hydrogen, and B: is not hydrogen. In certain embodiments, NE is at least one amino acid, peptide, lipid, phospholipid, glycoside, nucleoside, nucleotide, oligonucleotide, or polyethylene glycol. In certain embodiments, B" is MALade". In certain embodiments, B" is hydrogen. In certain embodiments, B"8 is optionally substituted alkyl. In certain embodiments, B"8 is -(C(Bza) (A) |pAev. In certain embodiments, BZ is -5C2H2C(-O)Bya, -5CHneo-tetrazolyl, -5CH2C(-O)MNON, - ZCHnO(O)O-alkyl-OC(-O)NHa, 5CHnC(-0 )O-alkyl-OC(-F0)ONZa,. -BSN2C(0)O-alkyl-OC(O)MNa. db or -"Z5CH2gC(Oalkyl)"z; B": there is OB2a, MALAd, at least one amino acid, peptide or glycoside; BA is substituted C1-C4 alkyl, optionally substituted C5-C0 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or B2A is a pharmaceutically acceptable cation; VZA is hydrogen, optionally substituted C.1-C10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; BA is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; and IN? is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In certain embodiments, BZ is -5CH2C(-O0)H'" In certain embodiments, BB is -ZCHnC(O)-at least one amino acid. In certain embodiments, B? is -5CH2C(-0O)-lysine. In certain embodiments, the WU is a -5CH2C(5O)-glycoside. In certain embodiments, B? is - ЗСН2ОС(-Ф)О-glucuronide. In certain embodiments, the UZ is -"5CH-tetrazolyl. In certain embodiments, the BB is -5C02H2C(-0O)MNON. In certain embodiments, HB is -5C2H2C(O)O-alkyl-OC(-O)NA. In certain embodiments, -5С2Н2С(-0)0-СН2-ОС(-О)НЗА. In certain embodiments, the BB is -5С0Н2С(-0)0О-СН(СН3)-ОС(-0О)ВЗА In certain embodiments, the BB is -БСН»С(-О)О- Сно»-ОС(- F)OVzA, In certain variants of implementation, BB with-5СНаС(-0)0О-СН(СН3)-ОС(-0)ОВА. In one aspect, BB is -ZSN»C(Oalkyl)»z. In one aspect, B': is OB2a, In another aspect, Ba is MAlade, In one aspect, B? is a group selected from -5СН2С(-0)Бе, -5СНе-tetrazolyl, -5СН2гО(-О)МНОН, - ЗСН2гО(-0)О-alkyl-ОС(-О)Б8, -ВСНаС(О)О -alkyl-C(O)OVZA, -5CH2C(O0)O-alkyl-OC(O)MA"VyB or -BSNoC(Oalkyl)z, so that VU is metabolized directly with the formation of B is -BSN»C(-OFO )OH. In one aspect, there is provided a compound of formula (III) or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer, or prodrug thereof: x-M vi in M ; taught in C formula (PP) where X is CH or M; M is 0, 5, 5(0), 5(0)2", MH, M(optionally substituted alkyl), MC(O) (optionally substituted alkyl) or CH"; A' is Н, СИ, ВГ, И, МН», methyl, ethyl, p-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted p-propyl, optionally substituted I-propyl, СЕз, СНЕ» or SNeoE; BZ and B are independently selected from H and lower alkyl, or BZ and VU, together with the carbon atom to which they are attached, form a 4-, 5- or b-membered ring, which optionally contains 1 or 2 heteroatoms selected from M, Bi; B: is selected from the group containing (a), (B), (c) and (4): ve Kk Ne t de vp dya (v) (v (s) shS) where: i--- represents a carbon-carbon single bond or a carbon-carbon double bond; O and 0" are independently chosen from M and CH; B is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl; AV, W i KE? are independently selected from Н, Е, СИ, Ви, CH3, СЕ3, СЕНг, СЕН, ethyl, i-propyl, cyclopropyl, methoxy, ОН, ОСЕ3, МН» and МНСОН3; A" is Cl, Be, I, CH", CE3, methoxy, n-propyl, cyclopropyl, (eg-butyl, cyclobutyl or methyl; and B, BZ, B1a and B15 are independently H or methyl. In certain embodiments, X is M. In other embodiments, MU is 5 or 0. carbon-carbon. In certain embodiments, BP is cyclopropyl. In certain embodiments, X is M; MU is 5; and B is Cl, Bg, I, optionally substituted methyl, CEz, CNE" or CNoE. In certain embodiments, BZ and EZ is not H. In one aspect, BZ and EZ are H. In certain embodiments, NU and KU, together with the carbon atom to which they are attached, form a 4-, 5-, or b-membered ring that optionally contains 1 or 2 heteroatoms selected from M, 5 and A. In certain other embodiments, VZ and KU, together with the carbon atom to which they are attached, form a 4-, 5-, or b-membered ring. In further or additional implementation options, the compounds of formula (II) have the following structure: sh- ; sh-M. M hi on m-k i z H ov k-« 0; he and r: in the same city. he gd s vn g Mun dya Son : : i o We 5 vi zhi Bu m pak zha a: v 0 Fo Fo so hi, Z, ! sh-m ; schi J on on Moh N M hu U M i y OM - uh on day ak zhk Kk Hu kit everything and Hvoya 0 im a M y n Gi Z - kh i oz a» y | iz and how M m, puppy ml nn M yun si on M Mn on ve sy shk vo od v vet sya shk M i o b v : zhi ih Her u | r. Va: and Y i ; lov with Y ko o sh- ch-E son M-M s sh-M i 4 he m-ya you mon DU Ж v ra naty an shk jshe "v shk shk yav o oo doyu - se ono a niovonnovai lysh y and ele Mokh zh -k on h yun , as I pr o E dayno po U 5 o sona ooo poyu d Ve kon v: posia a kry dya Kotov vena FILOvlo pd "zon DY AY dey ni a to Fo oyu SHUY eto liy time nia oyu ooo luzhnoy dum To zi: pi pe Sh drone and pr (e as du 3-kh "M - jin yuyu because he would he he to what what for ashvsansanrovi so o oshsheo so g K ; Sn -GZ and An A Z bl g, r 5095 o or As vy emo tea eat y y to M Fo vdis vi vein a viku down to Fo Odes still sudoku dir mo sho bot boju p Op oyu schedyuo rega do reg da in oh roi ih vh vi g v vo iy | , s g zny ho " do Pd be oyu oyu liy sleep liy Veetnsh lu vva Fo so so Fo that si NK NOI dr ron dochYn VZHYdur zhi" to sho 90 son oh so pon soci 090 . yes, yes, yes, yes, yes, yes, yes, yes, yes, yes, yes, yes, yes, yes, yes, yes, yes, yes, yes, yes, yes. Another aspect of the present invention provides methods for the synthesis of the compounds described herein. In certain embodiments, the compounds described herein can be prepared by the methods described below. These methods and examples are for illustration purposes only. Neither the methods nor the examples should be construed as limiting the present invention. In certain embodiments, the compounds described herein may be synthesized by any suitable method. In certain embodiments, the starting materials used in the synthesis of the compounds described herein are obtained from commercial sources, such as Yidgis Spetis! Co. (Mimashkeee, M/i5.), Zidta Spetis! Co. (51. I otsib, Mo.). In certain embodiments, the starting materials used for the synthesis of the compounds described herein are synthesized using methods and materials described, for example, in Mag, AOMAMSEYUO OVSAMIS SNEMIZTAM 47 Ey. (M/pPeu 1992); Sageu 4 Zipabrego, AROMAMSEO OVOAMIS SNEMIBTAM 47 Ei. Mob. A and B (Riepit 2000, 2001), and Step 5 MUtsiv, RVOTESTIME SOVOSHRB IM ONSAMIS 5UMTNEFbBIZ Z" Ea., (U/Peu 1999) (all of which are included in this description by reference). In certain variants of implementation, the following methods are used synthesis Formation of covalent bonds by the reaction of an electrophile with a nucleophile The compounds described here can be modified with various electrophiles or nucleophiles to form new functional groups or substitutions. The following table entitled "Examples of Covalent Bonds and Their Precursors" provides selected examples of covalent bonds and the resulting precursor functional groups that can be used to select from a wide range of electrophile and nucleophile combinations available. Precursor functional groups are shown as electrophilic groups and nucleophilic groups. Examples of covalent bonds and their precursors mine 77777771 fAldehydes 0 |Amines/anlines.//:// Use of Protecting Groups In certain embodiments of the reactions described herein, it is necessary to protect chemically active functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, when desired in the final product, to avoid their undesired participation in the reactions. Protecting groups are used to block certain or all chemically active segments and prevent such groups from participating in chemical reactions until the protecting groups are removed. It is better that each protection group is removed by other means. Protecting groups that are cleaved under completely dispartic reaction conditions satisfy the requirement of differential removal. Protecting groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal, and 1-butyldimethylsilyl are acid labile and, in certain embodiments, are used to protect chemically active carboxy and hydroxy groups in the presence of amino groups protected by hydrogenolysis-removable Cbr7 groups and Etos groups. which are unstable to fundamentals. In certain embodiments, the chemically active carboxylic acid and hydroxy group are blocked with base-labile groups, such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines blocked with acid-labile groups, such as II-butyl carbamate, or carbamates, which are stable in acidic and alkaline environments and are removed by hydrolysis. In certain embodiments, chemically active carboxylic acid and hydroxy functional groups are also blocked by hydrolytically removable protecting groups, such as a benzene group, while amino groups whose hydrogens are capable of bonding with acids are blocked by base-labile groups such as Ethos . In certain embodiments, the active carboxylic acid moieties are protected by conversion to ether compounds, as shown in the examples, or are blocked with protecting groups that are removed by oxidation, such as 2,4-dimethoxybenzyl, while the amino groups present are blocked with fluoride-sensitive silyl carbamates . Allyl blocking groups are used in the presence of acid- and base-protecting groups, since the former are stable and can be subsequently removed using metal or p-acid catalysts. For example, protection can be removed from an allyl-blocked carboxylic acid by a catalyzed Ra reaction in the presence of protective groups - acid-sensitive I-butyl carbamate or alkali-sensitive acetate amine. In certain embodiments, the compounds described herein, or intermediates thereof, are attached to a polymer. As long as such a residue is attached to the polymer, such a functional group is blocked and cannot react. Only after being released from the polymer, the functional group can react. In certain embodiments, the protective or blocking groups are selected from: A. / ly vesnu it TI g ia zoshiy Aios Vosk Tu gu TU U 4 th to schi "V ia --to i rMakh 4 s tare: Ta Kiya Other protective groups plus a detailed description of the methods that can be applied to create protective groups and their removal, are described in Steepe 5 M/tsiv, Rgoiesiime Stoirv5 ip Ogdapis 5upipeviv, Za Ed., Chdopp M/eu b Bop5, Mem/u Mogk, MU, 1999, and Kosiepvki, Rgoiesiime Stoirv5 ip Ogdapis 5upipeviv, Za Ed. / mok, MU, 1994, which are included in this description by reference Preparation of compounds of formula (I) Processes for the preparation of compounds of formula I are described herein. In certain embodiments, the synthesis of the compounds of this invention is carried out by methods such as those described in the following publications: UMO 2004/030611, UMO 2004/050643, M/0/2004/030611, O5 2008/0176850, 05 2006/013556, 05 5,939,462, and 7,435,752. According to one version of the synthesis, the correspondingly substituted (B, He, B") aniline is aminated with an activated carboxylic acid compound (12-SNAZ-C(0)-I", preferably Y" is a halide), where the activated carboxylic acid compound additionally includes group 12, that is lost (predominantly bromide) After anilide formation, this reaction product reacts with a -M/H substituted triazole or imidazole to expel the losing group and form the desired compound as shown below. U v ku 1 -k va ; In many h-m viv v" M Zh i'sro ce and JJ. j grovm. ke ve vk z mk me a e E - ! E shiy i" s in hm de VE ED; wonder PI: vk Y Kk v podre still eat- ise: g de do This scheme is advantageous when the triazole or imidazole is more valuable than the aniline, since it is not used until the last step and is not subject to the inevitable losses during the manipulation of the intermediates of the synthesis. The selection of vanishing groups, И ' and И? will depend to some extent on the particular choice of amine and to a lesser extent on the particular triazole or imidazole. Particular advantage is obtained when I" and 12 are a halide, preferably a chloride or bromide. Suitable solvents for the amination reaction include ethers, alcohols and hydrocarbons (predominantly halogenated), and the choice of solvents will depend, at least in part, on the chemical nature of the reactants. Regarding the solvents, catalysts and/or bases used in the above reaction, one can generally use the reasoning described in Section a). (US patent Mo 5,939,462). The reaction of the triazole/midazole and anilide precursors is typically carried out in a polar aprotic solvent such as OME in the presence of a base such as potassium carbonate. In certain cases, a foundation is not necessary. An example of an anilide formation reaction using chloroacetyl chloride is given below. vv v du v a" che V tu? vo veovomEon f not I rn Y ve vk YAN ie u y « Synthesis routes for the preparation of triazole precursors with various B' substitutions (Me, SNE, МН", СНг8ОМе, СЕз) are shown below. : : sh-m «y Nm Ye c5 ) and Ve Me moe me me it me Sr zov byu te tk v I z)binlenmvovdiye "peda t M i e ZrNuvtadicha i t 2 SNE; All of them have studied 95 EN and some of them are from Ken, like Fr. vn us vn KO gran 1 z us Zno maoke schem Kz ssnyuM Z rova , n Dom she these xz in Ki and Mann 0 Mmabme yes n'" st, lev nev " slogan vn ih he In certain embodiments, halogen-substituted triazole B" is obtained by dihalogenation of a triazole, followed by displacement of one of the halides, as shown below. Deu zn n noz Me I vos A me v Mod od ANNA Dnia Mzhe i d2 v ve vy vyro de y - OVO CYA; There is no I in y; weight UM VE g: t eyes? vu nvro i OME to shim ve ny NK. | what about me - se au v Ek In certain embodiments, halogen-substituted triazole B' is obtained by diazotization of aminotriazole, as shown below. pre ny M-vo y en dey s no t « psa Yad and I tA in zdi side - in v i te re Synthetic approaches to the preparation of imidazole derivatives are shown below. Mn o tyun sho / loh Ve Me mb o 00Я- MasMe i zh che - 6 nm -ya вn Kk What meOn Y "mn vo b iVos (Vo yn ya x Mem ; TEA V Mn pesto x MN emo Mn zegggogogivy MN, ry -- Hv not BOS, t y o pa 0 o o Ge) 2 BIREA In food / vy vn o t o doct u ru ve kv NA o on, o U Mo that A A - AH zn z mov zny to nm 78; y 2 ve vk p v v / shi az MAK o ON sh N popovovoe Ve bah v oyu Vera Y o. ve 0/9 09 Preparation of compounds of formula HER The compounds described herein can be prepared using a variety of synthetic approaches, as will be appreciated by those skilled in the art of chemical synthesis. Some of these approaches are listed below for illustrative purposes. The synthesis intermediate /2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl thibdoacetic acid can react with alcohol, thiol, primary or secondary amine in the presence binding agent (such as M, M'-dicyclohexylcarbodiimide (000), M, M'-diisopropylcarbodiimide (IS), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EC), etc.) with the formation ester, thioether or amide derivatives. Дх г. 1 and abs in all As v er vtutyattuya, OSNO sons Om van A S vos SO SO a a ach Ж shtm t vl y V pa. dk 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthib)acetic acid can also be converted to 2-(5-bromo-4-( 4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)dacetyl chloride after treatment with a small amount of chloride and then react with an alcohol, thiol, primary or secondary amine to form an ester or amide derivative . n-m majestically I s v sh-ya zhov 98 shk ker veze that A in suetro 5os : yan I and I and en same SHY I ve s čnaV" 7 F me A A When using a slightly different approach, the intermediate product 5-bromo- 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol can react with a derivative of 2-chloroacetic acid, 2-chloroethanethioate or 2-xporacetamide to form the same derivatives of ether, thioether or amide, which is above. Ka The intermediate product of the synthesis of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol can react with alcohol, thiol, primary or secondary amine to form the corresponding complex ester, of thioether or amide, which are then converted to 5-bromo derivatives, for example, by reaction with sodium nitrite / dichloroacetic acid / M-benzyl-M, M-diethylthanaminium bromide. sh-m still Mem oh Shk with this and ; Ku o : nd AH zna ate nan Mom." wasp, vyv? also Ooyachya OR VAMeeBVu ; Ov K-t SO still d / g a che, to her I nm vno ali nast mamo, wasp, wine; M in m. VVE vame: y B sao sha o ZU Khan Z sne ; m m-n m-k m "kh n veni hvn sity? nauch vetro cheno" OSA, ve vv oy I: aks o Kene VAaMEBV | mar» SO - s ev St y i SN GA U The synthesis intermediate /2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid can be combined (using standard coupling conditions amino acids) with the amine functionality of a natural or unnatural amino acid residue (α-amine or non-α-amine of such an amino acid as lysine) with the formation of amino acid conjugates such as the following. And r ma i m . ГЯ davnaevavn г я я в 98 seam А A В' is an optionally substituted side chain of a natural or unnatural amino acid. o» what o Zh vd Zh sha do schu non ! chne - vm i maya VbonOV yo mya so - so ha g Each of B" and A" is H, alkyl, optionally protected amino acid, optionally protected natural or unnatural nucleotide, etc. In certain embodiments, the synthesis intermediate 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid can be coupled (using standard amino acid coupling conditions) with the hydroxy group of a natural or unnatural glycoside to form glycoside conjugates such as those shown below. In certain embodiments, each of the other hydroxyl groups is protected, unprotected (ie, -OH), or further substituted. eat-- he n- chy o z z; Shi about ASV 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yltide)acetic acid can react with hydroxyl amine to form 2-(5-bromo-4 -(4-dcyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-M-hydroxyacetamide. The use of M-substituted hydroxylamine provides the M-substituted product. sh-k m-k vin vro you know and b no mnA-on 7 Don't pnntesszh! zh man si 3 KZ her high tvttio vin vya he ne he SO won lyn Man X A Other forms of compounds from the compounds described here Isomers In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all siv, yShapv, 5up, apium, epidedep (E) and 2yzatep (7) isomers, as well as their respective mixtures. In certain situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas given herein. In certain situations, the compounds described herein possess one or more choral centers, and each center exists in the A configuration or in the 5 configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms, as well as appropriate mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereomers obtained after a single preparative step, combination, or interconversion are suitable for the applications described herein. In certain embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of a given compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, resolving diastereomers, and isolating optically pure enantiomers. In certain embodiments, complexes capable of dissociation (eg, crystalline diastereomeric salts) are preferred. In certain embodiments, such diastereomers have different physical properties (eg, melting point, boiling point, solubility, chemical activity, etc.) and are separated based on the use of these differences. In certain embodiments, diastereomers are separated using choral chromatography or, preferably, separation/separation methods based on differences in solubility. In certain embodiments, the optically pure enantiomer is then separated, along with the resolving agent, by any practical means that does not result in racemization. Labeled compounds In certain embodiments, the compounds described herein exist in the form of labeled isotopes. In certain embodiments, the methods described herein include methods of treating diseases by administering compounds in the form of labeled isotopes. In certain embodiments, the methods described herein include methods of treating diseases by administering compounds in the form of labeled isotopes as part of pharmaceutical compositions. Thus, in certain embodiments, compounds described herein include isotopically labeled compounds that are identical to other compounds described except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that atomic mass or mass numbers that are usually found in nature. Examples of isotopes that can be included in the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, UZN, 790, 140, 19M, 180, 170, zr, gr , 855, 18E and 36СI, respectively. The compounds described herein and their metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds, such as those incorporating radioactive isotopes such as ZH and 77C, are used in medicinal preparations and/or in assays to assess substrate distribution in various tissues. The most commonly used isotopes are ZN and 170, which are easy to prepare and detect. Moreover, substitution with heavy isotopes such as deuterium, ie -H, provides certain therapeutic advantages associated with greater metabolic stability - for example, a prolonged half-life of ip mimo or the possibility of reducing the dose. In certain embodiments, such isotopically labeled compounds, their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives are obtained by any suitable method. In certain embodiments, the compounds described herein are labeled by other means, including, without limitation, the use of chromophores or fluorescent particles, bioluminescent labels, or chemiluminescent labels. Metabolites In certain embodiments, the compounds described herein exist as metabolites. In certain embodiments, the methods described herein include methods of treating diseases by administering such metabolites. In certain embodiments, the methods described herein include methods of treating diseases by administering such metabolites as part of pharmaceutical compositions. The compounds described here are metabolized through various metabolic mechanisms (for example, hydrolysis, oxidation, glycolysis, phosphorylation, alkylation, etc.). In order not to be bound by theory, the following scheme illustrates two possible cleavage sites in which a compound of formula (I) can be metabolized to form the indicated metabolites. Specialists in this field can foresee additional metabolic pathways with the formation of other metabolites, which are also included in the scope of the present invention. ЦЯ х-м "Ж M KM ж ян в - уз, в), ий Ж-м хз же Е MK Z ШИ y: в во е ' ve "SA Гхч Pharmaceutically acceptable salts In certain embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In certain embodiments, the methods described herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In certain embodiments, the methods described herein include methods of treating diseases by administering such pharmaceutically acceptable salts as part of pharmaceutical compositions. In certain embodiments, the compounds described herein possess acidic or basic groups and, accordingly, react with any of a number of inorganic and organic bases and inorganic and organic acids to form a pharmaceutically acceptable salt. In certain embodiments, these salts are prepared either during the final isolation and purification of the compounds of this invention or by separately reacting the purified compound in its free form with an appropriate acid or base and separating the resulting salt. Examples of pharmaceutically acceptable salts include those obtained by reacting the compounds described herein with a mineral, organic acid, or inorganic base, including salts such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate , butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrophosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate . , 1-naphthalene sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undecanoate, and xylene sulfonate. In addition, the compounds described herein can be prepared in the form of their pharmaceutically acceptable salts by reacting the compound in its free base form with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, meta phosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumarolic acid, O-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2 - naphthalene sulfonic acid, 4-methylbicyclo-(2.2.2|oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4"-methylene bis-(3-hydroxy-2-ene-1-carboxylic acid), C -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In certain embodiments, other acids, such as oxalic, although not pharmaceutically acceptable per se, are used in the preparation of salts used as intermediates in the preparation of the compounds of this invention and their pharmaceutically acceptable acid addition salts. In certain embodiments, those of the compounds described herein which contain a free acid group are reacted with an appropriate base, such as a hydroxide, carbonate, bicarbonate, sulfate, with a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic, primary, secondary or tertiary amine. Representative salts of alkali or alkaline earth metals include salts of lithium, sodium, potassium, calcium, magnesium, and aluminum, etc. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, MU(C-4 alkyl)a, etc. Exemplary organic amines used to prepare base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternization of any nitrogen-containing basic groups they contain. In certain embodiments, such quaternization produces water, fat-soluble products, or dispersible products. The compounds described herein can be prepared as pharmaceutically acceptable salts when the acid proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinated with an organic base. Base addition salts may also be prepared by reacting the free acid form of the compounds described herein with a pharmaceutically acceptable inorganic or organic base, including but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, M-methylglutamine, etc. n.; and inorganic bases, such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. In addition, salts of the compounds described herein can be obtained using salts of starting materials or intermediates. to solve In certain embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention also provides methods of treating diseases by administering such solvates as part of pharmaceutical compositions. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and, in certain embodiments, are formed by crystallization using a pharmaceutically acceptable solvent such as water, ethyl alcohol, and the like. Hydrates are formed when water serves as a solvent, alcoholates are formed when alcohol serves as a solvent. Solvates of the compounds described herein may be conveniently prepared or formed by the processes described herein. By way of example only, hydrates of the compounds described herein may be conveniently prepared by recrystallization from aqueous/organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methyl alcohol. In addition, the compounds provided herein can exist in both unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for purposes of the compounds and methods provided herein. Polymorphs In certain embodiments, the compounds described herein exist as polymorphs. The present invention provides methods of treating diseases by introducing such polymorphs. The present invention also offers methods of treating diseases by introducing such polymorphs as part of pharmaceutical compositions. Therefore, the compounds described herein include all their crystalline forms known as polymorphs. Polymorphs include different packing options in crystals of the same elemental composition of the compound. In certain cases, polymorphs have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. In certain cases, various factors, such as the solvent used for recrystallization, the rate of crystallization, and the storage temperature, lead to the predominance of one crystal form. Pro-medicine In certain embodiments, the compounds described herein exist in prodrug form. The present invention provides methods of treating diseases by administering such pro-drugs. The present invention also offers methods of treating diseases by introducing such pro-drugs as part of pharmaceutical compositions. In general, prodrugs are drug precursors that, after administration to an individual and subsequent absorption, are converted to an active or more active form by a process such as metabolic conversion. Certain prodrugs have a chemical group on them that makes them less active and/or gives them solubility or some other property. Only after modification of this group and/or its cleavage, an active drug is formed. Pro-drugs are often used because in certain situations they are easier to administer than the parent drug. They are, for example, bioavailable when administered orally, whereas the parent drug is not. In certain cases, prodrugs also have better solubility in pharmaceutical compositions than the parent drug. An example of a pro-drug would be, without limitation, a compound described herein that is introduced as an ester ("pro-drug") to allow passage across the cell membrane when water solubility impairs mobility, but which is then metabolically hydrolyzed to a carboxylic acid, of the active compound, already inside the cell, where solubility in water is useful. Another example of a prodrug would be a short peptide (polyamino acid) linked to an acid group, where this peptide is metabolized to release an active compound. (See, for example, Vypadaaga, "Oezidp apa Arriisayop oi Rgodgydv" ip A TehirooKoiOgyd Oezidp apa Oemeiortenpi, Ktozdaagt-I agzep and Vypidaaga Ea., 1991, Sparieg 5,113-191, which are included in this description by reference). In certain embodiments, prodrugs are created as reversible drug derivatives for use as modifiers that enhance drug transport to site-specific tissues. Until now, the development of prodrugs has been aimed at increasing the effective water solubility of the therapeutic compound to reach areas where water is the main solvent. In addition, prodrugs derived from the compounds described herein can be prepared by the methods described herein or known from other sources (for more details, see Baptsipieg ei a!., Viogdapis apa Medisipa! Spetivigu I eyegv5, 1994, 4, 1985) . By way of example only, suitable prodrugs may be prepared by reacting a non-derivative compound with a suitable carbamylating agent, such as, without limitation, 1,1-acyloxyalkylcarbanochloridate, raga-nitrophenyl carbonate, and the like. The compounds described herein in the form of pro-drugs, when these pro-drugs are metabolized further to the formation of a derivative set forth herein, are included within the scope of this invention. Indeed, certain of the compounds described herein are prodrugs of another derivative or active compound. In certain embodiments, prodrugs include compounds in which an amino acid residue or a polypeptide chain of two or more (eg, two, three, or four) amino acid residues is covalently attached via an amide or ether bond to a free amino, hydroxy, or carboxylic acid compounds of this invention. Such amino acid residues include, but are not limited to, the 20 naturally occurring amino acids and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtuline, homocysteine, homoserine, ornithine, and methionine. sulfone In other embodiments, prodrugs include compounds in which a nucleic acid residue or an oligonucleotide of two or more (eg, two, three, or four) nucleic acid residues is covalently attached to a compound of the present invention. Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, M-acyl derivatives, M-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, M-Maity bases, 5-supium bases, amino acid conjugates, phosphate ethers, metal salts and sulfonate ethers. Compounds having free amino, amido, hydroxy, or carboxylic acid groups can be converted into prodrugs. For example, free carboxyl groups can be converted into amides or alkyl ethers. In certain cases, all of these types of prodrugs include, but are not limited to, ether, amine, and carboxylic acid functional groups. Hydroxy prodrugs include esters such as, without limitation, acyloxyalkyl (eg, acyloxymethyl, acyloxyethyl) ethers, alkoxycarbonyloxyalkyl ethers, alkyl ethers, aryl ethers, phosphate esters, sulfonate ethers, sulfate ethers, and disulfide-containing ethers; ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as described in AdhapsedOgidOeimiguVemiemv 1996,19, 115. Pro-drugs derived from amine include, but are not limited to, the following groups and combinations of groups: "Koh syh syh sko she uh y y v y Z v y G-ya SE zh o - V "br shi -yazhy po soi 3 skopy i tse: ШЯ г. І І t 8 8 в po ia ko S she spo sey Koh vek shk y sho vn Ya vya yan and also sulfonamines and phosphonamides. In certain cases, sites on any part of the aromatic ring are sensitive to different metabolic reactions; accordingly, the incorporation of substitutions into the structure of the aromatic ring may reduce, minimize, or eliminate this metabolic pathway. Pharmaceutical compositions Pharmaceutical compositions are also described here. In certain embodiments, these pharmaceutical compositions contain an effective amount of a compound of formula !| or a metabolite, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. In certain embodiments, these pharmaceutical compositions contain an effective amount of a compound of formula | or a metabolite, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof and at least one pharmaceutically acceptable carrier. In certain embodiments, these pharmaceutical compositions are for the treatment of disorders. In certain embodiments, these pharmaceutical compositions are for the treatment of disorders in a mammal. In certain embodiments, these pharmaceutical compositions are intended to treat disorders in humans. Methods of introduction In certain embodiments, the compounds and compositions described herein are administered alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents in a pharmaceutical composition. The compounds and compositions described here can be administered by any method that ensures the delivery of these compounds to the site of their action. These methods include, but are not limited to, delivery by enteral routes (including oral, gastric or duodenal tube, rectal suppository, or rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardial, intradermal, intraduodenal, intramedullary, intra ulcerative, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and local (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration , although the most appropriate way may depend, for example, on the condition of the recipient and his disorder. By way of example only, the compounds described herein may be administered locally to the area in need of treatment, such as local infusion during surgery, topical application as creams or ointments, injection, catheter, or implant. Said implant is made of porous, non-porous or gelatinous material, including membranes, such as silicone membranes, or fibers. The introduction can also be carried out by direct injection in the place of pathologically changed tissue or organ. In certain embodiments, preparations suitable for oral administration are in the form of individual units, such as capsules, wafers or tablets, each of which contains a predetermined amount of active ingredient powder or granules; solution or suspension in an aqueous or non-aqueous liquid; or oil-in-water or water-in-oil liquid emulsion. In certain embodiments, the active ingredient is presented as a bolus, electuary, or paste. Pharmaceutical preparations that can be used orally include tablets, tight-fitting capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerin or sorbitol. Tablets may be made by compression or molding, optionally with one or more excipients. Compressed tablets can be made by pressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluents or lubricants, surfactants or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent. In certain embodiments, the tablets are coated with a film or scored on them, and their composition is designed to provide a slow or controlled release of the active ingredient from them. All drugs for oral administration should be in doses suitable for such administration. Close-fitting capsules may contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In certain embodiments, stabilizers are added. The core of the dragee can have an appropriate coating. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, varnish solutions and appropriate organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for identification or to indicate different combinations of doses of the active compound. In certain embodiments, the pharmaceutical preparations are intended for parenteral administration by injection, such as bolus injection, or continuous infusion. Preparations for injection can be made in a dosed dosage form, for example in ampoules, or in containers containing several doses, with an added preservative. The compositions may be in the form of a suspension, solution, or emulsion in an oily or aqueous medium, and may contain suspending, stabilizing, and/or dispersing agents. Preparations may be in single-dose or multi-dose containers, such as hermetically sealed ampoules or vials, and may be stored in powdered or freeze-dried (lyophilized) form, requiring only the addition of a sterile liquid carrier such as saline or sterile water , free from pyrogens, immediately before use. Injection solutions or suspensions for immediate administration can be prepared from sterile powders, granules and tablets of the previously described type. Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of active compounds, which may contain antioxidants, buffers, bacteriostatics and dissolved substances that make the preparation isotonic with the blood of the intended recipient; as well as aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or diluents include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous suspensions for injection may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, such a suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds according to the present invention, which allows the preparation of highly concentrated solutions. Pharmaceutical preparations can also be prepared as depot preparations. Such long-acting drugs can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be combined with suitable polymeric or hydrophobic materials (eg, as an emulsion in an acceptable oil) or ion exchange resins, or prepared as sparingly soluble derivatives, for example as a sparingly soluble salt. For buccal or sublingual administration, the compositions can be prepared in the form of tablets, lozenges, lozenges or gels according to the usual formulation. Such compositions may include an active ingredient in a base with a certain taste, which contains, for example, sucrose and gum arabic or tragacanth. Pharmaceutical preparations can also be prepared as rectal compositions such as suppositories or enemas that are retained, for example those containing a conventional suppository base such as cocoa butter, polyethylene glycol or other glycerides. Pharmaceutical drugs can be administered locally, that is, by non-systemic administration. This involves applying a compound of the present invention externally to the epidermis or buccal surface and instilling such compound into the ear, eye and nose so that the compound does not enter the bloodstream to a significant extent. On the other hand, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration. Pharmaceutical preparations suitable for topical administration include liquid or semi-liquid preparations capable of penetrating the skin to the site of inflammation, such as gels, liquid ointments, lotions, creams, ointments or pastes, and drops intended for administration to the ear, eye and nose. The active ingredient can be, for local administration, from 0.001 95 to 10 95 v/v, for example from 1 9" to 2 95 of the weight of the drug. However, it can be as much as 10 95 v/v, but preferably it will be less than 5 925 v/v, and more often from 0.1 Fo to 1 95 v/v of the weight of the drug. Pharmaceutical preparations for administration by inhalation are usually dispensed from an insufflator, nebulizer, pressure pack, or other traditional means of producing an aerosol spray. Pressurized packages may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of a pressurized aerosol, the dose can be determined using a metering valve. Alternatively, for administration by inhalation or insufflation, the pharmaceutical preparations may be prepared in the form of a dry powder composition, for example a powder mixture of the compound and a suitable powder base, such as lactose or starch. Such a powder composition can be presented in a dosage form, for example, in capsules, cartridges, gelatin packages or blister packs from which the powder can be administered using an inhaler or insufflator. It should be understood that, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other agents conventionally used for the type of preparation in question, for example, preparations intended for oral administration may include flavoring agents. Drugs The compounds or compositions described herein can be delivered in a vesicle, such as a liposome. The compounds and pharmaceutical compositions described herein may also be delivered using a controlled release system, or the controlled release system may be placed near the therapeutic target. In one embodiment, a pump may be used. The pharmaceutical compositions described herein may also contain the active ingredient in a form suitable for oral use, such as, for example, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use are optionally prepared according to a known method, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, in order to provide pharmaceutically elegant and palatable preparations. . Tablets contain the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients, which are necessary for the production of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; agents for granulation and disintegration, such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, such as starch, gelatin, polyvinylpyrrolidone, or gum arabic, and lubricants, such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or coated by known methods to mask the taste of the drug or to delay its disintegration and absorption in the gastrointestinal tract in order to maintain its effect for a longer period. For example, a water-soluble material such as hydroxypropylmethylcellulose or hydroxypropylcellulose can be used to mask the taste, and a material such as ethyl cellulose or cellulose acetate butyrate can be used to delay disintegration. Preparations for oral use can also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble a carrier such as polyethylene glycol or an oily medium such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active material in a mixture with auxiliary substances necessary for obtaining aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth, and gum arabic; dispersants or wetting agents can be a phosphatide of natural origin, such as lecithin, or the condensation products of alkylene oxide with fatty acids, such as polyoxyethylene stearate, or the condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethylene-oxyethanol, or the condensation products of ethylene oxide with an incomplete ester derived from fatty acids, and hexitol, such as polyoxyethylene sorbitol monooleate, condensation products of ethylene oxide with incomplete esters derived from fatty acids, and hexitol anhydrides, such as polyethylene sorbitol monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or p-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose, saccharin, or aspartame. Suitable pharmaceutical carriers include inert diluents or excipients, water and various organic solvents. Pharmaceutical compositions may contain, when desired, additional ingredients such as flavors, binders, excipients, etc. Therefore, for oral administration, tablets containing various excipients such as citric acid can be used with various disintegrating agents such as starch, alginic acid and certain complex silicates, and with binders such as sucrose, gelatin and gum arabic. Additional agents such as magnesium stearate, sodium lauryl sulfate, and talc are often necessary for tableting processes. Solid compositions of this type can also be used in soft and hard filled gelatin capsules. Accordingly, preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound may be combined with various sweetening or flavoring agents, coloring agents, and, if desired, emulsifying or suspending agents, along with diluents such as water, ethyl alcohol, propylene glycol, glycerin or combinations thereof. Oil suspensions can be obtained by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain a thickening agent such as beeswax, solid paraffin or cetyl alcohol. Sweeteners, such as those mentioned above, and flavoring agents may be added to provide the oral preparation with a pleasant taste. The addition of an antioxidant such as butylated hydroxyanisole or alpha-tocopherol may be used to preserve such compositions. Dispersible powders and granules suitable for preparing an aqueous suspension by adding water contain the active ingredient in admixture with a dispersing agent or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing and wetting agents, as well as suspending agents, may be those previously mentioned. Additional excipients such as sweeteners, flavors and colors may also be present. The preservation of such compositions can be ensured by the addition of an antioxidant such as ascorbic acid. Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oil phase can be vegetable oil, such as olive oil or peanut oil, or mineral oil, such as liquid paraffin, or mixtures thereof. Suitable emulsifiers can be phosphatides of natural origin, soybean lecithin, as well as esters or incomplete esters derived from fatty acids and hexitol anhydrides, such as sorbitol monooleate, and condensation products of these incomplete esters with ethylene oxide, such as polyoxyethylene sorbitol monooleate. Such emulsions may also contain sweeteners, flavorings, preservatives and antioxidants. Syrups and elixirs may contain sweeteners, such as glycerin, propylene glycol, sorbitol, or sucrose. Such preparations may also contain an agent that reduces irritation, a preservative, a flavoring agent, dyes, and an antioxidant. Pharmaceutical compositions can also be in the form of a sterile aqueous solution for injection. Among the acceptable diluents and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injection preparation may also be a sterile oil-in-water microemulsion for injection where the active ingredient is dissolved in the oil phase. For example, the active ingredient may first be dissolved in a mixture of soybean oil and lecithin. This solution in oil is then introduced into a mixture of water and glycerin and processed to obtain a microemulsion. Injectable solutions or microemulsions may be administered into the bloodstream of an individual by local bolus injection. Alternatively, it may be useful to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the active compound. In order to maintain such a constant concentration, a device for continuous intravenous administration can be used. An example of such a device is the intravenous pump Oeyes SABORI O05"M model 5400. Pharmaceutical compositions can be in the form of a sterile aqueous or oily suspension for injections, intended for intramuscular and subcutaneous administration. Such a suspension can be obtained in accordance with the known in this field of the method using those dispersing, wetting and suspending agents mentioned above.The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic diluent or solvent suitable for parenteral administration, for example as solution in 1,3-butanediol. In addition, sterile, fixed oils are widely used as a solvent or suspending medium. Any soothing fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of preparations for injection pharmaceutical compositions can also be administered in the form of suppositories for rectal administration of the drug. Such suspensions may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials include cocoa butter, glycerin with gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of 3 different molecular weights and polyethylene glycol fatty acid esters. Creams, ointments, jellies, solutions or suspensions can be used for local application, eis. containing a compound or composition according to this invention. Topical application, as the term is used herein, may include gargling. The pharmaceutical compositions can be administered intranasally by topical application of suitable intranasal solvents and appropriate delivery devices, or transdermally, using transdermal skin patches. When using a transdermal delivery system, the administration of the dose will, of course, be continuous rather than intermittent throughout the drug regimen. Such preparations may be conveniently presented in dosage form and may be prepared by any method well known in the art of pharmacy. All methods include the step of combining a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof (the "active ingredient") with a carrier that contains one or more auxiliary ingredients. In general, these preparations are prepared by uniform and thorough combining the active ingredient with liquid carriers or finely ground solid carriers, or both, followed, if necessary, by forming the product into the desired preparation.Pharmaceutical Forms The pharmaceutical composition may be, for example, in a form suitable for oral administration, such as a tablet, capsule, pill, powder; drugs with delayed release in the form of a solution or suspension; for parenteral injection in the form of a sterile solution, suspension or emulsion; for local administration in the form of an ointment or cream or for rectal administration in the form of a suppository. The pharmaceutical composition can be in dosed dosage forms intended for one-time administration of precise doses. Pharmaceutical composition may include a conventional pharmaceutical carrier or excipient and a compound of the present invention as an active ingredient. In addition, it may include other medical or pharmaceutical agents, carriers, adjuvants, etc. Exemplary forms for parenteral administration include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous solutions of polyethylene glycol or dextrose. Such dosage forms can optionally contain a suitable buffer. Doses The amount of pharmaceutical composition administered will primarily depend on the mammal being treated. In cases where pharmaceutical compositions are administered to humans, the daily dose will usually be determined by the attending physician taking into account the age, sex, nutrition, body weight, general health and response of the individual, the severity of the individual's symptoms, the exact indication or condition being treated, the severity, the time of administration, the route of administration, the distribution of the composition in the body, the rate of excretion, the combination of drugs and the discretion of the attending physician. In addition, the route of administration may vary depending on the condition and its severity. Preferably, the pharmaceutical composition is given a dosage form. In this form, the drug is divided into unit doses containing appropriate amounts of the active ingredient, for example, an effective amount to achieve the desired goal. Determining the correct dose for a particular situation is within the skill of one skilled in the art. In general, treatment is initiated at lower doses that are lower than the optimal dose of a given compound. Over time, the dose is increased in small increments until the optimal effect for the given circumstances is achieved. For convenience, the total daily dose can be divided and administered in parts throughout the day, if desired. The amount and frequency of administration of the compounds described herein and, where appropriate, other therapeutic agents and/or treatments will be adjusted at the discretion of the treating clinician (physician)) taking into account such factors as described above. Therefore, the amount of pharmaceutical composition administered can vary widely. The administration can be carried out in an amount from about 0.001 mg/kg of body weight to about 100 mg/kg of body weight per day (in one or more doses), preferably at least about 0.1 mg/kg of body weight per day. A specific therapeutic dose will be, for example, from about 0.01 mg to about 7,000 mg of the compound, and preferably is, for example, from about 0.05 mg to about 2,500 mg. The amount of active compound in a single dose of the preparation can vary or be adjusted from about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg, and more preferably from 10 mg to 200 mg, depending on the specific application. In certain cases, a dose level lower than the lower end of the above range may be more than sufficient, while in other cases even higher doses may be used without causing harmful side effects, such as when dividing such a high dose into several smaller doses and administering them during the day. The amount of compound administered will vary depending on the specific ISC of the COMPOUND USED. In combination therapy, when a given compound is not the only therapy, it may be possible to administer smaller amounts of the compound and still obtain a therapeutic or prophylactic effect. Combination Therapy The compounds described herein, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof, may be administered as a single therapy. The compounds described herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof may also be administered in combination with another therapy or therapies. For example, the therapeutic efficacy of one of the compounds described herein may be enhanced by the administration of an adjuvant (ie, the adjuvant alone may provide only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Or, by way of example only, the benefit obtained by an individual may be enhanced by administering one of the compounds described herein with another therapeutic agent (which also has a schedule of administration) that also confers therapeutic benefit. By way of example only, in the treatment of gout, which involves administration of one of the compounds described herein, increased therapeutic benefit may be provided by administration to the individual of another therapeutic gout drug. Or, by way of example only, when one of the side effects in an individual after taking a compound described herein is nausea, it may be appropriate to administer an anti-nausea drug in combination with the compound. Alternatively, additional therapy or therapies may include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression of the affected area, rest, altered diet, and the like. Regardless of the disease, disorder, or condition being treated, the overall benefit received by an individual may be cumulative from the two therapies or therapeutic agents, or the individual may experience a synergistic benefit. In cases where the compounds described herein are administered in combination with other therapeutic drugs, the compounds described herein should not be administered in the same pharmaceutical composition with other therapeutic drugs and may, due to different physical and chemical characteristics, be administered by a different route. For example, compounds/compositions of the present invention may be administered orally to achieve and maintain a desired blood level of the active compound, while another therapeutic agent may be administered intravenously. The compounds described herein may be administered simultaneously (eg, concurrently, substantially concurrently, or within the same treatment protocol), sequentially, or separately from other therapeutic agents. Initial administration may be performed according to an established protocol known in the art, and then, based on the observed effects, the dose, route of administration, and frequency of administration may be modified by an experienced clinician. The specific choice of compound and other therapeutic drug will depend on the diagnosis made by the attending physician and his judgment regarding the individual's condition and the optimal treatment protocol. In certain embodiments, the additional drug is an OVAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase inhibitor, a xanthine oxidoreductase inhibitor, a purine nucleoside phosphorylase (PMP) inhibitor, a uric acid transporter inhibitor, a glucose transporter inhibitor (GHT), a SI 0OT-9 inhibitor, family 2 solute transporters (facilitated glucose transporter), inhibitor of representative 9 (5I C2AZV), inhibitor of organic anion transporter (OAT), inhibitor of OAT-4 or their combinations. In certain cases, OVAT 1 is an ion exchanger that mediates urate transport. In certain cases, OVATI mediates the transport of urate in the proximal tubules. In certain cases, OVATI exchanges urate in the proximal tubules for lactate and nicotinate. In certain cases, xanthine oxidase oxidizes hypoxanthine to xanthine and further to uric acid. In certain cases, xanthine dehydrogenase catalyzes the conversion of xanthine, MAYU: and Hg2O into urate, MABN and NU. In certain embodiments, the additional drug is allopurinol, febuxostat (2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-triazole-5-carboxylic acid), EUH-051 (4-I5-pyridine- 4-il-1 H-C, 2. A|griazol-3-yl)ipyridin-2-carbonitrile), probenecid, sulfinpyrazone, benzbromarone, acetaminophen, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH), colchicine, glucocorticoid, androgen, COX-2 inhibitor , an ACE inhibitor, naproxen, sevelamer, zibutamine, troglitazone, proglitazone, other uric acid-lowering drugs, losartan, fibroic acid, benziodarone, salicylate, anlodipine, vitamin C, or combinations thereof. Diseases Described herein are methods of treating a disease in an individual suffering from said disease, comprising administering to said individual an effective amount of a composition containing a compound described herein or a pharmaceutically acceptable salt, solvate, polymorph, ester thereof , tautomer or prodrug. Also described are methods of preventing or delaying the onset of disease in an individual at risk of developing said disease, which include administering to said individual an effective amount of a composition containing a compound described herein or a pharmaceutically acceptable salt, solvate, polymorph, ether thereof, to prevent or delay the onset of disease, tautomer or prodrug. Also described are methods for the prevention or treatment of any disease or disorder in which abnormal levels of uric acid play a role, including, without limitation: hyperuricemia, gout, gouty arthritis, inflammatory arthritis, kidney disease, nephrolithiasis (kidney stones), inflammation joints, deposition of urate crystals in the joints, urolithiasis (formation of calculi in the urinary tract), deposition of urate crystals in the renal parenchyma, Lesche-Nyhan syndrome, Kelly-Siegmiller syndrome, exacerbation of gout, nodular gout, renal failure, or their combinations in human or other mammal. The methods described herein extend to such applications and to the use of the compounds of this invention in the manufacture of medicaments for the treatment of such diseases and disorders. Moreover, the methods described herein extend to administering to a human an effective amount of a compound described herein to treat any such disease or disorder. Subjects who may be treated with the compounds described herein or a pharmaceutically acceptable salt, ether, prodrug, solvate, hydrate, or derivative of said compounds in accordance with the methods of the present invention include, for example, subjects diagnosed with gout, gouty arthritis, inflammatory arthritis , kidney disease, nephrolithiasis (kidney stones), inflammation of the joints, deposition of urate crystals in the joints, urolithiasis (formation of calculi in the urinary tract), deposition of urate crystals in the renal parenchyma, Lesche-Nyhan syndrome, Kelly-Sigmailler syndrome, exacerbation gout, nodular gout, renal failure, or their combinations. In certain embodiments, an individual having an abnormal uric acid level is administered an amount of at least one compound described herein sufficient to modulate the abnormal uric acid level (eg, to a medically acceptable level). In certain embodiments, an individual treated with the compounds described herein exhibits abnormal uric acid levels where the blood uric acid level exceeds a medically acceptable level (ie, hyperuricemia). In certain embodiments, an individual treated with the compounds described herein exhibits abnormal uric acid levels when the blood uric acid level exceeds 360 μmol/L (b mg/dL) for females or 400 μmol/L (6.8 mg/dL ) for men. In certain embodiments, an individual treated with the compounds described herein exhibits abnormal uric acid levels, where the level of uric acid in the urine exceeds a medically acceptable level. In certain embodiments, an individual treated with the compounds described herein exhibits abnormal uric acid levels when the urinary uric acid level exceeds 800 mg/day (in males) or 750 mg/day (in females). In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) suffers from a cardiovascular disorder. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) suffers from an aneurysm; angina pectoris; atherosclerosis; stroke; cerebrovascular disease; congestive heart failure; coronary heart disease; and/or myocardial infarction. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) exhibits (a) C-reactive protein (CRP) levels greater than about 3.0 mg/L; (B) homocysteine levels greater than approximately 15.9 mmol/L; (c) levels of I and OI. above about 160 mg/dL; (4) NOA levels. below approximately 40 mg/dL; and/or (have) serum creatinine levels greater than approximately 1.5 mg/dL. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal levels of uric acid and (2) suffers from diabetes. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) suffers from type I diabetes. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal levels of uric acid and (2) suffers from type II diabetes. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal levels of uric acid and (2) suffers from loss of beta cells of the islets of Langerhans in the pancreas. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) suffers from insulin resistance and/or reduced insulin sensitivity. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) exhibits (a) a fasting plasma glucose level of 2126 mg/dL; (B) a plasma glucose level of 2200 mg/dL 2 hours after the glucose tolerance test; and/or (c) symptoms of hyperglycemia and occasional plasma glucose levels of 2200 mg/dL (11.1 mmol/L). In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) suffers from metabolic syndrome. In certain embodiments, a subject treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) suffers from (a) diabetes mellitus, impaired glucose tolerance, impaired fasting glucose, and/or insulin resistance, (B) at least for two conditions with (i) blood pressure: 2140/90 mm Hg. art.; (i) dyslipidemia: triglycerides (TO): 21.695 mmol/l and high-density lipoprotein cholesterol (HO-C) x0.9 mmol/l (men), "1.0 mmol/l (women); (her) central type of obesity: waist:hip ratio »0.90 (men); »0.85 (women), and/or body mass index »C30 kg/me; and (m) microalbuminuria: urinary albumin excretion rate of 220 mg/min. or an albumin:creatinine ratio of 230 mg/g. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) suffers from insulin resistance (ie, fasting insulin values above 25 95 among non-diabetic individuals) and (B) at least two states with (ii) central type of obesity: waist circumference »94 cm (men), »80 cm (women); (ii) dyslipidemia: TO 22.0 mmol/l and/or NOI -C « 1.0 mmol/l or treatment for dyslipidemia; (iii) hypertension: blood pressure 2140/90 mm Hg. Art. or antihypertensive treatment; and (im) fasting plasma glucose level of 26.1 mmol/l. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) exhibits at least three conditions of (a) increased waist circumference: 240 inches (males) and 235 inches (females); (b) elevated level of triglycerides: 2150 mg/dL; (c) reduced NOI level: « 40 mg/dL (men) and « 50 mg/dL (women); (4) increased blood pressure: 2130/85 mm Hg. Art. or taking medication for hypertension; and (is) elevated fasting glucose: 2100 mg/dL (5.6 mmol/L) or taking medications for hyperglycemia. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal levels of uric acid and (2) suffers from kidney disease or kidney failure. In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) exhibits oliguria (reduced urine production). In certain embodiments, an individual treated with the compounds described herein (1) exhibits abnormal uric acid levels and (2) produces less than 400 mL of urine per day (adult), produces less than 0.5 mg/kg/g of urine ( children) or produces less than 1 ml/kg/g of urine (infants). Uric acid In certain cases, purines (adenine, guanine), derived from food or tissue metabolism (cellular nucleotides undergo constant exchange), are catabolized in humans to their final oxidation product, uric acid. In certain cases, guanine is oxidized to xanthine, which, in turn, is further oxidized to uric acid under the action of xanthine oxidase; adenosine is converted to inositol, which is further oxidized to hypoxanthine. In certain cases, xanthine oxidase oxidizes hypoxanthine to xanthine and further to uric acid. In certain cases, as part of the reverse process, the enzyme hypoxanthine-guanine phosphoribosyltransferase (NORRET) utilizes guanine and hypoxanthine. AK m ne "zh Guanin nyu ; M sa : Y i | Ho M Go Mne on buk maode i Her i mouth ot MM she WASH, N -K r y m lyn lyn ne : zim still I5U in em Xanthine uric acid ribose ribose ddenosine Inosine Hepoxanthine In certain cases, the keto form of uric acid is in equilibrium with the enol form, which loses a proton at physiological pH values to form urate. In certain cases (for example, in serum conditions (pH 7.40; 379C)), about 98-95% of uric acid is ionized as the monosodium salt of urate. In certain cases, urate is a strong reducing agent and a powerful antioxidant. In humans, approximately half of the antioxidant capacity of plasma is determined by uric acid. : with |! no oh! i.e. the same oc i Y n non i IN Uric acid Uric acid Urate thenal-formai In certain cases, most of the uric acid dissolves in the blood and passes to the kidneys, where it is excreted by glomerular filtration and tubular secretion. In certain cases, a significant proportion of uric acid is reabsorbed by the renal tubules. One characteristic feature of the uric acid transport system is that, although the net activity of tubular function is the reabsorption of uric acid, this molecule is both secreted and reabsorbed as it passes through the nephron. In certain cases, reabsorption dominates in segments 51 and 53 of the proximal tubule, and secretion dominates in segment 52. In certain cases, however, bidirectional transport leads to the fact that drugs that inhibit uric acid transport decrease rather than increase uric acid excretion, discrediting their therapeutic utility. In certain cases, normal uric acid levels in adults (5.1:20.93 mg/dL) approach the solubility limit of urate (57 mg/dL at 37 "C), which creates a delicate physiological balance of urate. In certain cases, normal uric acid levels in women are about 1 mg/dL lower than in men. Hyperuricemia In certain cases, hyperuricemia is characterized by higher-than-normal levels of uric acid in the blood that are sustained over a long period of time. In certain cases, increased levels of urate in the blood can be due to increased production of uric acid (10-20 95) or reduced excretion of uric acid by the kidneys (80-90 95). In certain cases, the causes of hyperuricemia may include: - Obesity/weight gain - Excessive alcohol consumption - Excessive consumption of purines with food (with such products as mollusks, crustaceans, fish roe, scallops, peas, lentils, beans and red meat, especially offal - brains, kidneys, stomach, liver) - Certain medications, including low-dose aspirin, diuretics, niacin, cyclosporine, pyrazinamide, ethambutol, certain high blood pressure drugs and certain cancer chemotherapy drugs, immunosuppressive and cytotoxic drugs - Specific pathological conditions, especially associated with a high rate of cell turnover (such as a malignant tumor, leukemia, lymphoma or psoriasis), as well as high blood pressure, hemoglobin disorders, hemolytic anemia, sickle cell anemia, various nephropathies, myeloproliferative and lymphoproliferative disorders, hyperparathyroidism, kidney disease, conditions associated with insulin resistance and diabetes, post-transplant conditions, and possibly heart disease - Inherited enzyme defects - Abnormal renal function (eg, increased ATP metabolism, decreased glomerular filtration of urate) - Lead poisoning (saturnism or "lead gout") In certain cases, hyperuricemia may be asymptomatic, although it is associated with the following conditions: "Gout "Gouty arthritis " Uric acid calculi in the urinary tract (urolithiasis) "Deposition of uric acid in soft tissue (nodules) Uric acid deposition in the kidneys (uric acid nephropathy) "Impaired kidney function, which may lead to chronic or acute kidney failure Gout Prevalence The incidence of gout has increased over the past two decades and, in the United States, gout affects 2.7% of the population aged 20 years and older, which is more than 5.1 million American adults. Gout is more common among men than among women (3.8 95 or 3.4 million men vs. 1.6 95 or 1.7 million women), typically affecting men after their 40s and 50s (although gout attacks may occur after puberty when uric acid levels rise). An increase in the prevalence of gout from 2.9 to 5.2 per 1,000 people was observed between 1990 and 1999, and this increase occurred mainly in people over 65 years of age. Gout attacks are more common in postmenopausal women. In certain cases, gout is one of the most common forms of arthritis, accounting for approximately 5 to 95 of all arthritis cases. In certain cases, renal failure and urolithiasis occur in 10-18 95 individuals with gout and are common sources of morbidity and mortality from this disease. The main reasons In most cases, gout is associated with hyperuricemia. In certain cases, individuals with gout excrete approximately 40 95 less uric acid than individuals without gout for any given plasma urate concentration. In certain cases, urate levels rise until the saturation point is reached. In certain cases, deposition of urate crystals occurs when the saturation point is reached. In certain cases, these hardened, crystallized deposits (nodules) form in the joints and skin, causing inflammation of the joints (arthritis). In certain cases, deposits form in the joint fluid (synovial fluid) and/or joint lining (synovial lining). Common areas for these deposits are the big toes, feet, lower legs, and hands (less common areas include the ears and eyes). In certain cases, the skin around the affected joint becomes red and shiny, and the affected area itself becomes sensitive and painful to the touch. In certain cases, gout attacks become more frequent. In certain cases, untreated acute gout attacks lead to permanent joint damage and disability. In certain cases, tissue deposition of urate leads to: acute inflammatory arthritis, chronic arthritis, deposition of urate crystals in the renal parenchyma, and urolithiasis. In certain cases, the incidence of gouty arthritis increases 5-fold in individuals with serum urate levels between 7 and 8.9 mg/dL and 2-fold in individuals with levels » 9 mg/dL (530 μmol/L). In certain cases, individuals with gout develop kidney failure and end-stage kidney disease (ie, "gouty nephropathy"). In certain cases, gouty nephropathy is characterized by chronic interstitial nephropathy, which is facilitated by medullary deposition of monosodium urate. In certain cases, gout includes painful attacks of acute inflammatory arthritis in one joint, deposition of urate crystals in the joints, deposition of urate crystals in the renal parenchyma, urolithiasis (formation of stones in the urinary tract) and nephrolithiasis (formation of stones in the kidneys). In certain cases, secondary gout occurs in individuals with cancer, particularly leukemia, and those with other blood disorders (eg, polycythemia, myeloid metaplasia, etc.). Symptoms In certain cases, gout attacks develop very quickly, with the first attack often occurring at night. In certain cases, symptoms include sudden, severe joint pain and extreme tenderness in the joint area, joint swelling, and shiny red or purple skin around the joint. In some cases, attacks are infrequent, lasting 5-10 days, without any symptoms between attacks. In certain cases, attacks become more frequent and may last longer, especially when the disorder is uncontrolled. In certain cases, such attacks damage the affected joint(s), leading to stiffness, swelling, limited mobility, and/or persistent mild to moderate pain. Treatment In certain cases, gout is treated by reducing the production of uric acid. In certain cases, gout is treated by increasing the excretion of uric acid. In certain cases, gout is treated with drugs SHONVAT 1, xanthine oxidase, xanthine dehydrogenase, xanthine oxidoreductase, purine nucleoside phosphorylase inhibitor (PAP), uric acid transporter inhibitor (UAT), glucose transporter inhibitor (SI OT), family 2 solute transporters (relieved glucose transporter), representative 9 (5I1C2A9) inhibitor, organic anion transporter (OAT) inhibitor, OAT-4 inhibitor or their combinations. In general, the goals of gout treatment are i) to reduce pain, swelling and the duration of an acute attack, and i) to prevent future attacks and joint damage. In certain cases, gout attacks are successfully treated using combination therapy. In certain cases, gout is one of the most curable forms of arthritis. i) Treatment of an acute attack. In certain cases, the pain and swelling associated with an acute gout attack can be treated with medications such as acetaminophen, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH), or colchicine. In certain cases, the right drug controls gout within 12 to 24 hours, and the treatment is stopped after a few days. In certain cases, the drug is used in combination with rest, increased fluid intake, ice application, elevation and/or protection of the affected area. In certain cases, the above approaches to treatment do not prevent recurrent attacks and do not affect the main disorder - impaired uric acid metabolism. ii) Prevention of future attacks. In certain cases, lowering the serum uric acid level below the saturation level is a challenge to prevent further gout attacks. In certain cases, this is achieved by reducing the production of uric acid (for example, allopurinol) or increasing the excretion of uric acid with the help of drugs that promote the excretion of uric acid (for example, probenecid, sulfinpyrazone, benzbromarone). In certain cases, allopurinol inhibits the formation of uric acid, leading to a decrease in uric acid levels, both in serum and urine, and becomes fully effective after 2-3 months. ish Z n Hugnin "b "y | Xanthine- Do - Urate B and M Hypoxanthine cha I Apopurinop Ploxantin pomEnichuntsa vpovorenOtonkya In certain cases, allopurinol is a structural analogue of hypoxanthine (they differ only in the transposition of carbon and nitrogen atoms in positions 7 and 8), which inhibits the action of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and xanthine to uric acid. In certain cases, it is metabolized to the corresponding xanthine analog, alloxanthine (oxypurinol), which is also an inhibitor of xanthine oxidase. In certain cases, alloxanthin, although it inhibits xanthine oxidase more strongly, is less pharmaceutically acceptable due to low oral bioavailability. In some cases, fatal reactions due to hypersensitivity, bone marrow suppression, hepatitis and vasculitis have been reported with allopurinol. In certain cases, the frequency of side effects can reach 20 95 of all individuals treated with this drug. The treatment of disorders of uric acid metabolism has not developed significantly in the two decades since the introduction of allopurinol. In certain cases, drugs that promote the excretion of uric acid (for example, probenecid, sulfinpyrazone, and benzbromarone) increase the excretion of uric acid. In certain cases, probenecid causes an increase in the secretion of uric acid by the renal tubules and, in case of chronic use, mobilizes urate reserves in the body. In certain cases, 25-50 95 individuals treated with probenecid do not achieve a decrease in serum uric acid level of "6 mg/ dl In certain cases, insensitivity to probenecid is the result of intolerance to the drug, simultaneous intake of salicylate and impaired kidney function. In certain cases, a third of individuals develop intolerance to probenecid. In certain cases, the introduction of drugs that contribute to the excretion of uric acid also causes the formation of calculi in the urinary tract, gastrointestinal obstruction, jaundice and anemia. Lead poisoning or "lead gout" In certain cases, excess exposure to lead (lead poisoning) results in "lead gout," lead-induced hyperuricemia due to inhibition of tubular urate transport, resulting in reduced renal excretion of uric acid. In some cases, more than 95% of individuals with lead nephropathy develop gout. In certain cases, acute attacks of lead gout are more likely to occur in the knee than in the big toe. In certain cases, kidney disease occurs more often and is more severe in case of lead gout than in case of primary gout. In certain cases, treatment consists of eliminating further exposure to lead, using chelating agents to remove lead, and control acute gouty arthritis and hyperuricemia. In certain cases, lead gout is characterized by less frequent attacks than primary gout. In certain cases, lead-associated gout occurs in premenopausal women who do not develop normal gout as often. Lesche-Nyhan syndrome In certain cases, Lescher-Nyhan syndrome (I M5 or Nyhan syndrome) affects approximately one in 100,000 live births. In certain cases, I M5 is caused by a genetic deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (NORAT). In certain cases, YM5 is an X-linked recessive disease. In certain cases, IMO is detected already at birth in boys. In certain cases, this disorder leads to severe gout, poor muscle control, and mild mental retardation that manifests in the first year of life. In certain cases, this disorder also leads to self-mutilating behavior (eg, lip and finger biting, head banging), beginning in the second year of life. In certain cases, this disorder also leads to gout-like swelling of the joints and severe kidney problems. In certain cases, this disorder leads to neurological symptoms that include facial grimacing, involuntary spasms, and repetitive movements of the arms and legs similar to those seen in Huntington's disease. The prognosis for individuals with ME is poor. In certain cases, the life expectancy for an untreated individual with IM5 is less than about 5 years. In certain cases, the life expectancy of a treated individual with Y M5 exceeds approximately 40 years. Hyperuricemia and other diseases In certain cases, hyperuricemia is found in individuals with cardiovascular disease (CVD) and/or kidney disease. In certain cases, hyperuricemia is found in individuals with pre-hypertension, hypertension, increased proximal sodium reabsorption, microalbuminuria, proteinuria, kidney disease, obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, peripheral, carotid, and coronary artery disease. , atherosclerosis, congestive heart failure, stroke, tumor lysis syndrome, endothelial dysfunction, oxidative stress, elevated levels of renin, elevated levels of endothelin and/or elevated levels of C-reactive protein. In certain cases, hyperuricemia occurs in individuals with obesity (eg, central obesity), high blood pressure, hyperlipidemia, and/or abnormal fasting glucose. In certain cases, hyperuricemia is found in individuals with metabolic syndrome. In certain cases, gouty arthritis is an indicator of increased risk of acute myocardial infarction. In certain embodiments, administration of the compounds described herein to an individual is useful for reducing the likelihood of a clinical event associated with a disease or condition associated with hyperuricemia, including, without limitation, pre-hypertension, hypertension, increased proximal sodium reabsorption, microalbuminuria, proteinuria, kidney disease, obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, peripheral, carotid, and coronary artery disease, atherosclerosis, congestive heart failure, stroke, tumor lysis syndrome, endothelial dysfunction, oxidative stress, elevated renin levels, elevated endothelin levels and/or elevated C-reactive protein levels. In certain embodiments, the compounds described herein are administered to an individual suffering from a disease or condition requiring treatment with a compound that is a diuretic. In certain embodiments, the compounds described herein are administered to an individual suffering from a disease or condition requiring treatment with a compound that is a diuretic, wherein the diuretic causes retention of urate in the kidney. In certain embodiments, this disease or condition is congestive heart failure or essential hypertension. In certain embodiments, administration of the compounds described herein to an individual is beneficial for improving mobility or improving quality of life. In certain embodiments, administration of the compounds described herein to an individual is useful for treating or reducing the side effects of cancer treatment. In certain embodiments, administration of the compounds described herein to an individual is beneficial in reducing the toxicity of cisplatin to the kidneys. Kits The compounds, compositions and methods described herein are provided in kits for the treatment of disorders such as those described above. These kits contain the compound, compounds, or compositions described herein in a container and, optionally, instructions for using the kit according to the various methods and approaches described herein. Such kits may also include information such as references to scientific literature, package inserts, clinical trial results and/or summaries, etc., which show or establish the actions and/or benefits of the proposed composition, and/or which describe dosage, administration, side effects, interactions with other medications, or provide other information useful to a healthcare provider. Such information may be based on the results of various studies, for example, studies using experimental animals in models of ip mimo, as well as clinical trials with the participation of patients. The kits described here may be offered to health care providers, including doctors, nurses, pharmacists, formulary officials, etc. Kits may also, in certain embodiments, be sold directly to the consumer. The compounds described here can be used for diagnostics as well as reagents for scientific research. For example, the compounds described herein, alone or in combination with other compounds, can be used as tools in differential and/or combinatorial assays to elucidate the pattern of gene expression expressed in cells and tissues. As one non-limiting example, expression patterns in cells and tissues treated with one or more compounds are compared to control cells or tissues not treated with the compounds, and the resulting patterns are analyzed for different levels of gene expression as they relate to, for example, connection with the disease, signaling pathway, cell localization, expression level, size, structure or function of the studied genes. These assays can be performed on stimulated or unstimulated cells, and in the presence or absence of other compounds that affect expression patterns. In addition to being useful for the treatment of humans, the compounds and preparations of the present invention are also useful for the veterinary treatment of pets, exotic animals, and farm animals, including mammals, rodents, and the like. To a greater extent, this applies to such animals as horses, dogs and cats. The examples and preparations below further illustrate and confirm by way of example the compounds of this invention and the methods of preparation of such compounds. It should be understood that the scope of this invention is not limited in any way to the scope of the following examples and preparations. In the following examples, molecules with a single choral center exist as a racemic mixture, unless otherwise indicated. Molecules with two or more choral centers, unless otherwise indicated, exist as a racemic mixture of diastereomers. Individual enantiomers or diastereomers can be obtained by methods known to those skilled in the art. Examples II Chemical synthesis Example 1: 2-(4-(2,4-Dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yltide) acetic acid n-n n- re m-n on svu Kun pig svyti She I Y vanya i bo - 7000-70 Step A: Ethyl 2-bromoacetate (68 μL; 0.611 mmol) and potassium carbonate (0.17 g; 1.22 mmol) were added to a solution of /4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalene) -1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiol (0.2 g; 0.611 mmol) in THF (2.44 mL). The resulting mixture was heated at 60 "C for 18 hours. The mixture was concentrated, ethyl 2-bromoacetate (68 μl; 0.611 mmol) and DMF (1.2 ml) were added and heated at 60 °C for another 24 hours. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by 5aC (Intelligent Gas Chromatograph) (0-50 95 ethyl acetate/hexanes) to give ethyl 2-(4-(2,4-dimethyl -5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazole-z-ylthio)acetate in the form of a clear oil (0.137 g; 54 Vol). Step B: A solution of lithium hydroxide (1M aqueous, 0.436 mL, 0.436 mmol) was added to a solution of ethyl 2-(4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-( trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)acetate (0.09 g; 0.218 mmol) in THF/methyl alcohol/water (3/3/1; 1.5 mL) and stirred for 18 hours at room temperature. The crude reaction mixture was concentrated, acidified with HCl (1M aqueous, 4 ml) and extracted with ethyl acetate (2 x 3 ml). The combined organic extracts were concentrated to give 2-(4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-"(trifluoromethyl)-4H-1,2,4 -triazole-Z-ilthio)acetic acid in the form of an almost white foam (0.082 g; 98 95). Example 2: 2-(4-(4,7-Dimethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid nn v: fs yan Hu vn bich Ki Si FO 29, detsnnnofi: st-Yafya Step A: Ethyl 2-bromoacetate (87 μl; 0.783 mmol) and potassium carbonate (0.216 g; 1.57 mmol) were added to a solution of 4-(4,7-dimethylnaphthalen-1-yl)-4H-1,2,4 -triazole-3-thiol (0.2 g; 0.783 mmol) in THF (3.1 mL). The resulting mixture was heated to 60 °C for 1 hour. Another 1 ml of DMF was added, and the mixture was heated at room temperature for another 18 hours. Water (3 mL) was added and the mixture was extracted with ethyl acetate (3 x 3 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated, and purified with 502: (0-100 95 EtOAc/hexanes) to give ethyl 2-(4-(4,7-dimethylnaphthalen-1-yl)-4H - 1,2,4-triazole-3-ylthio)acetate in the form of a clear oil (0.231 g; 86 95). Step B: A solution of lithium hydroxide (1M aqueous, 0.88 mL, 0.488 mmol) was added to a solution of 4 ethyl 2-(4-(4,7-dimethylnaphthalen-1-yl)-4H-1,2,4-triazol- z-ylthioacetate (0.15 g; 0.44 mmol) in THF/ethyl alcohol/water (1:1:1, 7 mL) and the mixture was stirred for 2 hours at room temperature. The crude reaction mixture was then concentrated, acidified with NOCI (1M, 3 ml) and extracted with ethyl acetate (3 x 5 ml). The combined organic extracts were concentrated to give 2-(4-(4,7-dimethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid as an off-white solid (0.129 g; 94 95). Example C: 2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methyl propanoic acid It's Mao's fault, but Vymezuv: svy 1myov 0 FO Od A no A m p SHI eh ve vn whit mouth and whit vbkue 0-00 o da ih Step A: 3-Bromo-propionic acid ethyl ether (158 μL, 224 mg; 1.239 mmol) was added to a solution of 5-amino-4-(4-dicyclopropylnaphthalen-1-yl)-4H-I(1,2,4| triazole-3-thiol (0.35 g; 1.239 mmol) in DMF (2.5 ml). The resulting mixture was heated to 60 °C for 20 hours. The reaction mixture was concentrated and sonicated with ethyl ether several times, decanting the ethyl ether layer. The resulting light yellow oil was placed under high vacuum to give crude ethyl 3-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3z-ylthio)upropanoate as light brown oily foam, which was used directly in the next step (0.409 g; 87 95). Step B: 3-(5-Amino-4-(4-dcyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio) propanoate, (200 mg; 0.523 mmol), sodium nitrite (361 mg; 5.233 mmol, 10 eq.) and benzyltriethylammonium bromide (427 mg; 1.570 mmol, 3 eq.) were suspended in bromoform (3 mL) and stirred at room temperature for 30 minutes. Dichloroacetic acid (86 μl, 135 mg; 1.047 mmol, 2 equiv) was then added and the mixture was stirred at room temperature overnight with the flask covered with foil to protect from light. Water (5 ml) was added and stirring was continued for another 30 minutes. Then the reaction mixture was transferred to a separatory funnel and water and dichloromethane were added. The organic layer was collected, and the aqueous layer was washed with dichloromethane (2x). The combined organic extracts were dried over sodium sulfate, filtered, concentrated, and purified by flash column chromatography (6:14 hexanes/ethyl acetate) to give ethyl 3-(5-bromo-4-(4-cyclopropylnaphthalene-1) -yl)-4H-1,2,4-triazole-z-ylthio)propanoate as a light brown oil (111 mg; 47.6 Vol). Step C: An aqueous solution of lithium hydroxide (1M, 437 μl, 0.437 mmol, 3 equiv.) was added to a solution of ethyl 3-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4 -triazole-3-ylthio)upropanoate (65 mg; 0.146 mmol) in THF (1.5 mL) and methyl alcohol (1 mL). The mixture was stirred at room temperature for 2 h, and NOI (1M, 584 μL; 0.584 mmol, 4 eq.) was added. The mixture was concentrated, a little water was added, sonicated and an almost white solid mass was separated by filtration. The separated material was placed in a small amount of methyl alcohol, sonicated again, and then filtered to give 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol as almost white solid mass (39 mg, 78 b). Step 0: A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (50 mg; 0.144 mmol), ethyl 2-bromo-2-methylpropanoate ( 22 μL; 0.144 mmol) and diisopropylethylamine (76 μL; 0.433 mmol) in DMF (1 mL) was heated to 6090 for 20 h. Then the mixture was concentrated, sonicated in ethyl until complete dissolution and washed with 1M HCl. This mixture was extracted with diethyl ether (2 x 5 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give ethyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H -1,2,4-triazol-3-ylthio)-2-methylpropanoate as a brown oil (60 mg, 91 95). Step E: A solution of lithium hydroxide (1M aqueous, 358 μL, 0.358 mmol, 3 equiv.) was added to a solution of ethyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4 -triazole-3-ylthio)-2-methylpropanoate (55 mg; 0.119 mmol) in THF (1 mL) and methyl alcohol (0.5 mL), and the mixture was stirred for 2 hours at room temperature. The crude reaction mixture was then concentrated, acidified with NOSI (1M) and sonicated to separate the solids. Filtration gave 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoic acid as an off-white solid (39 mg, 76 b). Example 4: 2-(5-"Difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-z-ylthio)acetic acid is used for the treatment of pigs Step A: Triethylamine (0.11 mL; 0.786 mmol) and ethyl 2-bromoacetate (80 μL; 0.72 mmol) were added with stirring to a solution of 5-(difluoromethyl)-4-( 4-ethylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.2 g; 0.655 mmol) in dichloromethane (2.6 mL). The resulting mixture was stirred for 2 hours. The crude reaction the mixture was purified with 5040 (0-5095 EOAc/hexanes) to give ethyl 2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3- ilthio)dacetate as an off-white solid (0.246 g; 96 b). Step B: A solution of lithium hydroxide (1M aqueous, 0.77 mL; 0.77 mmol) was added to a solution of ethyl 2-(5-(difluoromethyl)- 4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate (0.15 g; 0.38 mmol) in THF/water (3:1; 1.5 ml), and the mixture was stirred for 8 hours at room temperature. The crude reaction mixture was then concentrated and acidified with HCl (1M, 3 ml), after which extracted with ethyl acetate (3 x 2 ml). The combined organic extracts were concentrated to give 2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid as an off-white foam (0.136 g; 99 9). Example 5: 2-(5-amino-4-(4-cdcyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoic acid mon 2 days M and write summers Step A: Ethyl 2-bromo-2-methylpropanoate (184 μl; 1.239 mmol) was added to a solution of 5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2 ,4-triazole-3-thiol (0.35 g; 1.239 mmol) in DMF (2.5 mL) and heated at 60 °C for 20 h, then a few crystals of potassium iodide were added and the mixture was heated at 70 °C another 24 hours. The temperature was then raised to 90 "C, and the mixture was heated for another 6 days. The mixture was then allowed to cool to room temperature, concentrated and dissolved in dichloromethane. Triethylamine and water were added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x), and the combined organic the extracts were dried over MabSO3, filtered, concentrated and purified by column chromatography (ethyl acetate) to give ethyl 2-(5-amino-4-(4-dicyclopropylnaphthalen-1-yl)-4H-1,2,4- triazole-3-ylthio)-2-methylpropanoate as a reddish-brown solid (0.134 g; 27 ro) Step B: A solution of lithium hydroxide (1M aqueous, 0.757 mL; 0.757 mmol) was added to a solution of ethyl 2-(5- amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate (100 mg, 0.252 mmol) in THF (2 mL) and methyl alcohol (1 mL), and the mixture was stirred at room temperature for 20 h. The crude reaction mixture was acidified with NOS (1M, 1 mL) and sonicated to separate the solids, which were then separated by phil by distillation to obtain 2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoic acid as a white solid (69 mg , 74 FUb). Example 6: /2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate acid m-n m-k M-k o. in. Step A: Triethylamine (0.087 mL; 0.623 mmol) and ethyl 2-bromoacetate (63 μL; 0.571 mmol) were added to a solution of 5-(fluoromethyl)-4-(4-methyl- 5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.144 g; 0.519 mmol) in dichloromethane (2.1 mL) and stirred at room temperature for 2 hours The crude reaction mixture was purified with 5020 (0-100 95 EtOAc/hexanes) to afford ethyl 2-(5-(Fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate in the form of an almost white solid mass (0.168 g; 89 Vol). Step B: A solution of lithium hydroxide (1M aqueous, 0.59 mL; 0.59 mmol) was added to a solution of ethyl 2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalene- 1-yl)-4H-1,2,4-triazole-3-ylthioacetate (107 mg, 0.294 mmol) in THF/water (3/1; 1.2 mL) and the mixture was stirred at room temperature for 18 h . The crude reaction mixture was concentrated, acidified with NOSI (1M, 3 ml) and extracted with ethyl acetate (3 x 3 ml). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give 2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1 ,2,4-triazole-3-ylthio)acetic acid. Example 7: iep-Butyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate web uv y To to A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (prepared as described above; 500 mg, 1.444 mmol), iep -butyl 2-bromo -2-methylpropanoate (270 μl, 1.444 mmol) and diisopropylethylamine (755 μl, 4.332 mmol) in DMF (3 ml) was heated at 60 °C for 20 hours. This mixture was then concentrated, diethyl ether (15 mL) was added and sonicated until all solids were dissolved. After that, the solution was washed with CARRIERS (1M, 10 ml) and extracted with diethyl ether (2 x 15 ml). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give t-butyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3- ilthio)-2-methylpropanoate as a light brown foam (yield: 532 mg, 75 95). Example 8: 2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-z-ylthio)acetic acid more: ztu Kk Sodium hydroxide solution (2M aqueous, 33.7 mL; 67 mmol, 2 equiv.) was added to a suspension of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole -3-ylthio)-N-(2-chloro-4-sulfamoylphenyl)acetamide (prepared according to a previously published method; 20 g, 34 mmol) in ethyl alcohol (200 mL), and the resulting mixture was heated under an irrigation condenser for 4 h. Activated carbon (10 g) was added and the mixture was stirred at room temperature for 12 hours, after which the activated carbon was removed by filtration. The coal was washed several times with ethyl alcohol, the resulting filtrate was concentrated. Water (200 mL) was added, then concentrated to approximately one third of the volume to remove all the ethyl alcohol. Water (200 mL) and ethyl acetate (250 mL) were added, the mixture was vigorously stirred for 15 minutes, and the organic layer was removed. The aqueous layer was cooled to 096 and acidified with NOSI (1M), resulting in the formation of an opaque oily precipitate. The mixture was extracted with ethyl acetate (III), and the combined organic extracts were dried over sodium sulfate and concentrated to give 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole -Z-ylthio)acetic acid in the form of an almost white solid mass (11.2 g; 82 Vol). Example 9: 2-(4--4-DCDicyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoic acid hi sk uyan vbbry se urny siv ron iy r o ta Z I -Й Щ я-n--e і Step A: Ethyl 2-bromo-2-methylpropanoate (89 μL; 0.596 mmol) and diisopropylethylamine (0.31 mL; 1.789 mmol) were added to a solution of 4-(4-dicyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)- 4H-1,2,4-triazole-Z-thiol (0.2 g; 0.596 mmol) in DMF (1.2 mL) and the mixture was heated at 60 °C for 20 h. The mixture was concentrated, acidified with NOSI (1M aqueous, 2 ml) and extracted with ethyl acetate (3 x 3 ml). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by column chromatography (0-25 95 EIOAc/hexanes) to afford ethyl 2-(4-(4-cyclopropylnaphthalen-1-yl-5-(trifluoromethyl)- 4H-1,2,4-triazole-z-ylthio)-2-methylpropanoate in the form of a clear oil (0.1. g; 37 Ob). Step B: A solution of lithium hydroxide (1M aqueous, 0.67 ml, 0.67 mmol) was added to a solution of ethyl 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2 ,4-triazol-3-ylthio)-2-methylpropanoate (0.g; 0.22 mmol) in THF (0.88 mL) and the mixture was stirred at room temperature for 18 h. The crude reaction mixture was concentrated; water (100 ml) was added, followed by washing with ethyl acetate (2 x 40 ml). The aqueous layer was acidified with HCl (1M aqueous, 10 ml) and extracted with ethyl acetate (30 ml). The combined organic extracts were dried over sodium sulfate and concentrated to give 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)- 2-methylpropanoic acid as an almost white solid (49 mg, 53 Vol). Example 10: 1-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylic acid vv suon I'm a father - and in! apart from them I - 60 C with ME " and in a Step A: A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (100 mg; 0.289 mmol), ethyl 1-bromocyclobutanecarboxylate (47 μL; 0.289 mmol) and diisopropylethylamine (151 μl; 0.866 mmol) in DMF (1 ml) was heated at 60 °C for 4 days. After cooling to room temperature, the mixture was concentrated and partitioned between dichloromethane (15 mL) and HCl (1M aqueous, 15 mL). The aqueous layer was extracted with dichloromethane (2 x 15 mL), and the combined organic extracts were dried over sodium sulfate, concentrated, and purified by column chromatography (4095 EtOAc/hexanes) to give ethyl 1-(5-bromo-4-(4 -cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ucyclobutanecarboxylate in the form of a light yellow sticky foam (yield: 75 mg, 55 95). Step B: A solution of lithium hydroxide (1M aqueous, 0.387 mL, 0.387 mmol, 3 equiv.) was added to a solution of ethyl 1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4 -triazole-3-ylthio)cyclobutanecarboxylate (61 mg; 0.129 mmol) in THF/methyl alcohol (2/1; 3 mL) and the mixture was stirred at room temperature for 18 h. The mixture was acidified with NOI (1M aqueous, 0.645 mL, 0.645 mmol, 5 equiv.), concentrated, water (10 mL) was added and extracted with diethyl ether (2 x 15 mL). The combined organic extracts were dried over calcium chloride and concentrated to give //1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ucyclobutanecarbonate acid in the form of an almost white solid mass (43 mg, 75 95). Example 11 Several compounds of formula (I) were prepared according to the protocols described in the previous examples. Analytical data for these compounds are shown in the table below. II Biological assessment Example 12: Analysis of uric acid accumulation Creation of stable cell lines expressing the POVATI transporter: The full-length human IVATI gene (51 C22A12) was subcloned from the plasmid YASMU6-XI 5 (Ogidepe) into the eukaryotic expression plasmid RSMUb/Meo (Ogidepe) using Moi I restriction sites. Genetic sequencing (determining the sequence of nucleotides in the gene-carrying molecule) confirmed the sequence of POVATI, as it is given in Seprapk (accession number MM 144585.2). Human embryonic kidney cells NEK29Z (ATOSIA SVI-1573) were propagated in EMEM tissue culture medium as described by ATOS in an atmosphere of 595 CO" and 9595 air. Transfections of NEK293 cells with the pROMUb/Meo/OVATI construct were carried out using the reagent for transfection I 2000 (Ipigodep), as described by the manufacturer. After 24 hours, transfected cells were plated in 10-cm tissue culture dishes where they were grown overnight, after which the medium was replaced with fresh medium containing 418 (Ssirso) at a final concentration of 0.5 mg/ml. Colonies resistant to the drug were selected after about 8 days, after which they were tested for the activity of "C-uric acid transport". NEK29Z/igai cells were transferred to 9b-well plates covered with Roiu-O-I uzipe at a density of 75,000 cells per well. Cells were grown overnight (20-26 hours) at 379C in an incubator. The tablets were allowed to reach room temperature, after which the medium was washed in one wash using 250 μl of wash buffer (125 mM sodium gluconate, 10 mM Nere5 pH 7.3). The compound or solvent was added to the assay buffer with C14 uric acid to a final concentration of 40 μM uric acid with a specific activity of 54 tbCi/mmol. The composition of the buffer for analysis: 125 mM sodium gluconate, 4.8 mM potassium gluconate, 1.2 mM potassium phosphate, monobasic, 1.2 mM magnesium sulfate, 1.3 mM calcium gluconate, 5.6 mM glucose, 25 mM NEREZ5, pH 7.3. Plates were incubated at room temperature for 10 minutes, then washed three times using 50 μl of wash buffer and three times using 250 μl of wash buffer. Mistovsipi 20 scintillation fluid was then added and the plates were incubated overnight at 45°C until equilibrium was reached. Finally, the tablets were read on TorSoishpi Riaieye VNeadeg and received EC50 values. (See Epotoyo eyi ai., Maishge, 2002, 417, 447-451 and Aplai eyi a/., u. Vioi. Spet., 2004, 279, 45942-45950.) Compounds of formula (I) obtained as described above in examples 1-11, be investigated according to the method described above, with the establishment of values of ЕСзо. The following table summarizes the activity of these compounds in the uric acid accumulation assay, where A is ESvo from 1 nM to 1 µM; B is ESovzo from 1 μM to 30 μM; and C is ES30 above 30 µM (M/A means no data). not | NMME SKYU MNg, SNKOKOVOKM-Ya) 5 yrga 1.33 (7.15 "B MerIteetko SCHE. 1A ; y ze 1414.05|S iso 2.68 (t, Z NU 2.76 - 2.87 (ha, 1 H) 4.29 14, "7,265 Nya 2 NO 4.35 - (May) I 55.2 NO, In k-k NM Mnya. PM5O-45) 5 rrt 1.31 4 165 century, 1 H) 1.65 - they 1.53 (631) 22148, 3 NO 224 iv, Z 234. 247, 1 NO 2.60 | Mass: i in, Z NV in, i. Z H) (v. 1 V) 1v o (5 Na, 2 NO 230 203 (t, 1 NO 4.35 - 4.56 hu, 2 NO 77 (Me (B.I НР1297иЛг.5.,1 N) 0 "Я MM (400 МН, DM 5 рр 1.18 0.3 NO 258.3 NO КИ У 2.75 (8.3 NI4.03- 415 8.4 N) 69983 , NO 745 -7.53(1,2 Mass: 2А SS Nu tyav(va, nyat vvnya 1 VVIV vni EyaYU M) Y vn) t. zn NMA (00 МН, ОМ5О-5) 6 ro 2455, 52.75 (in, 3 SCHO. K in 4.03 04,.2«3.32 No, 2 NO) 7Yu (in, 1 NO) 74 - 753 (t, 237.56 | Mass: 28 SS (a8.25871, 166 NI, 1 NU 8.11 (4, eЯ7I nya, NO (B, B) (me) o and 12.94 (tv. EN H MM (440 MN, OM) and yr 080 - 9.93 (t, 2 HB) I pok I.22 (sh.5NU254- 361 (t, 2H) 270279 (1 2 M) 3.14-3.23 Mass: ZA so (t, 3 NU 3.98 4.08 (t . NO (t. v. NU 8.60 (4, ev. No AND NO NM (0 MH, GMO) o yr 9.50 - 392 (t, 2 H) 1.07 - T.A 12306.5Н)254-362(8.1Н) 2771 2684 NI, 2) 328 Mass: zv Fo (y, le 6.8O, 3.38 Nu, Z NI 4.03 is, 705 Che, 2 NU 7.15 4, 445 ,98 levoo on NO and NO 1Н1752-77l1 (so NO MY) TlLu(ada, ev 40, 693,26 No, NU. 55a, 1 NMIME SKYU Mykh, SNEOKOKOKM- 4) o rrgy 0.85 - 0.94 o, Z -e - or OO ny48-124(t,5Н) 1.61 (8,3 N) 1.66 (8,3 N) 2.42 - 2.52 (t, zo o 1Н3406-4La i a NI Ta 5 o Na NIV - 7.35 (p , 460 04 A " KENYA, eto, xx, 1 NU 59 (a, ev, y (M) y Nx,1 3 7.69 (aa, lek 40, 595, 124 Ne, 1 H) Ya.58 (a, le . 50 NOT IN and | "I ME (400 МН, BM5О25) 5 ррив 0.80 - 1.00 yo, 2 NO - sr 123, WITH NK, WITH NO. 54 (in, 3 NO 2.55 - 2.65 (tyu, AND NO 7.05 Mass : ZE and (av NI EN) pelvis et. Ne, EN 7.59 s 2-76 Na, 1| 432.00 |A o IV) 7.67 (ai, 28.34, 7.00, 1.04 Shcheh, 1 NZ 7.76 (ai, 58.40, 7.05, | (MY) Kn NAiNNIVvoa, EV ON, NO 12.97 - 135 (t, 1 NU ke shini "I MM (400 Mnya, OMBO-y,) 5 times 1.20 0.715 NAZNI Oasa: 4 137-145, 3 NU 3.23 (a, 7.46 Vy, 2 8) 4.08 - 4.18 (pi, 4 8) | 392.05 | С 7.06- 7.36 (80, 2 NU 7.60 - 7.76 t, 4 H) 8.3044, 1 V) (MAT) Kn, izhe 'Ya MMK (400 MY", OM5O-18) B rr 141 0, 77.57 NU, Z H) M U asa: av" er 3.2349,.7-7.60 g. 2 N)4.09 (5.2 N) 7.07 - 7.36 (t,2N) 7.53. | 364.04 VI 7.80 pt, 5 NO 8.29 a, 0-8.29 Nx . VO 1.50 A and (8,3) 1.53(8,3 N) 241 - 2.50 (t, 1 N) 3.90 (4,.257.25 Ne, 2 N) Mass; 05 43045, 28) 7.31 - 7.44 (sq, Z M) 7.60 (yes, le8.34,700,124 | (Mat) a No, 1) 7.69 (404, 258.40, 5.95, 1.24 No, 1) 8.57 4, 258.29 НнЕ1 Roma H MMK (400 МН», BMBO-) 6 rt 0.76 - 0.96 (p, Z 8) 1.12- not stump Y.21 (p, 2 H)1.3348,3 NO 1.38(8,3 B) 256 ZbO(B1 NU BA sa. 5V sh (8,2 Nu 7.04 (4 , .2e8.29 MN», KN) 7.35 - 7.45 b, 2 H) 7.58- 765 |39711 |C (sh, 1 H) 767-774 (t, 1 NU 8.5644, 28.29 Nya, 1 B) 12.80 dya. WE) 5.1 NMME (0 MN, OMEOO roti 2013 3159-17 uch M) 172 - 184 (36 2 NU 2.08 - 2.19 -zl6( "A, - (y). 184 (t, 2 H) 208-219 (p, 1 H) 224-236 (p | aa, bA cho 4 NGO. 2.73 (t. 2 NI I OV - 4.23 (p 4 NI 3.23 (4, 25145 Ne, 36910 C and 1NI5Z35( lena NT (Y, let NN) 75 OM) 28 NO 1 schy "TMM (00 Mykh, SNOOKOVOVM-OY b rot o VE 004,2 "a e MAT iso voy bI NNYAV wasa. 7 to 242-251(n.1 NU.17 (a, 7.88 НХ, 1 B) 728-742, Z H) 364.11 A 7.58 (444, le8.20,6.95, 1.14 Ne, 1 NI 766 (I, leya40, 65, MY) le nya NIV 57 (a, le8.29 No, 1 H) NMME (400 My, OMEOchi in yr: 34 0914.9 3- . Her inn; I ! zhk Iova, 2) 254-261 (v, H) 3994, LAB NU Z NUT | sa. a (a, le788 z, IN) 744 (40.74 No, EN) 7.59 - 7706, 2 H) 14045 7.75 (in le762, 1.14 Na, 1 B) 8.59 (4, ln8.50 Ne, Z B) 12.94 (re. | MAT) z..1 NO their MG NNMA 06 MN MBO B rrtoYA 095,2 NU 115: Ge E-I with still I - we still I . No , KNU 7.63 "7.73 (in, 2 I) | (Fig A 7.73 27.79 (in, 1 N) 8.60 44.2e5.39 Na, 1 1) E3.17 (ve. in. 1 8) NMA 400 MN, SNIOVOVONM-F B rr o VK - 09501, , DU H)148-127(p5H)195-220(p2H)225-242 (0.2 8) that 5 2A3-2.52(n,1 2.75 - 2.87 b, 2 3) 411 54.15 (ta, 2 II) 7.21 | Mass: tod 55. (8,.2e80Yyu Ne, E NU 7.33 - 738 (t, 1 NU 7.38 - 7431, 1 3 761 (Me MA , (give, /e8.29, 6.95, 1.14 Nizh, IN) 7.70 ( 44, 840, 7.05, 1.14 МН, 1 НУ 8.58 (9, .2е8.29 НУ, EN) ME (400 МН, MeОБ) bovto vo Ya, NI. (t, EN) 2.31 - 2.42 (t, IN) 2.55 (p, /e8.37, 5.43 No, 1 NU 2.50 -| Mass: 108 444.02 | MA so 2.VE (t, 2 NU 3-64 (d.Yae705 No, 2 NO) 7.14 (in , lion NN) | (Met) 7.45 47.53 (5.7 N) 7.64 (dai, Le8.34, 740, 1.24 nya, 1 НУ7.Т3 (444, 78.40, 6.95, 1.24 Ne, 1 N) 8.65 (4, L»8.50 Mig, 2 VO R oil TN MMK (300 МНх, ОМЯОчИ6) Z рр 155- и Ko 4 NO 325 V и8,3 N) 2.67 (,726.32 Nt, 7 1) 4.01 (0, 5.80 Ex, 2 N) 7.07 (8, | Mass: DB znan (d, 22809 Ne, EN) 8.70 (5, 1 NU 12.02 (g, v., with NI and TN KhMK (200 MN", OMI5O-46) 5 repo 1.19, 72705 Nx, with NU VED AND IN NO ) 2.59 -2.65 (zhu, 2 H) 4.06 «4.19 (iv, 4 M) 7.41 (8, 1 H) 8.65 (8, E| (Me) what What PnKINovo MN, OMO-4615 рrt 1119 1.2-7.15 NU, Z M) vas I66(Be 8.2) 72 - 1 86ishu2 NU 228 (B, Z NU 26 26 | | Ne 23.59. 332,12 cho AD8 t, 4) 207 (ant VE NN) to (a, tian nia NI Om ) catch, and V she Y 27 | tea" (5.3 NO 217 (B e612 Nya, 2 8) 2.24 (8, 3 H) 2.58 - 2.55 (to, 2 M) | 318,08 | С 406(,2 NI 116,1 NU yaz, 1 NII292 0, 1 Z (Mt) vo sov p km voy mne, vM5o-a) 5 rrsh155-18a (vu I NIK: 2.30 y, 5 H) 2.67 (0,.2e6.32 2,2 04,01(4,.72e580 NU, 2) | Mass: 28 cho 7.07 4,.7:7.88 g, 1 11) 7.20 (4, 728.09 Nkh, IN) 8.70 (8, 1 ) (Me o 12.92. NI vyaa(DI NU (Mal) ep VEDE de 32 NI2.25-237(,6 N) 7154-7226 Na 1 N) 7.22 (6.8. 18) (278,07 |С chi 7.354144, 2-64 Nx, 1 H) (MA) at 7.58 - 772 (t, 3 B) 778-784 syu, 1 NO (Ma) Sh- y Z shk y 'N MM (400 МНх, ПМ5О-45) b ry 194 (g. 8., 3 M) 207(5.3) Mass: 36 ie H28(v,3 NN) 744-724 (4 NU TZOV (Me and K-ya on MMK (406 MN", OMUOYA)rrt oti, Z Ya, Me aka and in Ya-311 Ne, 23.50 (8, Z NI 7.13 DYA, Ae7.62, 1.14 Ne, 1 NU 7.30 | Mass: 37 | «km t 280.02 |C (4, le8.29 Ne, 1 NU 7.35 (8, 227.67, 1.66 Na, 1 MU 754-760 | (Me) (sh.,Y 1) shk Yak 'N MM (400 MN, ЮМ850th,) 5 yr 1.93 (5.6 1) 2.05(5.3 8) | Mass: Zv Zlo v, NI to 734 (t, 2 V) 7.36- 742 (v, 1 V) (me). o NMYMK (00 МН, ОМ и рр и 00. ny эх I.24 (to, Z H) 2.54 - 2.64 (v, 1 H) 4.01 (0.2-145 Nya, 2H)4.07- Mass: 46 44712, 2 H) 748 (y, 7e7.67 Na, 1 80 7.53 (4, et z, 1 H) 136910 s Я zla yty, 114 Ne, 1 H) 7276 - 7.83 (t, 2 NU 8.34 (q. 3. MY) NI Vvo (a, 28.29 Ne, 1 8) H MM. (400 MY", PMYASNYAO in ert 0278 - 0.02 (t, 2 NN. 16 she ti pane (4, /8.50,207 2) 2.54 42.59 (shchu 1 F) 3.11 (8.2 NUT sa. 47 uz (v. 2 R 7.23 (4, 28.09 Na, 1 NO 7.38 « 7.44 (pi, 1 H) 746-752. 341.03 A (p, 1 80) 7.60 «7,57, 1 NU 7.72 (ad4, le840,695,124 well MY) BUT Vl, 8.50 NO, 1) that yu- 0 MMESYUYU MN, OM5O-) 6 рrt 080 -096ishyu Z NT OYA- ne ke s y y and 1224 (sq., 5 НО 1.39 - 1.49 (10, Z M) 2.56 - 2.64 (ий, EN) 4.00 - 4.13 | Mass: 48 3 (I 2 N) 4.22 (49, 216,35, 7.29 Nx, 1 N - 093 (t, 2 H)114- m-ya, y and tari x; , ny 122(p,2H)135(5-1-746 Na, NU2.35- Zb (t 1 NUZ YAZ U | sa. 49 3.99 in, 1 8) 6.39 (g. 8.3 37.25 7e7.57 ny 1174344, 355 ,07 "tv Na, 185 7.55 (ai, 227.67, 2.28 Ne, IN) 7 - Tatu M) НО7Л7О- tli, NO 8588. No 1 B) TYA x pni "N MM (300 MYH, SNI OKOVOVM- 5 rot 1.23 0.3 NO 3.20 mass: in" cha (d52 804.03 b, 2 NU 5.01-5.43 (ip, 2 NI) 7.07-7.65 (in, 4 H) 8.02» 346.0 yo 8.22 half, 2 1 ) (May) r ; Ba and | 7 "yin MM (300 MY", PIMO-) 5 yr: 2.75 (5.3 H34.0245.2 V) Mass: oo 6.95 - 7.38 (t, 1 H3 7.50--8.21 (tv, 5 NV) (M ) nya and brown in TYA MM 00 MN", MO 8 yr 1.50 1.82 4t,4 N) 2.13 Mass: 5th pom ; I also N shk 5 z cho -2385(t,4 N) 2.64 (3, 3 37.02 - 7.71 (I, 4 SHHI (ME) NMME00 МН, МОР) b reto 85 05 NO: fish and 126(1,2Н)202(8,18)248-2594 1 Н)406(Vsv NO aga: 56 6.70 - 7.03 (v. 1 1) 7.23 (4 , -8.29 M, 1 H) 745 (4.2e7.46 Nx, 376.06 to 18) 7.54 - 7.66, 2 837.68 7.755, 1 H) 8.630.2e8.50 Ne, M) 1 NO «I NMmMkiyuoMn:, OM5OyuoBro p ZE i 2.7745.3 N)4.10-4.26(t, 4 NU 7.0044,.2e7.88 No, 1 NU 7.08- | Mass: b1 iso T38 in, 1 NU 7.54 (5.1 N) 7.58 « 7.72 (t, 2 N) 8.14 - 8.20 (t, 1 (Me and and th NYM 400 MN, OM5O-4) b yr 155.3 NU 7653 "IR pak SK t.5a (in 1 NUT ZV. 7 7 ( ace NO VL6 (I Tv NA 1 H) 1303 | (Mn) (g. 3.1 soch NO MMA 000 MN, РМ50-15 5 ррех 4.04 (in, 2 H) 7.19 (4.1 8) | Mass: ba cho 7000 1695-738(8.1 NU 750-821 (tv, Z Yu) (Me) In TYA MMV sob MN, MBO) B rot. 17 1251, 3) 160-vot 1.72(t, 2 H) 1.78 (apiv, Le5 12 Mt, 2 H) 205-216, 1) |Mass: cho 2.28-2.40 (p, 4 N) 2.60 (,P-6.33 No, 2 N) 4.12. 44.29 (t, 4 I) (Me 722-730 (t, 2 B) roles TEMOI ME BMBOCHK B yr 150 72 ZNU TV vet (aniv. 26.01 Cl, 2 NU 2.10, e16.74,593 r, ENI2.26 00 | Mass : 67 zov, I NU zv ochvla I DON'T KNOW AoVsaozio Tu 7.29 (t, 2 NO 13.09 (bg, 5.1 8) sh NYM 200 MN", MY mouth: 09103 "TB ELE FF No, 2 H)7.1544, 728.09 M, 1 8) 7.2514, le767 NO NO 761. |4182 Z 1 LEbt, 2 NO 775 (leva, DYA Na, NO 8.59 (625829 g, | (MY) 1 vein and more in. | ok ; ; М . Н MMA (300 МН», BM5O-4,) 8 rrit 2.78 ( 8.3 B) 3.54 (3.2 N) | Mass: 74241) 7.52--7785 (t,4 NO B.21 (0.2 N) (We) And that "I MMA 1400 ME", SNIGOKOROVM-I 5 rrin 1.48 (6, 75745 roi ne, ZN)zayaifltvo naz VZ lvi Z Ov(V VAH sa. t «t Ne, 2 H) 725 - 7.28 (t, 1 H) 7.30 - 7.44 (o, 1 H) 7.50 (4, /7e7.46. | 405.95 | A i | Nx, 112) 7.60 (444, 7-829, 6.95, 1.14 Na, 1 NU 764 -TlO(t, 1 mM) t 8.21 (y,e8.79 NE, 1 N) a-i i 'Ya mmya (400 Mne, VMO rest 4075 NE N)Oasa. 74 3.22 (du le7 AB Ne, 2 H) 4.01 (4, 723.66 Ne, 2 H) 7.17 (8, .2-8.09 | 391.92 | A dO She, 1 T.V - 7.77 (t, 4 HO) 8.30 44, A-8.50 Nx, 1 B) (We) I MMA (400 Mne, OM5O-4. 5 yr 0.81 - 0.93 (t, Z NO) 1.10- an Tozhitv, 5 NUT I (mu, 5.47 Na, 1 NO 3.98 i 4.16 (vz, 4 B) Mass: 76 tr Tit Vona NI Tv (6, 746 NI, IN) 7.62 7.72 (pi | 431,96 o 287.77 (aa, 8.34, 750, 1.24 Na. 1 NIA BI (6, 228.29 No, 1 (WE) NI and o » n MM (oo MN, Mabby 5 rot 0.83 40.94 st, 2 NE Л - 78 sho Phi. for al, yu 25 (8,2 NI 43: 255it, 1 NI ZYAZ (8, Z NN) 647 loc; and, On and 7.29 (y, "767 zh, E NU 7.35 (ai, 45933, (May) ; ZAZNA let Nya, 1 B) 8.53 (0, eo33 Nyh, 1 NU M, l-ry H MM (40O MN), Me) b rryayu 145 (6 la746 NU, 3 NI 322 Sh Her I 4 (a. 760 NYA, NU Z YAZ, 3 NU Z.89 4.14 (ka, 2 H) 6.49 (y, Mass: 2 7 ke Na Er . c) 6 pieces of wood 0.85 - (696 (t, 2 "y 1118-1531 (5.5 Nu 54 - BI (yuyu, Z NO 2.47 E, U-8.5), 5.49 Mass: 85 Fo | NE 11409423 (t . "7.14 b, 1 NU 8.54. 561 z, 1 NI sh on NM (chyu MN, SN OKOKOKM 2) 5 firewood 0.88 - 196 sl, 2 ki NI149-156i8yu 2 NE 162 (t,3 NU 2.48 EN, ev. 47, 5.42 Mass: same Nx 1 Na35 (az, 251467, 727 Na, 3 NO 7.23 (48, 711.20, 8.29 child 9 A shk Mk, 1 H) 735-744 (t, 2 H) 7.64 (ti,2e8.40,6.05,145,145 | (MY) not NN) 7 -7.77 (shsh, 1 NO) 8.60 (aa, 58.29, 560 NO, 1 NO NMMY (400 MN. YUM8O-avI 6 yr 0.87 - 0.94 sv, 2 NO 1.15 - nih I21it 2 NU 141.9) 255263 (t 1 NU ZU Yasa. 88 : Not Z NTIV (a, eV O9 Not 1 NU 7470, 767 Nx, 1 NN) 766 146Оo1 С So sa, e7.bB7 NN, 1 NU TV - 7.72 t, 1 НО 7.7 I (848, ye840, 695, | (M) 14 NO, 1 NIV bok nya For NNI MMK (00 Mykh, SNEOKOKOKM-e) 4 roti 324.15 t What Na Z H)I150( AT Av NE, Z NI 1.65 (8 . 5 NN) 1.66 (8, 3 NO 3.25 ven o (f.a-7.53 No, 2 N) 4.06 - 414 (t, 2 N) 7.16 (8, 258.50 Na, 1) | Mass: what Tana No, 1 NO va, tA AT 17.57 (a, (Me y JaeV.34, 7,106 NO, 1 NO 756 (aa, e8,45, 7.00, 135 NN 8.21 (4, 8.50 Ne, | H) and A kum NN ZHME (400 MN, PMS) b rogo 1.37 « 1.44 in, Z NI 1.50 o (8,3) 1.54 (5, 3 NU 3.22 sub, 7.43, 404 Na, 2 NU 7.04 (I, Mass: oo B? Na, NU) U.58 - 7.67 st, Z NU 7.68 - 7.75 (pa, KN) 8.29 44, (Me A - «fe8.29 No, 1 HO 13.09 (g. 8., 1 H) Example 13: Metabolic stability of ip mito The metabolic stability of ip mito was evaluated in rat and human liver microsomes (VI M/NI M). The incubation mixer contained the following: 1 µM test compound, 17 mg/ ml NI M/VI M, 100 mM potassium phosphate buffer with pH 7.4; 1 mM MAORN and 5 mM Maosi". This mixture was pre-incubated for 3 minutes before the 330-minute incubation at 37 "C. The reaction was started by the addition of MAORN and ended by adding the same volume of acetonitrile with an internal standard. Incubation samples without MAORN were used as control samples. After vortexing and centrifugation, the supernatant was injected into the I C-M5/M5 system for quantification. According to this method, the compound preparedin example ZE above (2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-z-ylthio)-2-methylpropanoic acid), the results of which are given in the following tables. ZNO Mon Compound about /about THOSE WHO REMAINED Example ZE n-M E leads a dream about. vu 9752 90 9850.1 Fo A Example 14: Methyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate male. SCHE re mo ne nina r vinen fe: Mene se MEKNe a v shi yan t TE Fe S. all . all VOKet S « Meakiyurrki; So again, Vs K- sh- "three nyat vtuitryn not in whom ME mayusiosoy Vovumn! 1-Cyclopropylnaphthalene Cyclopropylmagnesium bromide (150 mL; 0.5M in tetrahydrofuran) was added slowly to a solution of 1-bromonaphthalene (10 g, 50 mmol) and (1,3-Bividiphenylphosphino)propane. nickel(I) dichloro in tetrahydrofuran (10 mL) which was stirred at 090. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, after which ethyl acetate and aqueous ammonium chloride were added. After extraction, the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-cyclopropylnaphthalene (6.4 g, 76 U). 1-Cyclopropyl-4-nitronaphthalene sodium nitrile (30 mL) was slowly added (over 2 hours) to 1-cyclopropylnaphthalene (6.4 g; 38 mmol), which was stirred at 02. The reaction mixture was stirred at 09C for another 30 minutes, after which it was slowly poured into ice. Water was added, then ethyl acetate. After extraction, the organic layer was washed with an aqueous solution of sodium hydroxide (1 95) and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-cyclopropyl-4-nitronaphthalene (5.2 g; 64 b). mn A 1-Amino-4-diclopropylnaphthalene A solution of 1-cyclopropyl-4-nitronaphthalene (5 g, 23 mmol) in ethyl alcohol (200 ml) was stirred under a hydrogen atmosphere in the presence of Ra/s (10 95 net, 1.8 g). The reaction mixture was shaken overnight, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-amino-4-diclopropylnaphthalene (3.1 g, 73 Vol). bottom 1-Cyclopropyl-4-isothiocyanatonaphthalene Thiophosgene (1.1 g; 9.7 mmol) was added with stirring to a solution of 1-amino-4-cyclopropylnaphthalene (1.8 g; 9.7 mmol) and diisopropylethylamine (2 equiv. ) in dichloromethane (50 ml) at 0 C. The reaction mixture was shaken for 5 minutes at 0 "C, after which an aqueous solution of NOI (1 95 solution) was added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. Hexane was added and filtered precipitate that formed. The solvent was evaporated to give 1-cyclopropyl-4-isothiocyanatonaphthalene (1.88 g, 86 b). mb a 5-Amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2 ,4-triazole-3-thiol A mixture of aminoguanidine hydrochloride (3.18 g; 29 mmol), 1-cyclopropyl-4-isothiocyanatonaphthalene (3.24 g; 14 mmol) and diisopropylethylamine (3 equiv) in DMF (20 mL) stirred at 50 "C for 15 hours. The solvent was removed under reduced pressure, toluene was added and the solvent was evaporated again. Sodium hydroxide solution (2M, 30 mL) was added, and the reaction mixture was heated at 50 °C for 60 hours. The reaction mixture was then filtered, and the filtrate was neutralized with aqueous HCl (2M). The mixture was filtered again, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol (2.0 g; 49 Vol). and- C tour Methyl 2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate Methyl 2-chloroacetate (0.73 ml; 8.3 mmol) was added dropwise over 5 minutes to a suspension of 5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol (2.24 g; 7.9 mmol) and potassium carbonate (1.21 g; 8.7 mmol) in DMF (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 h, then slowly poured with stirring into ice water. The reddish-brown precipitate was collected using vacuum filtration and dried under high vacuum at 50 "С for 16 hours in the presence of P2O5 to obtain methyl 2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-z-ylthio)acetate (2.24 g; 80 Ob). rev vit Methyl 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-ylthio)acetate Sodium nitrile (2.76 g; 40 mmol) was added to of a solution of methyl 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate (0.71 g; 2 mmol) and benzyltriammonium chloride (1 .63 g; 6 mmol) in bromoform (10 ml). Dichloroacetic acid (0.33 mL; 4 mmol) was then added and the reaction mixture was stirred at room temperature for 3 hours. The mixture was placed directly into a 7-inch silica gel column packed with dichloromethane (DCM). The column was first eluted with DCM until all bromoform was removed, then with acetone/DCM (5:95) to give methyl 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2, 4-triazole-3-ylthio)acetate (713 mg, 85 Vol). Example 15: 2-(5-Bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid A solution of lithium hydroxide (98 mg; 4.1 mmol) in water (10 mL) was added dropwise over 5 minutes to a solution of methyl 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)- 4H-1,2,4-triazol-3-ylthio)acetate (prepared as described in example 1 above; 1.14 g; 2.7 mmol) in ethyl alcohol (10 ml) and THF (10 ml) at 0 "WITH. The mixture was stirred at 090 for another 45 minutes, and then neutralized to pH 7 by adding a solution of 0.5 M NOSI at 090. The resulting mixture was concentrated by massio to 1/5 of its original volume, then diluted with water (520 ml) and acidified to pH 2-3 by adding 0.5M NOA to obtain a sticky solid mass. (When the product comes out as an oil during acidification, DCM extraction is recommended.) The reddish-brown solid was separated by vacuum filtration and dried under high vacuum at 50 °C for 16 h in the presence of P2O5 to give 2-(5-bromo- 4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (1.02 g; 93 95). Example 16: Sodium 2-(5-bromo-4 -(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate M-M n-M yx x - mia; a man (vo) o /x A Aqueous solution of sodium hydroxide (1M, 2.0 ml, 2.0 mmol) was added dropwise over 5 minutes to a solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-Z -ilthio)acetic acid (810 mg; 2.0 mmol) in ethyl alcohol (10 ml) at 10 "С. The mixture was stirred at 10 °C for another 10 minutes. Volatile solvents were removed by evaporation to dryness to give sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as a solid (850 mg, 100 95). Example 17: Potassium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate M-M sh-Y GU Ux . vm tv on vent two Kk I o KOH (ad) SHA o 9 t C : y An aqueous solution of potassium hydroxide (1M, 2.0 ml, 2.0 mmol) was added dropwise over 5 minutes to a solution of 2-(5-bromo- 4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (810 mg; 2.0 mmol) in ethyl alcohol (10 ml) at 10 "С. The mixture was stirred at 1090; 10 more minutes. Volatile solvents were removed by evaporation to dryness to afford potassium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as a solid ( 884 mg, 100 95). Example 18: 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)-M-hydroxyacetamide in 7 parts. A solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (1.0 mmol) in THF (2 ml) and methyl alcohol (2 ml) were added to a solution of sodium hydroxide (5 mmol) and 50% aqueous hydroxyl amine (2 ml). After stirring for 1 hour at room temperature, water (4 mL) was added and the volatile solvents were removed by massio. Then the solution was neutralized to pH 7-8 by adding HC (1M), and the resulting precipitate was separated by filtration to obtain 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4- triazole-3-ylthio)-M-hydroxyacetamide. Example 19: 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)-M(H"a, B) acetamide AZ la AKA, cotton wool nn de wortue Fo so -A in Phosphorus oxychloride (2.6 mmol) was added dropwise over 5 minutes to a solution of 2-(5-bromo-4-(1- cyclopropylnaphthalen-4-yl)-4H-1,2,4 -triazole-3-ylthio) acetic acid (2.2 mmol) and amine (МНА"аВ; 2.2 mmol) in pyridine (22 ml) at 090. The mixture was stirred at 092 for another 1 hour, after which the reaction mixture was quenched by adding of water (1 ml). Volatile solvents were removed by IP massio, after which DCM (200 mL) was added. The organic phase was washed with water (1 x 50 ml), saturated sodium carbonate solution (1 x ml) and brine (1 x 50 ml), dried over Ma»5O»x and concentrated to dryness. Ethyl alcohol and water were added to obtain a solid mass, which was separated by filtration. An additional product was obtained by extracting the DCM filtrate. The combined product was concentrated, dried and purified by column chromatography (eluent acetone/DCM) to give 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole -Z-ylthio)-M(B2a, B")-acetamide. Example 20: 2-(2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)acetic acid ; Where are you from? And ome viv OMme ; ; about; glycine ethyl ether hydrochloride (0.21 g; 1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g; 1.86 mmol), 1-Hydroxy-7-azabenzotriazole (0.25 g; 1.86 mmol) and 2,6-lutidine (0.43 mL; 3.71 mmol; 3.0) were added to a solution of 2-(5-bromo-4 -(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (0.5 g; 1.24 mmol) in dichloromethane (6.18 mL) and the mixture was stirred at room temperature for 18 hours. Purification with 5020 (0-100 95 EIOAc/hexanes) provides 2-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthioacetamido) acetic acid. Example 21: 2-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)acetic acid m-m АХ М-М in! An aqueous solution of lithium hydroxide (1M, 0.8 ml; 0.8 mmol) was added to a solution of ethyl 2-(2-(5-bromo-4-(4-cyclopropylnaphthalene) 1-yl)-4H-1,2,4-triazole-z-ylthio)dacetamido)dacetate (0.4 mmol) in a mixture of 31, THF/H2O (1.6 mL), and the mixture was stirred for 18 h at room temperature temperature The crude reaction mixture was concentrated and acidified with aqueous HCl (1M, 1.2 ml), and then extracted with ethyl acetate (3 x 3 ml). The combined organic extracts were dried (sodium sulfate), filtered and concentrated to give 2-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3 - ilthio)dacetamido)acetic acid. Example 22: Methyl 2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)dacetamido)propanoate m-m o en H o in tu ng teme "tugu tone ryh Ger ts - I a a Alanine methyl ether hydrochloride (1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol), 1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 ml; 3.71 mmol) was added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yltide)acetic acid ( 0.5 g; 1.24 mmol) in dichloromethane (6.18 mL). The mixture was stirred for 18 hours at room temperature, then purified with 5 (0-100 95 EAs/hexanes). Examples 23: 2-(2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthioacetamido)propanoic acid M-k o M-M Gu Z ots m «otu on | "that's the MES hell; a so - sko »: this member of the Gu An aqueous solution of lithium hydroxide (1M, 0.8 ml; 0.8 mmol) was added to a solution of methyl 2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4 -triazole-z-ylthio)acetamido)propanoate (0.4 mmol) in a 3:11 mixture of THF/H2O (1.6 mL), and the reaction mixture was stirred for 18 hours at room temperature. The crude reaction mixture was concentrated and acidified with aqueous HCl (1M, 1.2 ml), and then extracted with ethyl acetate (3 x 3 ml). The combined organic extracts were dried (sodium sulfate), filtered and concentrated to give the desired product. Example -: 24: Methyl //2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-phenylpropanoate the soft cry of the storm to us; vtru "toma sho z o sv, fi Zny sa - and oninininninininn iy Phenylalanine methyl ether hydrochloride (1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol), 1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2 ,6-lutidine (0.43 mL, 3.71 mmol) was added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-z-ylthio )acetic acid (0.5 g; 1.24 mmol) in dichloromethane (6.18 mL). The mixture was stirred at room temperature for 18 h, then purified with 5020 (0-100 95 EOAc/hexanes). Example 25: 2-(2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido-3-phenylpropanoic acid ХА ХА ШЧІ tsonev still sho | | SHHI school An aqueous solution of lithium hydroxide (1M, 0.8 ml; 0.8 mmol) was added to a solution of methyl 2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4 -triazole-z-ylthio)acetamido)-3-phenylpropanoate (0.4 mmol) in 31, THF/H2O (1.6 mL) and the mixture was stirred for 18 h at room temperature. The crude reaction mixture was concentrated and acidified with aqueous HCl (1M, 1.2 ml), and then extracted with ethyl acetate (3 x 3 ml). The combined organic extracts were dried (sodium sulfate), filtered and concentrated to give the desired product. Example 26: Methyl 2-((9H-fluoren-9-yl)umethoxy)carbonylamino)-6-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4 -triazol-z3-ylthio)dacetamido)hexanoate o o M-k m-Ome MM N Me SHIK oo ni-chen You OA to the child what? from the height of MASONnetos ve in TU nEtus o shin shchi o ; with so so Methyl 2-((9H-fluoren-9-ylmethoxy)carbonylamino)-6-aminohexanoate (M-a-Ethos-lysine. (MHg)-OMe, 1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol), 1-hydroxy-7- Azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL; 3.71 mmol) were added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1, 2,4-triazole-3-ylthio)acetic acid (0.5 g; 1.24 mmol) in dichloromethane (6.18 mL). The mixture was stirred at room temperature for 18 h, then purified with Ba (0-100 95 EIOAc/hexanes). Example 2: 2-(1,2-Dihydroxyethyl-4,5-dihydroxytetrahydrofuran-z3-yl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol- Phosphorus oxychloride (2.4 mmol) was added dropwise over 5 minutes to a solution of 2-(5-bromo-4-(1- cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-z-ylthio)acetic acid (810 mg; 2.0 mmol) in pyridine (20 ml) at 0 "C. The mixture was stirred at 09b for another 1 hour , after which a solution of 1,2:5,6-Di-O-isopropylidene-o-Y-glucofuranose (320 mg; 2.0 mmol) in pyridine (5 mL) was added dropwise over 5 minutes. The mixture was stirred at 090 for another 1 hour and 1 hour at 20 "C, then quenched by adding water (1 ml). Volatile solvents were removed by massio and DCM (200 ml) was added. The organic phase was washed with water (1 x 50 ml), saturated sodium carbonate solution (1 x 50 mL) and brine (1 x 50 mL), dried over sodium sulfate, and concentrated to dryness. Ethyl alcohol and water were added to form a precipitate, which was collected by filtration. were obtained by extracting the DCM filtrate. The combined product was concentrated, dried and purified by column chromatography (eluent acetone/DCM). Ethyl alcohol and water were added to form a precipitate which was collected by filtration. The combined solid was dissolved in a mixture of acetic acid (25 mL) and water (5 mL), heated at 60 °C for 3 hours. Example 28: 2-hydroxy-2-(3,4,5-trihydroxytetrahydrofuran-2-yl)ethyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2, 4-triazole-3-ylthio)acetate m-Mm but m-m Zh M. sn Bo OH dych okon vo Go. weight B; He u thuyu with C and Phosphorus oxychloride (2.4 mol) was added dropwise over 5 minutes to a solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol- z-ylthio)acetic acid (810 mg; 2.0 mmol) in pyridine (20 mL) at 090. The mixture was stirred at 090 for another 1 hour, after which 1,2-O-isopropylidene-o-Y was added dropwise over 5 minutes -glucofuranose (440 mg; 2.0 mmol), dissolved in pyridine (5 ml). The mixture was stirred at 09°C for another 3 hours and 1 hour at 20°C, and then quenched by adding water (1 ml). Volatile solvents were removed by massio and DCM (200 ml) was added. sodium carbonate solution (1 x 50 mL) and brine (1 x 50 mL), dried over sodium sulfate, and concentrated to dryness. Ethyl alcohol and water were added to form a precipitate, which was collected by filtration. Additional product was obtained by extraction of the filtrate with DCM. The combined product was concentrated, dried and purified by column chromatography (eluent acetone/DCM). The combined solid was dissolved in a mixture of acetic acid (25 ml) and water (5 ml), heated at 60 °C for 3 hours. Volatile solvents were removed from the mass. Ethyl alcohol and water were added to form a precipitate which was collected by filtration. Example 29: 3-(2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetoxy)-2-hydroxypropyl oleate Phosphorus oxychloride (2 A mmol) was added dropwise for 5 minutes to a solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H- 1,2,4-triazole-z-ylthio)acetic acid (810 mg; 2.0 mmol) in pyridine (20 mL) at 090. The mixture was stirred at 090 for another 1 hour, after which glycerol monooleate ( 715 mg, 2.0 mmol), dissolved in pyridine (5 ml). The mixture was stirred at 090 for 3 hours and 1 hour at 20 °C, after which it was quenched by adding water (1 ml). Volatile solvents were removed by mass and DCM (200 ml) was added. sodium carbonate solution (1 x 50 ml) and brine (1 x 50 ml), dried over Ma5O", concentrated to dryness and purified by column chromatography (eluent acetone/DCM) to obtain 3-(2-(5-bromo -4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetoxy)-2-hydroxypropyl oleate. Example 30: (2, 35, 48, 5H8)-5- (6-amino-9UN-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2, 4-triazol-3-ylthio)acetate MH" Sk. Shchi rnon st fi anun and drink! a The title oxyribonucleoside compound is prepared according to the synthesis scheme shown above. Protecting groups may be used which may or may not be removed at the end of the synthesis. Example 31: (28, 35, 5I)-3-hydroxy-5-(5-methyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)utetrahydrofuran-2-yl)methyl 2 -(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate The title deoxyribonucleoside compound is obtained according to the synthesis scheme shown above. Protecting groups can be used, which can be removed or do not remove at the end of the synthesis. Example 32: (28, 35, AB, 58)-5-(4-amino-2-oxopyrimidine-1 (2H)-yl)-4-hydroxy-3-(phosphonooxy)tetrahydrofuran-2 -ylylmethyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate MN MN. che ee Dyu, SM SD la, SH dit o "I un STA yin O-v-0 | I OR The title deoxyribonucleoside compound is obtained according to the synthesis scheme shown above. Protecting groups may be used which may or may not be removed at the end of the synthesis. Example 33: 2-(5-Bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-yltide)acetic acid - REA conjugate is active i obro Odin BO vysh lvovyvov Fe 3 7 As EshNnchikhakisna group i : d d The title RES-conjugate (REY - polyethylene glycol) is obtained in accordance with the synthesis scheme shown above. Protecting groups may be used which may or may not be removed at the end of the synthesis. Example For: Solubility of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)dacetate - free acid, sodium salts and piperazine Up to 1.00 ml (or 0.50 ml) of the test solvent in an Eppendorf tube was added to various weighed amounts of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate ( in the form of free acid, sodium salts and piperazine), recording the weight. When approaching the saturation point, the addition was stopped, and the Eppendorf tube was shaken at a constant speed of 1000 rpm. at 22 "C for 24 hours. Then the tubes were centrifuged for 5 minutes at 10-15,000 rpm. and checked for precipitation. Samples were diluted with acetonitrile/water (1/1) (or isopropyl alcohol for hexane) and analyzed by HPLC against known standards. The results are shown in the table below. Solvent 001 virausdt t em outijvraaiu Solvent - : : : Acetone 11111111 Ї11117791Ї111111110026сС1С Watern485). ОИ Ї111111492 РЕБЯ00 7 Ї1711111111111111111Ї11111112 | 24 VYUAS 17 Ї11111111111111111111Ї11111211117111111110055..ІLY Acetonitrile.o////// 15476 ІІ oMethyl alcohol | 0519309 HER Hexane/////777777771-418411 HER oDichloromethane./////|177711»2153 HER Ethyl alcohol (HER 77777717! PI Clinical examples Example 35: Reduction of uric acid activity ip mimo Reduction of uric acid activity by the compounds described here has been demonstrated in a double-blind, placebo-controlled, multiple-dose-escalation study in healthy adult male volunteers as follows. This study was conducted in accordance with the latest version of the Declaration of Helsinki and the ISN (International Conference on Harmonization) note on good clinical practice guidelines (SRMR/ISN/135/95). 16 healthy men aged 18 to 45 years inclusive, with a body mass index (BMI) of 18-30 kg/m inclusive, who gave written informed consent, had not smoked for at least 6 months, had not received medical treatment for 2 weeks before screening (2 months for enzyme-inducing drugs), except rarely for acetaminophen.Subjects were in the clinic from the day before the first dose until 72 hours after the last dose on Day 17 and returned for assessment on Day 2151. The study was conducted using (4-(2-(5-bromo-4-(4-cyclopropane-naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)dacetamido)-3 -chlorobenzoic acid as potassium salt), in the form of a 100-mg solid powder in size 2 gelatin capsules. The same size 2 gelatin capsules contained a placebo. Subjects were randomized to receive an equal number of placebo capsules or active compound capsules. Capsules (active or placebo) were administered orally from 24 0 ml of water 30 minutes after standard breakfast (morning dose) and lunch (evening dose) for 14 days. 16 individuals (8 individuals (6 active and 2 placebo) per dose group). and. Group 1: Placebo r. Group 2: 300 mg (3 x 100-mg capsules) from example 1 twice a day. with. Group 3: 500 mg (5 x 100 mg capsules) from example 1 twice a day. Blood samples were taken from individuals on days 0, 3, 7, 14 and during the last examination on day 21-1. Serum uric acid levels were determined using standard automated methods. The results are shown in the following table (uric acid levels in μmol/L). Sechova. SERE- o tavtav (SVO: |oBAZov|5OBBLOYE 95168 | 39.57 | 78.514 Plagov Cohen (1722269 3444537) 5AVO | -38.067 | 34498 tsebo (60.30917: (p-4) 142752 88 85OB7 "from T23, 43618 | 46.872351 | 16.3570 | -35.093 | 59,480 eovoga IED Z2B: 1329570 | 26.59140 | 26.7660 | «48179 | 11.30! collapse (tk 1440568 | 3528657 | 101,388-95,89 | lvevoe СИ62753y | 21.33316 | 52.25536 | -119.852 | 203422 |-68.402 (p-6) -121.2401 -54.00608 26.15516 | 64.06680 | -1404.982 | -201.637 |-60.075 (- 81.47624; Survey | -2.2801 7691810 30.80866 | 75.46549 | 0.8922 | -114.796 | 77.919 , 97547 | -112,120 | -179,630 | -47,584 1276837 | C Seboge) 17,50482 | 4287789 | 144239 | 168923 | -59,480 Your: 1931590 12022578 | 49.54283 27.3608 | -54.722 | 98142 79.25368 SI. - confidence interval; 5.E. - standard error; 5.0. - standard deviation. In Fig. 1 and 2 show the levels of uric acid (in mg/dl and μmol/l, respectively) on days 0, 3, 7 and 14 of administration of the compound from example 1 in doses of 300 mg, 400 mg or 500 mg twice a day. In Fig. Figure 4 shows changes in the level of uric acid (in mg/dl and μmol/l, respectively) on days 3, 7 and 14 of administration of the compound from example 1 in doses of 300 mg, 400 mg or 500 mg twice a day. In Fig. 5 shows changes in the level of uric acid (μmol/dL) on days of administration of the compound from example 1 in doses of 300 mg, 400 mg or 500 mg twice a day. Example 36: Clinical test of the comparative effectiveness of /4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthioacetamido)-3-chlorobenzoic acid against Indomethacin Staging This was a double-blind, parallel-group, multicenter, randomized, 5-day study. Endpoints The primary efficacy endpoint is: and. Individual assessment of pain. Secondary efficacy endpoints are: and. Sensitivity of the studied joint; r. Swelling of the studied joint; and Proportion of individuals who discontinued treatment due to lack of efficacy. Treatment scheme Individuals were randomized into 2 groups: a control group (n-100) and an experimental group (n-100). The control group received indomethacin (75 mg) sustained-release capsules (twice a day) for two weeks. In the experimental group, 4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthioacetamido)-3-chlorobenzoic acid was administered in the form of a potassium salt as 100 mg hard powder in size 2 gelatin capsules for two weeks Inclusion criteria Male or female 28 years of age Established diagnosis of gout according to the 1980 ACA criteria for classification of acute arthritis and primary gout Acute attack of clinically diagnosed gout less than 48 hours before randomization A total score of 5 for the three symptoms of pain (0 to 4 on a Likert scale), tenderness (0 to 3), and swelling (0 to 3), with a pain score corresponding to at least moderately severe pain (ie, 2, C or 4 points on a Likert scale) Women of childbearing age must present a negative test for pregnancy Women of childbearing age must be infertile or on contraception Statistical methodology Primary analysis is based on the change from baseline in the individual pain score calculated from the means responses from Day 2 to Day 5 of the study using a catch-all approach that included all study subjects who started treatment. All individual efficacy variables (except those endpoints defined as ratios) are estimated by AMSOMA (a model that includes study site conditions, group |(monoarticular acute gout vs polyarticular|, baseline covariate, and treatment group), without 2-way interactions with treatment. Comparability of treatment groups is assessed using 95 95 confidence intervals for the pairwise difference between treatments. The 9595 confidence interval for individual pain scores must fall completely within the limits of comparability (ie, 50.5 Likert units). Endpoints, defined as ratios, are compared between groups using Fisher's exact test. Assumptions of normality and homogeneity are evaluated using, respectively, the Shapiro-Wilk statistic and Levene's test. If a significant interaction (rb0.050) is detected, the nature of this interaction is evaluated and further exploratory analyzes are performed. Example 37: A clinical trial to compare the effectiveness of 4-(2-(5-bromo-4-(4- cycloprop). lnnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthioacetamido)-3-chlorobenzoic acid in hypertensive subjects Hypothesis Thiazide-induced hyperuricemia reduces the effectiveness of thiazides in controlling blood pressure, leads to endothelial dysfunction and increases the frequency of insulin resistance and impaired glucose tolerance. Study design This study is a randomized, double-blind, placebo-controlled clinical trial of 8-week duration in which a total of 220 African-Americans with untreated stage I hypertension were enrolled, who were randomized and treated as follows: The experimental group received chlorthalidone (25 mg/day ) and potassium chloride (40 mEq./day) for 4 weeks. Then these patients were randomized to additionally receive the compound 4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthiodacetamido)-3-chlorobenzoic acid in as potassium salt (300 mg/day) or placebo Dose 4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido )-3-chlorobenzoic acid was adjusted to achieve serum uric acid levels between 4 and 5.5 mg/dL.All subjects received a low-sodium diet.Endpoints The primary endpoint was reduction in systolic blood pressure. Secondary endpoints assessed changes in endothelial function, ambulatory blood pressure, body composition, systemic inflammation, metabolic parameters, oxidative stress, and renal hemodynamics. Inclusion criteria: African-Americans (including black individuals in the Caribbean, Africa, Canada, etc.) Men or women 18 years of age or older Not using any antihypertensive drug with an average clinical blood pressure in a sitting position between 140/90 and 159/99 mm Hg. Art. A protein/creatinine ratio in an unscheduled single portion of urine is less than 0.5 (which roughly corresponds to a 24-hour urinary protein excretion of 500 mg/day) Calculated glomerular filtration rate on a modified diet of 60 ml/min/11.73m? or more Not using allopurinol or probenecid for at least 1 month prior to inclusion in the study Exclusion criteria: History of cancer or malignant hypertension " Confirmed total white blood cell count less than 2500/mm3, anemia or thrombocytopenia " Known history of liver disease A known secondary cause of hypertension " Known diabetes or a fasting blood glucose level of 126 mg/dL or more " History of heart failure, acute myocardial infarction or stroke, or taking a B-blocker or calcium channel blocker for cardiovascular indications other than to lower blood pressure Abnormal ECG that requires medical intervention History of clinical or renal biopsy or evidence of renal parenchymal disease Acute attack of gout within 2 weeks preceding inclusion in the study History of drug abuse in the past 2 years, including drugs, cocaine, or alcohol (more than 21 drinks per week) " The circumference of the hand is more than 52 cm, which prevents pressure measurement using the cuff Pregnancy or planning pregnancy during the study or breastfeeding " History of non-adherence to the treatment regimen, inability to meet the requirement of this study, or simultaneous participation in another study "Non-observance of fasting before obtaining screening laboratory data. When a participant was clearly not fasting, he/she will be excluded if the unplanned blood glucose level is 200 mg/dL or more. If the fasting blood sugar level exceeds 126 mg/dL, it should be confirmed with a measurement the next day, as required by the criteria of the American Diabetes Association. Example 38: Clinical trial in hyperuricemia or hyperuricosuria Setting up the research This study is a 4-week, randomized, double-blind, placebo-controlled clinical trial that enrolled a total of 100 individuals with atherosclerosis who were randomized and treated as follows: The experimental group will take 4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthiodacetamido)-3-chlorobenzoic acid in the form of potassium salt ( 300 mg/day) The control group will take atorvastatin (80 mg/day). Main inclusion criteria "Male and female individuals Age from 3 to 75 years " At least one obstruction of the main vessel of the heart with at least 20 95 narrowing of the diameter of the lumen on visual assessment. " "Target vessel" for intravascular ultrasound ordering with no more than 50 95 luminal narrowing in a segment at least 30 mm long (the "target segment"). This target vessel must not have previously undergone intervention or be a candidate for intervention at the time of initial catheterization . "Low-density lipoprotein cholesterol (01-C) between 125 and 210 mg/dL after a washout period of 4-10 weeks if the individual is taking antihypertensive medications. " Blood uric acid level greater than 360 μmol/L (6 mg/dL) for women or 400 μmol/L (6.8 mg/dL) for men; urine uric acid level greater than 800 mg/day (for men) or 750 mg/day (for women). End points: The primary measure of effectiveness is the return of uric acid levels to medically acceptable levels. Secondary endpoints are: and. Change of TRU r. Change of percent plaque PRU Example 39: 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yltib)acetic acid was administered to 12 healthy subjects objects as follows: and. 100 mg, fasting (4 subjects) r. 100 mg, state after eating (4 subjects) with. 200 mg, fasted (4 subjects) All groups showed signs of decreased uric acid levels, as shown in Fig. 6. The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes that may be suggested by those skilled in the art should be included within the scope of the present invention as defined in the appended claims . Fig. 1 Levels of uric acid in serum (mg/dp) on days 0, 3, 7, and 14 after administration of 4-(2-(5-bromo-4-(4-cyclopropylnaphthalene-151l1)1-4H-1 2 4 -triazole-Z-ylthioacetamido)-3-chlorobenzoic acid in the form of the capium salt in humans when using doses of 300 mg, 400 mg or 500 me twice a day: 5 I shi child. A - sh PlacevBoshe ! Zm, 8 E k i Shk Y 2 meals a day Y I " 500 mg i i 2 times/day i : t Z adog : I 2 meals a day" 1 | : - i Ash ; a: o. -- II Weekend Day Z Day 7 Day 104 The last moment of observation Fig. 2 Serum uric acid levels (μmol/l) on days 0, 3, 7, and 14 after administration of 442-(5-bromo-4H4-cyclopropylnaphthalpen-1-yl1)-4H-1,2 4-triazole-3-ylthio )dacetamido)-3-chlorobenzoic acid in the form of a potassium salt in humans when using doses of 300 mg, 400 mg or 500 mg twice a day --- - ' and i ! IZ i shcha - - N mo | sh ply. I A - z -- Z mg i zo Shi She Shi Shi 1 g: Ii 50 g ! - ? Fig. From Zmich, levels of uric acid in serum (mg/dL) by 3.7 | 14 days after administration of 4-(245-bromo-4-44-cyclopropypnaphthalen-1-yl)-4H-1,2 a-triazopeZaltuacetamido)-3-chlorobenzoic acid in the form of potassium salt in humans when using doses of 300 mg, 400 mg or 500 mg twice a day shi shnn ! : 05 fl tnnnui m tot t t nettiaya no nannyeu ze t tyanta s kva : ; and ! ! and ! sen «u y t i 05 - pi SSS E ZO mg i 0-- y y SHO 2 timesday 2- 1 a 508 ; and tral day and how pt opti division i M zrzideni oda sho ! N I - ! y br z i -3 no na aa v aa a V a a aa a aa a i i - poyu zhyanyu ter tttstya poto clarification of the sentence at the end. zkchikchnoga nt peezhtozhijo i sheokiyavya vin nyu Fig. 4 Changes in serum uric acid levels (μmol/l) at 3, 7 14 days after administration of 4-(2-4(5-bromo-4-(4-cyclopropylnaphthapen-1-yl)-4H-1,2,4 -triazop-Z-ylthio)acetamido)-3-chlorobenzoic acid in the form of potassium salt in humans when using doses of 300 mg, 400 mg or 500 mg twice a day ! with. and oh N! n - ' -260 | : and - dreams - - o Z Ppacebo I I 300 mg -0 i- I . 2 times a day x With zke ty still BO mg -B0 ! : " 2 dinners / - her. s. neck, dO m N Vo Y . 2 raznuden -00 | : - shi drinking I 420 4 - pnia I odad i ---- TT os o o "160 yannia i i Fig. 5 Changes in serum uric acid levels (µmol/l) by treatment days after administration of 452" (5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-43-1,2,4-triazol-3-ylthio) acetamido)-3-chlorobenzoic acid in the form of sopi potassium in humans when using doses. 300 mg, 400 mg or 500 mg twice a day ah with Ш Ш ! Prpacebo Z a -- - w-- ХХ ЕЕ ЕИ Ж 10 -- - - г! same Day 3 E st Day 7 5 i t --- t a Dena mya V I i i C 5 I i- zt Treatment p Fig. 6 Increase in daily excretion of uric acid after oral administration of a solution of 245-bBromo-4-(4-cyclopropypnaphthalene-1-47)-4H.-1,2,4-triazol-3-yltib)acetic acid. GI E o i i : Z i I B 3004 i 5 8 ! ve i t rn I 1 Bh 200, ve I I t Zhe x ZHE 30 ! E 3 I ge and ich ' y 1308 mg natoie 100 mg smallpox of food 200 mg fasting