MXPA06007197A - Triazole, oxadiazole and thiadiazole derivative as ppar modulators for the treatment of diabetes - Google Patents

Abstract

The present invention is directed to compounds represented by the following structural formula, Formula (I):wherein:(a) X is selected from the group consisting of a single bond, O, S, S(O)2 and N;(b) U is an aliphatic linker;(c) Y is selected from the group consisting of O, C, S, NH and a single bond;(d) W is N, O or S;(e) E is C(R3)(R4)A or A and wherein;(f) A is selected from the group consisting of carboxyl, tetrazole, C1-C6 alkylnitrile, carboxamide, sulfonamide and acylsufonamide. The other substituents are defined in the claims;the compounds are modulators of peroxisome proleferator activated receptors (PPARs) and are useful for the treatment of diabetes and other metabolic disorders.

Description

DERIVATIVE OF TRIAZOL, OXADIAZOL AND TIADIAZOL AS MODULATORS OF THE RECEIVER ACTIVATED BY THE PROLOYER OF PEROXISOMA (PPAR) FOR THE TREATMENT D? DIABETES BACKGROUND OF THE INVENTION Peroxisome proliferator-activated receptors (PPARs) are elements of the nuclear hormone receptor superfamily, a large and diverse group of proteins that mediate ligand-dependent activation and transcriptional repression. Three subtypes of PPAR have been isolated: PPAR, PPAR? and PPARd. The expression profile for each isoform differs significantly from the others, with it, the PPARa is expressed mainly, but not exclusively in the liver; the PPAR? it is expressed mainly in adipose tissue; and the PPARd is expressed ubiquitously. Studies of individual PPAR isoforms and ligands have revealed their regulation of the processes involved in insulin resistance and diabetes, as well as lipid disorders, such as hyperlipidemia and dyslipidemia. PPARα agonists, such as pioglitazone, may be useful in the treatment of diabetes mellitus not dependent on insulin. Such PPAR agonists? they are associated with insulin sensitization.

PPARa agonists, such as fenofibrate, may be useful in the treatment of hyperlipidemia. Although clinical evidence is not available to reveal the usefulness of PPARD agonists in humans, several preclinical studies suggest that PPARd agonists may be useful in the treatment of diabetes and lipid disorders. The frequency of conditions that comprise Metabolic Syndrome (obesity, insulin resistance, hyperlipidemia, hypertension and atherosclerosis) continues to increase. New pharmaceutical agents are needed to address the clinical needs not covered by patients. PPARd agonists have been suggested as a potential treatment for use in the regulation of many of the parameters associated with the Metabolic Syndrome and Atherosclerosis. For example, in nondiabetic, obese rhesus monkeys, a PPARd agonist reduces circulating triglycerides and LDL, lowers basal insulin levels and increases HDL (Oliver, WR et al., Proc Nat Acad Sci 98: 5306-5311; ). It is thought that the insulin sensitization observed with the use of a PPARd agonist is partly due to decreased myocellular lipids (Dressel, U. et al., Mol Endocrinol 17: 2477-2493; 2003. In addition, atherosclerosis is considered As a disease consequence of dyslipidemia and may be associated with inflammatory diseases, the production of reactive protein C (CRP) is part of the acute phase response to many forms of inflammation, infection and tissue damage. Low-grade inflammation marker Plasma CRP levels of more than 3 mg / L have been considered predictive because of the high risk of coronary artery disease (J. Clin. Invest 111: 1085-1812, 2003). PPARD agonists are believed to mediate inflammatory effects, however, the treatment of macrophages stimulated with LPS with a PPARd agonist has been observed to reduce the expression of iNOS, IL-12 and IL-16 (Welch, JS et al., Proc Na ti Acad Sci 100: 6712-67172003). It may be especially desirable, when the active pharmaceutical agent selectively modulates a subtype of the PPAR receptor to provide an especially desirable pharmacological profile. In some cases, it may be desirable when the pharmacological agent selectively modulates more than one subtype of the PPAR receptor to provide a desired pharmacological profile.

Brief description of the invention The present invention is directed to compounds represented by the following structural formula I: and pharmaceutically acceptable stereoisomers, salts, solvates and hydrates thereof, wherein: (a) R 1 is selected from the group consisting of hydrogen, Ci-Cs alkoyl, C?-C8 alkenyl, C?-C8 heteroalyl, aryl-alkenyl Co -4, aryl-heteroalguyl C? -C4, heteroaryl-alkoyl Co-C4 and cycloal-guilaryl C3-C6 ~ alyl C0-2, and, wherein Cx-C8 alkenyl, Ci-Cs alkenyl, aryl-C0-C4 alkyl, aryl -heteroalkyl C? -, heteroaryl-C0-4 alkoyl, C3-C6 cycloal-guilayl-alkenyl Co-2, are each optionally substituted with one to three substituents independently selected from R1 '; (b) R1 ', R26, R27, R28 and R31 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C6-C6 alkoyl, C6-C6-C00R12 alkoyl, alkoxy Cj- C6, haloalkyl Ci-Cβ, haloalyloxyC?-C6, cycloalkyl C3-C7, aryloxy, aryl-alkoyl Co-C, heteroaryl, heterocycloalguyl, C (0) R13, COOR14, 0C (0) R15, 0S (0 ) 2R16, N (R17) 2, NR18C (0) R19, NR20SO2R21, SR22, S (0) R23, S (0) 2R24, and S (O) 2N (R25) 2; R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R 24 and R 25 are each independently selected from the group consisting of hydrogen, Ci-Cβ alkoyl and aryl; (c) V is selected from the group consisting of algayl Co-Cß and heteroalguyl C? ~; (d) X is selected from the group consisting of a single bond, O, S, S (0) 2 and N; (e) U is an aliphatic linker wherein a carbon atom of the aliphatic linker is optionally replaced with O, NH or S, and wherein such an aliphatic linker is optionally substituted with one to four substituents each independently selected from R30; (f) W is N, O u S; (g) Y is selected from the group consisting of C, O, S, NH and a single bond; (h) E is C (R3) R4) A or A and wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C 1 -C 6 -annitrile, carboxamide, sulfonamide and acylsulfonamide; wherein the sulfonamide, acylsulfonamide and tetrazole are each, optionally substituted with one to two groups independently selected from R7; (ii) each R7 is independently selected from the group consisting of hydrogen, C6-C6 haloalguil, C0-C4 aryl algayl, and alkenyl C? -C6; (iii) R3 is selected from the group consisting of hydrogen, C3-C5 alkoxy and C1-C5 alkoxy; and (iv) R 4 is selected from the group consisting of H, C 1 -C 5 alkoxy, C 1 -C 5 alkoxy, aryloxy, C 3 -C 6 cycloalkyl and aryl alkoyl C 0 -C, and R 3 and R 4 are optionally combined to form a C 3 cycloalkyl C, and wherein alkenyl, alkoxy, aryloxy, cycloalguyl and aryl-alkenyl are each optionally substituted with one to three substituents each independently selected from R26; (i) R8 is selected from the group consisting of hydrogen, C al-C4-alkoyl, C al-C4-alkenyl, and halo; (j) R9 is selected from the group consisting of hydrogen, C1-C4 alkenyl, C al-C4 alkenyl, halo, aryl-C0-C aryl, heteroaryl, C?-C6 allyl and OR29, and wherein aryl-C0- C4 alkenyl, heteroaryl, are each optionally substituted with one to three independently selected from R27; R29 is selected from the group consisting of hydrogen and alguyl Cj.-C; (k) RIO, Rll, are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, Ci-Ce alkoyl, C? -C6 alkynyl, C? -C6-C00R12 alkoxy, alkoxy C0- Cd, haloalguilo C? -C6, haloalguiloxi C? -C6, cycloalguilo C3? C, aril-algilo C0-4, aril-heteroaroalguilo C? -, heteroaryl-alguilo C0-4 / cycloalguilaril C3-C6-alguilo Co ~ 2, aryloxy, C (0) R13 ', COOR14', OC (0) R15 ', 0S (0) 2R16', N (R17 ') 2, NR18'C (0) R19', NR20 'S02R21', SR22 ', S ( 0) R23 ', S (0) 2R24'f and S (0) 2N (R25') 2; and wherein aryl-C0- alkyl, aryl-heteroalguyl C? -C, heteroaryl-C0-4 aligyl and C3-C6 cycloal-guilayl-C0-2 aligyl, are each optionally substituted with one to three, independently selected from R28; and wherein RIO and Rll are optionally combined to form a fused bicyclic ring of 5 to 6 elements with the phenyl to which they are attached; (1) R12 ', R12", R13', R14 ', R15', R16 ', R17', R18 ', R19', R20 ', R21', R22 ', R23', R24 ', and R25', are each independently selected from the group consisting of hydrogen, Ci-Ce alkyl and aryl; (m) R30 is selected from the group consisting of Ci-Ce alkoyl, C0-4 aryl-alkoyl, C? -4 aryl-heteroalguyl, Co-4 heteroaryl-alkoyl and C3-C6 cycloal-guilayl-C0-2 algayl, and where Ci-Ce alkyl, C0-4 aryl alkoyl, aryl-C6-4 heteroalkyl, C0-4 heteroarylalkyl and C3-C3-Cd alkoyl C0-2 cycloal-guilary are each optionally substituted with one to three substituents each independently selected of R31; (n) R32 is selected from the group consisting of hydrogen, halo, C6-C6 aligyl, C1-C6 haloal-guyl, and C-Cß allyloxy; and (o) is optionally a link to form a double bond at the indicated position. A further embodiment of the present invention is a compound of the Formula la: the A further embodiment of the present invention is a compound of Formula Ib: Ib wherein W1 is 0 u S. An additional embodiment of the present invention is a compound of the formula le: A further embodiment of the present invention is a compound of Formula II: II and pharmaceutically acceptable stereoisomers, salts, solvates and hydrates thereof, wherein: (a) R1 is selected from the group consisting of hydrogen, Cj.-C8 alkenyl, C? -C8 alkenyl, C0- arylalguilo, aryl heteroalguyl C ~ C4, heteroaryl-alkoyl Co ~ C4 and C3-C6 cycloal-guilary ~ alkenyl Co-2, and, wherein Cj.-C8 alkenyl, C? -C8 alkenyl, arylC0-C4 alkyl, aryl-heteroalkyl C? 4, C0- heteroarylalkyl, C3-C6 cycloalkylaryl-C0-2 alkyl, are each optionally substituted with one to three substituents independently selected from R1 '; (b) Rl ', R26, R27, R28 and R31 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, Cj.-C6 algayl, C6-C6-C00R12 alkoyl, alkoxy C? ~ C ?, haloalkyl Ci-Cβ, haloalyloxy Ci-Cβ, cycloalguile C3-C7, aryloxy, aryl-alkoyl C0-C4, heteroaryl, heterocycloalguilo, C (0) R13, COOR14, 0C (0) R15, OS ( 0) 2R16, N (R17) 2, NR18C (0) R19, NR20SO2R21, SR22, S (0) R23, S (0) 2R24, and S (O) 2N (R25) 2; R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R 24 and R 25 are each independently selected from the group consisting of hydrogen, Ci-Cβ alkoyl and aryl; (c) V is selected from the group consisting of alkoxy Co-C8 and heteroalguilo C? -4; (d) X is selected from the group consisting of a single bond, 0, S, S (0) 2 and N; (e) U is an aliphatic linker wherein a carbon atom of the aliphatic linker is optionally replaced with 0, NH or S, and wherein such an aliphatic linker is optionally substituted with one to four substituents each independently selected from R30; (f) Y is selected from the group consisting of C, 0, S, NH and a single bond; (g) E is C (R3) R4) A or A and wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C?-C al, carboxamide, sulfonamide and acylsulfonamide; wherein the sulfonamide, acylsulfonamide and tetrazole are each, optionally substituted with one to two groups independently selected from R7; (ii) each R7 is independently selected from the group consisting of hydrogen, C6-C6 haloalkyl, C0-C aryl, and alkenyl C? -C6; (iii) R3 is selected from the group consisting of hydrogen, C1-C5 alkoxy and C5-C5 alkoxy; and (iv) R 4 is selected from the group consisting of H, C 1 -C 5 alkoxy, C 1 -C 5 alkoxy, aryloxy, C 3 -C 6 cycloalkyl and aryl alkoxy Co-C 4, and R 3 and R 4 are optionally combined to form a C 3 cycloalkyl C4, and wherein alkenyl, alkoxy, aryloxy, cycloalguyl and aryl-alkenyl are each optionally substituted with one to three substituents each independently selected from R26; (h) R8 is selected from the group consisting of hydrogen, C? -C alkoyl, C1-C4 alkenyl, and halo; (i) R9 is selected from the group consisting of hydrogen, C1-C4 alkenyl, C?-C4 alkenyl, halo, aryl-alkoyl Co-C4, heteroaryl, allyl Ci-Cg and OR29, and wherein aryl-C0-C4 alkenyl, heteroaryl, are each optionally substituted with one to three independently selected from R27; R29 is selected from the group consisting of hydrogen and C1-C4 alkoyl; (j) RIO, Rll, are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C-β-algayl, C?-C6-alicylenyl, C al-C6-C00R12-alkoyl, alkoxy C0-C6, haloalguilo C? -C6, haloalguiloxi C? -C?, Cicloalguilo C3-C7, aril-alguilo C0-4, aril-heteroaroalguilo C1-4, heteroaril-alguilo Co-4, cicloalguilaril C3-C6-alquico C0- 2, aryloxy, C (0) R13 ', C00R14', 0C (0) R15 ', OS (0) 2R16', N (R17 ') 2, NR18'C (0) R19', NR20 'S02R21', SR22 ', S (0) R23', S (0) 2R24 ', and S (0) 2N (R25') 2, and wherein aryl-C0-4 alkyl, aryl-heteroalguyl C? ~ C, heteroaryl-alkenyl Co -4 and C3-C6 cycloal-guilayl-C0-2 aligyl are each optionally substituted with one to three, independently selected from R28, and wherein RIO and Rll are optionally combined to form a fused bicyclic ring of 5 to 6 elements with the phenyl to which they are attached: (k) R12 ', R12", R13', R14 ', R15', R16 ', R17', R18 ', R19', R20 ', R21', R22 ', R23', R24 ' , and R25 ', are each selected ions independently of the group consisting of hydrogen, Ci-Cβ alkoyl and aryl; (1) R30 is selected from the group consisting of C?-C6 alkyl, C0-4 ar aryl-alkyl, C? -4 ar aryl-heteroalkyl, heteroarylCo-4alkyl and C3-C6-cycloalkylaryl-C al-2 al-alkylaryl, and wherein Ci-Cβ alkoyl, C0-4 aryl alkoyl, C? -4 aryl heteroalkyl, Co-4 heteroaryl alkoyl and C3-C6 cycloal-guilayl-alkoyl Co-2, are each optionally substituted from one to three substituents each one independently selected from R31; (m) R32 is selected from the group consisting of a bond, hydrogen, halo, Ci-Ce alkyl, C6-C6 haloalbumyl, and Ci-Cβ alkyloxy; and (n) is optionally a link to form a double bond in the indicated position. Another embodiment of the present invention is a compound of Formula III: lll and pharmaceutically acceptable stereoisomers, salts, solvates and hydrates thereof, wherein: (a) R1 is selected from the group consisting of hydrogen, C?-C8 alkyl, C?-C8 alkenyl, C?-C8 heteroaligyl, C0-4 alkoyl, C1-C4 aryl heteroalkyl, C0-C4 heteroaryl-alkeyl, and C3-C6 cycloal-guilary ~ alkenyl Co ~ 2, and, wherein C al-C8 algeryl, C?-C8 alkenyl, aryl-C al-alkoyl C4, C4-4 aryl heteroalyl, C0-4 heteroaryl alkoyl, C3-C6 cycloal-guilayl-alkenyl Co-2, are each optionally substituted with one to three substituents independently selected from R1 '; (b) R1 ', R26, R27, R28 and R31 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, Ci-Ce alkyl, C6-C6-COOR12 alkyl, Ci-alkoxy - Ce, C?-C6 haloalipyl, C?-C6 haloal-yloxy, C3-C7 cycloal-guyl, aryloxy, C0-C4 aryl-alkoyl, heteroaryl, heterocycloal-guyl, C (0) R13, C00R14, 0C (0) R15, OS (0 ) 2R16, N (R17) 2, NR18C (0) R19, NR20SO2R21, SR22, S (0) R23, S (0) 2R24, and S (0) 2N (R25) 2; R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each independently selected from the group consisting of hydrogen, Ci-Ce alkyl and aryl; (c) V is selected from the group consisting of alkoxy Co ~ C8 and heteroalguilo C? -4; (d) X is selected from the group consisting of a single bond, 0, S, S (0) 2 and N; (e) U is an aliphatic linker wherein a carbon atom of the aliphatic linker is optionally replaced with 0, NH or S, and wherein such an aliphatic linker is optionally substituted with one to four substituents each independently selected from R30; (f) Y is selected from the group consisting of C, 0, S, NH and a single bond; (g) E is C (R3) R4) A; wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C 1 -C 6 -annitrile, carboxamide, sulfonamide and acylsulfonamide; wherein the sulfonamide, acylsulfonamide and tetrazole are each, optionally substituted with one to two groups independently selected from R7; (ii) each R7 is independently selected from the group consisting of hydrogen, C6-C6 haloalguil, C0-C4 aryl algayl, and alkenyl Cl_C6 / (iii) R3 is selected from the group consisting of hydrogen, C1-C5 alkoyl and C5-C5 alkoxy; and (iv) R4 is selected from the group consisting of H, C3-C5 alkoxy, C1-C5 alkoxy, aryloxy, C3-C6 cycloalkyl, and C0-C4 aryl aligyl, and R3 and R4 are optionally combined to form a C3 cycloalkyl. -C4, and wherein alkenyl, alkoxy, aryloxy, cycloalguyl and aryl-alkenyl are each optionally substituted with one to three substituents each independently selected from R26; with the provision that when Y is O, then R4 is selected from the group consisting of C1-C5 alkoyl, C1-C5 alkoxy, aryloxy, C3-C6 cycloalkyl and C0-C4 arylaguilo, and R3 and R4 are optionally combined to form a C3-C4 cycloalkyl, and wherein alkenyl, alkoxy, cycloalguyl and aryl-alkenyl are each optionally substituted with one to three each independently selected from R26; (h) R8 is selected from the group consisting of hydrogen, C al-C4-alkoyl, C?-C4-alkenyl, and halo; (i) R9 is selected from the group consisting of hydrogen, C1-C4 alkoyl, C1-C4 alkenyl, halo, C0-C4 aryl-alkoyl, heteroaryl, C6-C6 allyl and OR29, and wherein aryl-C0-C4 alkenyl, heteroaryl, are each optionally substituted with one to three independently selected from R27; R29 is selected from the group consisting of hydrogen and C1-C4 alkoyl; (j) RIO, Rll, are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, Ci-Cβ alkoyl, C? -C6 alicylenyl, C? -C6 alkoyl-COOR12", alkoxy C0-C6, haloalguilo C? -C6, haloalguiloxi C? -C6, cycloalguilo C3-C, aril-algilo C0-4, aril-heteroaroalguilo C? ~ 4, heteroaryl-C0-4 alkyl, cycloalguilaryl C3-C6-alguilo C0 -2, aryloxy, C (0) R13 ', C00R14', 0C (0) R15 ', OS (0) 2R16', N (R17 ') 2, NR18'C (0) R19', NR20 'S02R21', SR22 ', S (0) R23', S (0) 2R24 ', and S (0) 2N (R25') 2; and wherein aryl-C0-4 alkyl, aryl-heteroalguyl C-C4, heteroaryl-alkenyl C0-4 and C3-C6 cycloal-guilayl-C0-2 alkeyl are each optionally substituted with one to three, independently selected from R28; and wherein RIO and Rll are optionally combined to form a fused bicyclic ring of 5 to 6 elements with the phenyl to which they are attached; (k) R12 ', R12", R13', R14 ', R15', R16 ', R17', R18 ', R19 ', R20', R21 ', R22', R23 ', R24', and R25 ', are each independently selected from the group consisting of hydrogen, Ci-Cβ alkoyl and aryl; (1) R30 is selected from the group consisting of Ci-Ce alkyl, aryl-Co-4 alkyl, aryl-heteroalkyl C -4 -4, heteroaryl-C0-4 alkyl and C3-C6 cycloal-guilary-C0-2 alkyloyl, and wherein Ci-Cß alkoyl, C0-4 arylalkyl, C -4 -4 aryl-heteroalguyl, heteroaryl-alkoyl Co ~ 4 and C3-C6 cycloal-guilayl-alkenyl Co-2 are each optionally substituted from one to three substituents each independently selected from R31; (m) R32 is selected from the group consisting of a bond, hydrogen, halo, C6-C6-alkoyl, C1-C6-haloal-guyl, and C6-C6 alkoxyloxy; and (n) is optionally a link to form a double bond in the indicated position. In one embodiment, the present invention also relates to pharmaceutical compositions comprising at least one compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, and a pharmaceutically acceptable carrier. In another embodiment, the present invention relates to a method for selectively modulating a PPAR delta receptor, which comprises contacting the receptor with at least one compound represented by Structural Formula I, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof. In another embodiment, the present invention relates to a method for modulating one or more of the PPAR alpha, beta, gamma and / or delta receptors. In a further embodiment, the present invention relates to a method for making a compound represented by Structural Formula I. It is believed that the compounds of the present invention are effective in the treatment and / or prevention of Metabolic Disorder, Type II Diabetes, hyperglycemia, hyperlipidemia, obesity, coagulopathy, hypertension, atherosclerosis and other disorders related to Metabolic Disorder and cardiovascular diseases. In addition, the compounds of this invention may be useful for decreasing fibrinogen, increasing HDL levels, treating kidney disease, controlling desirable weight, treating demyelinating diseases, treating certain viral infections and treating liver disease. In addition, the compounds may be associated with some clinical side effects that the compounds currently used to treat such conditions.

Detailed Description of the Invention The terms used to describe the present invention have the following meanings. As used herein, the term "aliphatic linker" or "aliphatic group" is a non-aromatic, which consists solely of carbon and hydrogen and may optionally contain one or more units of unsaturation, eg, double bonds and / or triple (also referred to in this document as "alguenilo" and "alguinilo"). An aliphatic or aliphatic group, can be straight chain, branched chain (also referred to herein as "alguilo"), or cyclic (also referred to herein as "cycloalguilo"). When they are straight or branched chain, an aliphatic group typically contains between about 1 and about 10 carbon atoms, more typically between 1 and about 6 carbon atoms. When cyclic, an aliphatic typically contains between about 3 and about 10 carbon atoms, more typically between about 3 and about 7 carbon atoms. The aliphatics are preferably straight chain or branched chain Ci-Cio groups (i.e., fully saturated aliphatic groups), more preferably, branched or straight chain Ci-Cd alkyl groups. Examples include, but are not limited to, methyl, ethyl, propyl, n-propyl, iso-propyl, n-butyl, sec-butyl and tert-butyl, Additional examples include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclohexyl and the like. Such an aliphatic linker is optionally substituted with one to four substituents each independently selected from R30. It may be preferred that the aliphatic linker be substituted with zero to two substituents, each independently selected from R30. In addition, it may be preferred that a carbon of the aliphatic linker be replaced with an O, NH or S. Finally, it may be preferred that the aliphatic linker be purely alkyl, without carbon replaced with an O, NH or S. The term "alkyl" unless otherwise indicated, it refers to those groups of a certain number of carbon atoms of either a branched or straight saturated configuration. As used in this document, "alguilo Co" means that there is no carbon and therefore represents a bond. Examples of "alguyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl, pentyl, hexyl, isopentyl and the like. Aligyl as defined above, may be optionally substituted with a designated number of substituents as set forth in the above mentioned embodiments. As used herein, the term "alguiloxo" means an alkyl group of the designated number of carbon atoms, with a substituent "= 0". The term "alkenyl" or "alginyl" means a hydrocarbon chain of a specified number of carbon atoms of either the branched or straight configuration and having at least one carbon-carbon double bond, which may occur in any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, vinyl, alkenyl, 2-butenyl and the like. Alkenyl as defined above, may be optionally substituted with a designated number of substituents as set forth in the above mentioned embodiments. The term "alguinyl" means a hydrocarbon chain of a specified number of carbon atoms of either a branched or straight configuration and having at least one carbon-carbon triple bond, which may occur at any point along the chain. Examples of alguinyl is acetylene. Alginyl as defined above, may optionally be substituted with the designated number of substituents as set forth in the aforementioned embodiment. The term "heteroalguyl" refers to a branched hydrocarbon chain medium of a specified number of carbon atoms, wherein at least one carbon is replaced by a heteroatom selected from the group consisting of O, N and S. The term "cycloalguyl" refers to a saturated or partially saturated carbocycle containing one or more rings of 3 to 12 carbon atoms. carbon, typically 3 to 7 carbon atoms. Examples of cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclopentyl, and the like. "Cycloalkylaryl" means that an aryl is fused to a cycloalguyl, and "Cycloalguilaryl-algayl" means that the cycloalguilaryl is linked to the original molecule through the algane. Cycloalkyl as defined above, may be optionally substituted with a designated number of substituents as set forth in the aforementioned embodiment.

The term "halo" refers to fluoro, chloro, bromo and iodo. The term "haloalogyl" is a C6-C6 alkyl group, which is substituted with one or more halo atoms selected from F, Br, Cl and I. An example of a haloalguyl group is trifluoromethyl (CF3). The term "alkoxy", represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy and the like. Alkoxy as defined above, may be optionally substituted with a designated number of substituents as set forth in the aforementioned embodiment. The term "haloalyloxy" represents a haloalbumyl Ci-Cβ group bonded through an oxygen bridge, such as OCF3. The term "haloalyloxy" as defined above, may be optionally substituted with a designated number of substituents as set forth in the aforementioned embodiments. The term "aryl" includes carbocyclic aromatic ring systems (e.g., phenyl), fused polycyclic aromatic ring systems (e.g., naphthyl and anthracenyl) and aromatic ring systems fused to carbocyclic nonaromatic ring systems (e.g. , 2,3, 4-tetrahydronaphthyl). "Aryl" as defined above, may optionally be substituted with a designated number of substituents as set forth in the above-mentioned embodiments. The term "arylalguilo" refers to an aryl alkyl group which is linked to the original molecule through the alguilo group, which may also be optionally substituted with a designated number of substituents as disclosed in the aforementioned embodiment. When arylalguilo is arylalguilo Co, then the aryl group is directly attached to the original molecule. Similarly, arylheteroalguyl means an aryl group linked to the original molecule through the heteroalguyl group. The term "acyl" refers to species of alkylcarbonyl, arylcarbonyl and heteroarylcarbonyl. The term "heteroaryl" group as used herein, is an aromatic ring system having at least one heteroatom such as nitrogen, sulfur or oxygen and includes monocyclic, bicyclic or tricyclic aromatic ring of 5 to 14 carbon atoms. containing one or more heteroatoms selected from the group consisting of O, N and S. The "heteroaryl" as defined above, may be optionally substituted with a designated number of substituents exposed in the aforementioned embodiment. Examples of heteroaryl are, but are not limited to, furanyl, indolyl, thienyl (also referred to herein as "thiophenyl"), thiazolyl, imidazolyl, isoxazoyl, oxazoyl, pyrazoyl, pyrrolyl, pyrazinyl, pyridyl, pyrimidyl, pyrimidinyl and purinyl, cinolinyl, benzofuranyl, benzothienyl, benzotriazolyl, benzoxazolyl, guinoline, isoxazolyl, isoginoline and the like. The term "heteroarylalkyl" means that the heteroaryl group is linked to the parent molecule through the alkyl portion of the heteroarylalkyl. The term "heterocycloalkyl" refers to a non-aromatic ring, which contains one or more oxygen, nitrogen or sulfur and includes a non-aromatic monocyclic, bicyclic or tricyclic ring, of 5 to 14 carbon atoms, which contains one or more heteroatoms selected from O, N or S. The "Heterocycloalguyl" as defined above, may be optionally substituted with a designated number of substituents as set forth in the aforementioned embodiment. Examples of heterocycloalguyl include, but are not limited to, morpholine, piperidine, piperazine, pyrrolidine and thiomorpholine. As used herein, "alguilo" groups include straight chain and branched chain hydrocarbons, which are completely saturated. When "" is optionally a bond that forms a double bond in the five element heterocycle, possible heterocycles include: As used in this document, the phrase, "selectively modulated" means a compound whose EC50 for the declared PPAR receptor is at least ten times lower than its IC50 for the other PPAR receptor subtypes. PPARd has been proposed to be associated with and dissociated from selectively co-repressors (BCL-6) that control stimulated and basal anti-inflammatory activities (Lee, C-H, et al., Science 302: 453-4572003). The PPARd agonists are thought to be useful in attenuating other inflammatory conditions such as inflammation of the joints and connective tissue as occurs in rheumatoid arthritis, related autoimmune diseases, osteoarthritis, as well as thousands of other inflammatory diseases, Crohn's disease and psoriasis. When a compound represented by the Formula Structural I has more than one guiral substituent, it can exist in diastereomeric forms. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example, chromatography or recrystallization and the indivl enantiomers within each pair can be separated using familiar methods by those skilled in the art. The present invention includes each diastereomer of compounds of Structural Formula I and mixtures thereof. Certain compounds of Structural Formula I can exist in different stable conformational forms. which can be separable. Torsional asymmetry due to restricted rotation about a single asymmetric bond, for example, due to spherical obstruction or ring chain, may allow the separation of different conformers. The present invention includes each conformational isomer of compounds of Structural Formula I and mixtures thereof. Certain compounds of Formula I can exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of Structural Formula I and mixtures thereof. The term "pharmaceutically acceptable salt" refers to salts of the compounds of Structural Formula I, which are considered to be acceptable for clinical and / or veterinary use. Typical pharmaceutically acceptable salts include aqueous salts prepared by reacting the compounds of the present invention with an organic or mineral acid or an organic or inorganic base. Such salts are known as acid addition salts and base addition salts, respectively. It will be recognized that the particular counter ion that forms a part of any salt of this invention is not of a critical nature, as soon as the salt as a whole is pharmaceutically acceptable and as soon as the counter ion does not contribute to the undesired qualities of salt as a whole. These salts can be prepared by methods known to the person skilled in the art. The term "active ingredient" means the compounds generically described by Structural Formula I, as well as the salts, solvates and hydrates. The term "pharmaceutically acceptable" means that the carrier, diluent, excipient and salt are pharmaceutically compatible with the other ingredients of the composition. The pharmaceutical compositions of the present invention are prepared by methods known in the art using readily available and well-known ingredients. "Prevention" refers to reducing the likelihood that the recipient will incur or develop any of the pathological conditions described in this document. The term "prevent" is particularly applicable to a patient who is susceptible to the particular pathological condition. "Treat" refers to mediating a disease or condition, and preventing or mitigating its further progress or improving the symptoms associated with the disease or condition. "Pharmaceutically effective amount" means such an amount of active ingredient which will elicit the biological or medical response of a tissue, system or mammal. Such a quantity can be administered prophylactically to a patient thought to be susceptible to the development of a condition or disease. Such an amount when administered prophylactically to a patient may also be effective in preventing or decreasing the severity of the mediated condition. Such an amount is proposed to include an amount, which is sufficient to modulate a PPAR receptor or prevent or mediate a disease or condition. Generally, the effective amount of a compound of Formula I will be between 0.02 to 500 mg per day. Preferably, the effective amount is between 1 to 1,500 mg per day. Preferably, the dosage is from 1 to 10,000 per day. More preferably, the dose may be from 1 to 100 mg per day. The desired dose may be presented in a single dose or as divided doses administered at appropriate intervals. A "mammal" is an individual animal that is an element of the taxonomic class of Mammals. The mammal class includes humans, monkeys, chimpanzees, gorillas, cattle, pigs, horses, sheep, dogs, cats, mice and rats. Administration to a human is more preferred. The compounds and compositions of the present invention are useful for the treatment and / or prophylaxis of cardiovascular diseases, to elevate serum HDL cholesterol levels, to lower serum triglyceride levels and to lower serum LDL cholesterol levels. Elevated levels of LDL and triglycerides, and lower levels of HDL, are risk factors for the development of heart disease, stroke and disorders and diseases of the circulatory system. In addition, the compounds and compositions of the present invention can reduce the influence of undesirable cardiac events in patients. The ordinary skill specialist will know how to identify humans who will benefit from the administration of the compounds and compositions of the present invention. The compounds and compositions of the present invention may be useful for treating and / or preventing obesity. In addition, these compounds and compositions are useful for the treatment and / or prophylaxis of non-insulin-dependent diabetes mellitus (NIDDM) without weight gain or reduced by patients. In addition, the compounds and compositions of the present invention are useful for treating or preventing temporary or acute disorders in insulin sensitivity, sometimes occurring after surgery, trauma, myocardial infarction, and the like. The ordinary skill specialist will know how to identify humans who will benefit from the administration of the compounds and compositions of the present invention. The present invention further provides a method for the treatment and / or prophylaxis of hyperglycemia in a human or non-human mammal, which comprises administering an effective amount of active ingredient, as defined herein, to a non-human or a human hyperglycemic mammal. in need of it. The invention also relates to the use of a compound of Formula I as described above, for the manufacture of a medicament for treating a condition mediated by the PPAR receptor. A therapeutically effective amount of a compound of Structural Formula I can be used for the preparation of a medicament useful for treating Metabolic Disorders, diabetes, treating obesity, lowering triglyceride levels, lowering serum LDL levels, raising plasma level of High density lipoprotein and treat, prevent or reduce the risk of developing atherosclerosis, and prevent or reduce the risk of having a first or subsequent event of atherosclerotic disease in mammals, particularly in humans. In general, a therapeutically effective amount of a compound of the present invention typically reduces serum triglyceride levels of a patient by approximately 20% or more, and increases serum HDL levels in a patient. Preferably, the HDL levels will be increased by approximately 30% or more. In addition, a therapeutically effective amount of a compound, used to prevent or treat NIDDM, typically reduces the serum glucose levels, or more specifically, HbAcl, of a patient by about 0.7% or more. When used in this document Metabolic Syndrome, includes pre-diabetic insulin resistance syndrome and the resulting complications thereof, insulin resistance, non-insulin dependent diabetes, dyslipidemia, hyperglycemia, obesity, coagulopathy, hypertension and other complications associated with diabetes. The methods and treatments mentioned in this document include the foregoing and cover the treatment and / or prophylaxis of any combination of the following: pre-diabetic insulin resistance syndrome, complications resulting therefrom, insulin resistance, non-diabetes Insulin dependent or Type II, dyslipidemia, hyperglycemia, obesity and complications associated with diabetes include cardiovascular diseases, especially atherosclerosis. In addition, the methods and treatments mentioned in this document include the foregoing and encompass the treatment and / or prophylaxis of any combination of the following inflammatory and autoimmune diseases: respiratory distress syndrome in adult, rheumatoid arthritis, disabling disease, Crohn's disease, asthma, systemic lupus erythematosus, psoriasis and bursitis. The compositions are formulated and administered in the same general manner as detailed herein. The compounds of the present invention can be used effectively alone or in combination with one or more additional active agents, depending on the desired target therapy. The combination therapy includes the administration of a unique pharmaceutical dosage composition, which contains a compound of Structural Formula I, a stereoisomer, salt, solvate and / or hydrate thereof ("Active Ingredient"), and one or more active agents additional, as well as administration of an Active Ingredient compound and each active agent in its own separate dosage formulation. For example, an Active Ingredient and an insulin secretagogue, such as inhibitors of biguanides, thiazolidinediones, sulfonylureas, insulin or α-glucosidase, can be administered to the patient as a whole in a single oral dosage composition, such as a tablet or capsule. , or each agent is administered in separate oral dosage formulations. Where the separate dosage formulations are used, an Active Ingredient and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; The combination therapy is understood to include all of these regimens. An example of prevention or combination treatment of atherosclerosis can be where an Active Ingredient is administered in combination with one or more of the following active agents: antihyperlipidemic agents; agents that raise the plasma HDL; anti-hypercholesterolemic agents, fibrates, vitamins, aspirin and the like. As noted above, the Active Ingredient can be administered in combination with one or more additional active agents. Another example of combination therapy can be observed in the treatment of diabetes and related disorders, wherein the Active Ingredient can be effectively used in combination with, for example, inhibitors of sulfonylureas, biguanides, thiazolidinediones, α-glucosidase, other secretagogues of the insulin, insulin, as well as the active agents discussed above to treat atherosclerosis.

The Active Ingredients of the present invention have valuable pharmacological properties and can be used in pharmaceutical compositions containing a therapeutically effective amount of the Active Ingredient of the present invention, in combination with one or more pharmaceutically acceptable excipients. The excipients are inert substances such as, without limitation, carriers, diluents, fillers, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, wetting agents, binders, disintegrating agents, encapsulating material and other conventional adjuvants. The appropriate formulation is dependent on the chosen route of administration. Pharmaceutical formulations typically contain from about 1 to about 99 weight percent of the Active Ingredient of the present invention. Preferably, the pharmaceutical formulation is in unit dosage form. A "unit dosage form" is a physically discrete unit containing a unit dose, suitable for administration in human subjects or other mammals. For example, a unit dosage form can be a capsule or tablet, or a number of capsules or tablets. A "unit dose" is a predetermined amount of the Active Ingredient of the present invention, calculated to produce the desired therapeutic effect, in association with one or more pharmaceutically acceptable excipients. The amount of active ingredient in a unit dose can be varied or adjusted from about 0.1 to about 1500 milligrams or more in accordance with the particular treatment involved. It may be preferred that the unit dosage be from about 1 mg to about 1000 mg. The dosage regimen using the compounds of the present invention is selected by one of ordinary skill in the medical or veterinary arts, in view of a variety of factors including, without limitation, species, age, weight, sex and medical condition of the container, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the container, the dosage form used, the particular compound and the salt of the same employee, and the like. Advantageously, the compositions containing the compound of Formula Structures I or salts thereof, can be provided in unit dosage form, preferably each dosage unit containing from about 1 to about 500 mg are administered, although of course, it will be understood It is readily apparent that the amount of the compound or compounds of Formula I, currently administered, will be determined by a specialist, in view of all relevant circumstances. Preferably, the compounds of the present invention are administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three or more times per day. Where the supply is via transdermal forms, of course, the administration is continuous. Suitable routes of administration of pharmaceutical compositions of the present invention include for example, oral administration, eye drops, straight, transmucosal, topical or intestinal: parenteral delivery (bolus or infusion), which includes intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or infraocular injections. The compounds of the invention can also be administered in a targeted drug delivery system, such as, for example, in a liposome coated with endothelial cell-specific antibody. Solid form formulations include powders, tablets and capsules. Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The pharmaceutical compositions of the present invention can be manufactured in a manner that are the same as known for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The following pharmaceutical formulations 1 and 2 are illustrative only and are not intended to limit the scope of the invention in any form.

Formulation I Hard gelatin capsules were prepared using the following ingredients: Quantity (mg / capsule) Active Ingredient 250 Dry starch • 200 Magnesium stearate 10 Total 460 mg Formulation 2 A tablet was prepared using the following ingredients: Amount (mg / tablet) Active Ingredient 250 Microcrystalline cellulose 400 Silicon dioxide, smoked 10 Stearic acid 5 total 665 mg The components are mixed and compressed to form tablets each weighing 665 mg. In yet another embodiment of the compounds of the present invention, the compound is radioetigated, such as with carbon-14, or tritiated. Such radioetigated or tritiated compounds are useful as reference standards for in vitro assays to identify new PPAR receptor agonists. The compounds of the present invention can be used to modulate insulin secretion and as search tools. Certain compounds and compositions within the scope of the invention are preferred. The following conditions, embodiments of the invention and characteristics of the compound listed in tabular form can be independently combined to produce a variety of preferred compounds and process conditions. The following list of embodiments of this invention is not intended to limit the scope of this invention in any form. Some preferred characteristics of compounds of formula I are: a) R3 is methyl; b) R4 is hydrogen; c) R3 and R4 are each hydrogen; d) R3 and R4 are each methyl; e) A is carboxyl; f) X is -O-; g) X is -S-; h) X is a unique link; U is CH (R30); ü is CH2CH (R30); U is CH2CH (R30) CH2; ü is CH2N (R30) CH, U is CH2OCH2; ü is CH2CH2CH2; U is CH2; U is CH2NHCH2; U is CH2N (CH3) CH2; U is CH2N (CH (CH3) 2) CH2; U is CH2N (CH2CH2CH3) CH2; U is CH2N (CH2CH3) CH2; W is N; W is O; (w) W is S; (x) R30 is CH3; (y) R30 is phenyl; (z) R30 is CH2CH2CH2CH3; R30 is CH2CH2CF3; R30 is CH2CH = CH2; R30 is CH (CH3) 2; R30 is CH2CH2CH3; R30 is CH2CH3; R9 is methyl; R9 is hydrogen; R9 is C1-C3 alkoyl; R8 is methyl; R8 and R9 are each hydrogen; RIO is CF3; RIO is haloalguil; RIO is haloalygoxy; Rll is hydrogen RIO and Rll are each hydrogen; Rll is haloalguil; RIO and Rll combine to form a bicyclic fused; (rr) RIO and Rll combine to form a naphthyl substituent with the phenyl to which they are attached; (ss) R1 is optionally substituted C2-C3 arylalguilo; (tt) R1 is substituted C2 arylalkyl; (uu) R1 is C6-C8 heteroalkyl; (vv) Rl is heteroalguyl wherein one of the carbon atoms is replaced with an oxygen; (ww) Rl is heteroalguyl wherein two of the carbon atoms are replaced with an oxygen; (xx) Rl is substituted with an R1 '; (yy) R1 is alkenyl C? -C3; (zz) R1 is alguilox C? -C; (aaa) R1 is C al-C4 aligyl; (bbb) R32 is hydrogen; (ccc) in the ring of five elements, each forms a double bond in the position designated in Formula I; (ddd) V is to a link; (eee) V is alguilo C ^ -Cs; (fff) V is CH2; (ggg) V is CH2CH2; (hhh) V is CH2CH2CH2; (iii) Y is O; (jjj) And it's S; (kkk) Y is C; (111) Y is C, NH, or a bond; (they look) E is C (R3) (R4) A; (nnn) R3 is hydrogen; (ooo) R3 is C6-C2 aligyl; (ppp) R4 is alguilo C? -C2; (ggg) R3 and R4 are each hydrogen; (rrr) R3 and R4 are each methyl; (sss) A is COOH; (ttt) The aliphatic linker is saturated; (uuu) The aliphatic linker is substituted with C1-C3 alkenyl; (vvv) The aliphatic linker is substituted with one to three substituents each independently selected from R30; (www) The aliphatic linker is substituted with one to two substituents each independently selected from R30; (xxx) The aliphatic linker is alguilo C? ~ c3; (yyy) The aliphatic linker is alguilo C? ~ C2; (zzz) The aliphatic linker is C-C3 alguilo and a carbon is replaced with an -O-; (aaaa) a compound of Formula IV: IV (bbbb) A compound of Structural Formula V: (cccc) A compound of Structural Formula VI; vi (dddd) A compound of formula VII: VII (eeee) A compound of Structural Formula VIII: (ffff) A compound of Structural Formula Villa: Villa Igg? Íg) A compound of Structural Formula IX: IX (hhhh) A compound of Structural Formula X: (iiii) A compound of Structural Formula XI: XI (jjjj) A compound of Structural Formula XII: (kkkk) ün Composite of Structural Formula XIII: (1111) Aryl is a phenyl group; (mmmm) Aryl is a naphthyl group; (nnnn) A compound of Formula I which selectively modulates a delta receptor; (oooo) An active ingredient, as described herein, which is a PPAR coagonist that modulates a gamma receptor and a delta receptor; (PPPP) An active ingredient, as described herein, for use in the treatment of cardiovascular diseases; (cfPIFJ.) An active ingredient, as described herein, for use in the treatment of Metabolic Disorder; (rrrr) An active ingredient for use in the control of obesity; (ssss) An active ingredient for use in the treatment of diabetes; (tttt) An active ingredient that is a PPAR receptor agonist; (uuuu) A compound of Formula I selected from the group consisting of 2-methyl-2-acid. { 4- [3- (5-naphthalen-2-ylmethyl-2 H- [1,2,4] triazol-3-yl) -phenoxy} propionic Reaction Reaction 1 1 b 1 d 1 fijustB of Functional Group if necessary Chiral Separation 1 + isomers of Formula I The compounds of Formula I are prepared by the reaction of either a carbonyl hydrazone la in the presence of a carbonitrile Ib or a carbonyl hydrazone Id in the presence of a carbonitrile le to give intermediates 2. The reaction to form the triazole nucleus 2 occurs in the presence of a strong base, for example, sodium, lithium or potassium alkoxides, or sodium, lithium or potassium hydroxides, in a polar protic solvent such as low molecular weight alkanols for example, methanol, ethanol or n- or i-isopropanol at reaction temperatures from room temperature to the reflux temperature of the mixture. Compound 2 is alkylated with a primary or secondary alkenyl halide RZ, wherein R includes the definition of both R32 and Rl in the presence of a base eg sodium, lithium or potassium carbonate or bicarbonate in a polar aprotic solvent, for example, acetonitrile, acetone or DMF at room temperature at the reflux temperature of the mixture. Catalytic Kl can be added to facilitate total aligilation by in situ replacement of R-Z if Z is Cl or Br, to the more reactive R-I alkylation reagent. The allylation with R gives a maximum mixture of regio, and therefore optical, isomers of Formula I. Since the racemic mixtures of Formula I are separated and isolated by guiral chromatography to pure isomers at times, it is required that the racemic mixtures of Formula I have adjustments of functional groups, guizás, leading the mixtures to optimal separation in the guiral chromatography procedure. The functional group settings anticipated in this document and appreciated by one skilled in handling organic reactions include, manipulations of carboxylic acid derivatives, if applicable, to either low molecular weight esters such as ethyl or methyl esters or esters with spherical obstruction such as t-butyl esters. Alternatively as will be appreciated by one of skill in the art in the execution of synthetic methodologies, ester functionalities, if applicable, can be adjusted to free carboxylic acids by saponification of low molecular weight esters with sodium, lithium or potassium hydroxides in polar aprotic solvents, such as methanol, ethanol or hydrolysis of strong acid from hindered esters, for example, t-butyl esters with TFA in a weakly polar aprotic solvent such as methylene chloride or dichloroethane. Other manipulations of functional groups include the conversion of ketones or aldehydes if applicable, to ketals and acetals, with low molecular weight alkanoids and strong acid, for example, ticosic acid and sulfuric acid. Alternatively, acetals and ketals, if present, can be converted to the corresponding carbonyl compound with strong acid and hydrated lower alkanols or with BBr3 in dichloromethane or dichloroethane. The starting materials for the above Reaction Essene can often be commercially available, particularly for carbonitrile le and Id compounds. Other carbonitriles of formula le and Ib can be prepared, as is common to one skilled in the art. of organic manipulations, from 1) commercially available or known carboxylic acids by conversion to primary amides, followed by dehydration with a Vilsmeier reagent or 2) commercially available or known carboxyaldehydes by conversion to oximes, followed by dehydration with a Vilsmeier reagent. The idrazones of the formula la and Ib are prepared from the corresponding carboxylic acids or acid halides and hydrazines in dichloromethane or dichloroethane in the presence of a base such as pyridine, triethylamine or sodium, lithium or potassium bicarbonate or carbonate. A particularly useful reference for the preparation of the Id is Xu, Yanping, et. to the. J. Med. Chem. 46 (24) (2003) p. 5121-5124, wherein the analogous reactions can be applied to the synthesis of the Id using commercially available or known carboxylic acids.

Preparation 1 (compound 1) Example 2A (compound 2A) The compound or preparation 1 is taken [Xu, et. to the. Loe Sit. (2003)] (1.34 mg, 4 mmol) in methanol (30 mL). To this solution, 4-methylbenzylnitrile (1.04 mg, 8 mmol) was added, followed by sodium methoxide (75 mg). The reaction was heated to reflux (~80 ° C) with stirring for 24 hours. The mixture was diluted with ethyl acetate (50 mL). The ethyl acetate was washed with water (3 x 60 mL), dried (Na 2 SO 4), and concentrated on a rotoevaporator to give an oily residue. The residue was purified on a column of silica gel to give Example 2A as an oil (670 mg). m / z: M + l 450.

Example 2B-2D Examples 2B to 2D shown in the following Table were synthesized in accordance with the procedure of Example 2A, from Preparation 1 using appropriate nitrile shown in the following Table.

Example 3 The compound of Example 2A (120 mg) was taken in 50% TFA-dichloromethane (5 mL). The mixture was stirred at room temperature for 18 hours. The solvent was removed in a rotoevaporator and the residue was dried under high vacuum to give an oil (101 mg). m / z: 394 (M + l).

Examples 3B-3D Examples 3B to 3C synthesized are shown in the following table in accordance with the procedure for Example 3A, using TFA mediated by hydrolysis of the appropriate t-butyl esters of Examples 2B to 2D.

Example 4A Mix 4-b of 4f 2-Ethoxyethyl bromide (0.1 mL) was added to a solution of 2A (70 mg) in anhydrous DMF (1.5 mL), followed by K2C? 3 anhydrous powder. The reaction mixture was heated to 50 ° C with stirring for 18 hours. The mixture was diluted with ethyl acetate (30 mL) and the ethyl acetate was washed with water (3 x 30 mL). The ethyl acetate layer was dried (Na2SO) and concentrated to a rotoevaporator to give an oily residue. The residue was purified on a silica column to give approximately a regioisomeric 40-60 mixture of Example 4A as an oil (62 mg). m / z: 522 (M + l).

Examples 4B to 4F Compounds 4B to 4F synthesized are shown in the following Table in accordance with the procedure for 4A of 2A using appropriate albyl bromide as shown in the Table below.

Mix 4-b of 4f Example 5A Mixture-5a The triazole mixture from Example 4A (61 mg) was taken in 50% TFA-dichloromethane (4 mL). This mixture was stirred at room temperature for 4 hours. The solvent was removed on a rotoevaporator and the residue dried under high vacuum to give the regioisomer mixture of Example 5A in an oil (30 mg), m / z: 466 (M + 1).

Examples 5B to 5F Example 5B to 5F synthesized is shown in the following Table according to the procedure for 5A, by TFA-mediated hydrolysis of tert-Jutyl esters of Examples 4E to 4C.

Mixtures of Examples SB to 5F (m / z) Example R M + l 5B 496 5C 452 5D 494 5E ^ C (CH3) 3 540 5F CH. 464 Examples 6 and 7 Concentrated H2SO4 was added to a solution of the mixture of Example 5-A (70 mg) in methanol (25 ml). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed to a pegent volume and the residue was diluted with ethyl acetate (30 ml). The ethyl acetate layer was washed with water (3x30 mL), dried (Na2SO4) and concentrated to a rotoevaporator to give an oily residue (71 mg). The residue was purified on a guiral HPLC column to give the pure examples 6 and 7.

Example 6: (15 mg), m / z: 480 (M + l).

Example 7: (19 mg), m / z: 480 (M + l) Example 8 The triazole ester of Example 6 (15 mg) in methanol (2 mL) was taken. Aqueous 2N NaOH (1 mL) was added to this solution. The mixture was stirred at room temperature for 2 hours. The solvent was evaporated in a rotoevaporator and the residue was dissolved in water (5 mL). The solution was acidified to pH ~ 3 with 0.1M aqueous HCl to give a solution of beds. The mixture was extracted with CH2C12 (3 x 10 ml). The combined layers of CH2C12 were dried (Na2SO4), concentrated in a rotoevaporator, and then dried under high vacuum to give Example 8 (11 mg). m / z: 466 (M + l).

Example 9 Example 9 was synthesized according to the procedure for example 8 by NaOH-mediated hydrolysis of the ester of example 6. m / z: 466 (M + 1).

Example 9a Example 9a was synthesized using the general method for Example 3A and Reaction Scheme I. m / z: 436.3.

Example 10 2-Methyl-2- (4-. {3- [5- (4-trifluoromethyl-phenyl) -2H- [1,2,4] triazol-3-yl] -propyl tert-butyl ester .}. - phenoxy) -propionic 4- (Trifluoromethyl) benzonitrile was added (0.52 g, 3.0 mmol) and potassium tert-butoxide (0.023 g, 0.21 mmol) were added to a solution of 2- [4- (3-hydrazinocarbonyl-propyl) -phenoxy] -2-methyl- tert-butyl ester. propionic (0.5 g, 1.5 mmol) in MeOH (5 mL). The mixture was stirred at reflux overnight. An additional 0.2 equivalents of potassium tert-butoxide was added and the reaction was stirred for 24 hours. The crude was cooled with water, the MeOH was removed in vacuo, and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried with MgSO 4, and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 4: 1) giving 0.32 g (44%) of the title compound, Example 10 as a pale yellow oil. MS data (ER +) m / z 490.6 [M + H].

EXAMPLE 11 2-Methyl-2- (4-. {3- [5- (4-trifluoromethyl-phenyl) -2H- [1, 2,4] triazol-3-yl] -propyl] -phenoxy acid ) -propionic TFA (0.31 mL, 3.98 mmol) was added to a solution of Example 10 (0.65 g, 1.33 mmol) in CH2C12 (6.5 mL). The mixture was stirred at room temperature overnight. By CCD, a significant amount of the starting material remains. The solvent and the residual TFA was removed in vacuo. The crude material was purified by flash chromatography (Hexanes / EtOAc 2: 1 and 1: 1) to afford 0.16 g (28%) of Example 10 as a white solid, and 0.4 g of the recovered starting material. MS data (ER +) m / z 434.3 [M + H].

HO OR BnBr / AgzO / EtDAE BnO O R u yield 65-75% R Commercially available yields 85-95% R30a is R30 or H.

General Procedure for the Reaction Scan 2 BnBr / Ag2O / EtOAC 65% performance Commercially available BnBr (1.1 mmol) and Ag20 (1.1 mmol) were added to a solution of commercial starting material (1.0 mmol) in EtOAc (5 mL / mmol). The mixture was refluxed overnight. The reaction was followed by CCD (Hexane / EtOAc 1: 1). The reaction was filtered through celite and the solvent was removed under vacuum. The crude material was purified by flash chromatography (Hexane and Hexane / 20% EtOAc), to obtain a compound of formula A from Reaction Estrus 2.

The benzyl derivative compound of formula A of Reaction Streak 2 (1.0 mmol) was dissolved in EtOH (0.8 m). Then, hydrazine monohydrate (3.0 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexane / EtOAc 4: 1). The solvent was removed under vacuum. The residue was dissolved in EtOAc and washed with water. The organic layer was dried and concentrated. The crude material was used without further purification. 4- (Trifluoromethyl) benzonitrile (2.0 mol) and potassium tert-butoxide (0.6 mmol) were added to a solution of acylhydrazine, a compound of formula B from Reaction Spindle 2 (1.0 mmol) in MeOH (2.4 M). The mixture was stirred at reflux for 24 hours. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The crude material was quenched with water, the MeOH was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried with MgSO, and concentrated in vacuo. The raw material was purified by Biotage (Hexane / EtOAc 4: 1) to obtain a compound of formula C of Reaction Estrus 2.

R = alkyl group Triazole alkylation: KOH powder was added (2.2 mmol), R-I (Br) (2.0 mmol) and Bu4NBr (0.2 mmol), to a solution of the corresponding triazole-derived Compound C from Reaction Spindle 2 (1.0 mmol) in THF (5 mL / mmol). The mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The oil was quenched with water and added EtOAc. The aqueous layer was extracted with EtOAc (2X). The organic layer was separated, dried with MgSO 4, and concentrated in vacuo. The raw material was purified by Biotage (Hexane / EtOAc 7: 1 and 4: 1) to obtain a compound of formula D of Reaction Runner 2).

FROM Pd (C) (10-20% by weight) and NH4 + COO "(10-20 mmol) was added to a solution of the triazole compound of formula D from Reaction Spindle 2 (1.0 mmol) in EtOH (5 mL / The mixture was stirred at 80 ° C overnight.The reaction was followed by CCD.The reaction was filtered through celite and the solvent removed under vacuum.The crude material was purified by Biotage (Hexane / EtOAc 1 : 1) to obtain a compound of formula E of Reaction Estrus 2.

Reaction Run 2A K2C03 (1.1 mmol) and 4-fluoro-nitrobenzene (1.0 mmol) were added to a solution of the corresponding triazole derivative (C) of Reaction Eskene 2a (1.0 mmol) in DMSO (20 mL / mmol) and the mixture was stirred at 90 ° C overnight. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The reaction was quenched with ice / water and DCM was added. It was extracted again with 20% DCM / MeOH. The organic layers were combined and dried with MgSO 4, and concentrated in vacuo. The crude was purified by flash chromatography (Hexane / EtOAc 9: 1) to obtain Formula D of Reaction Essene 2. Pd (C) (10% by weight) was added to a solution of the triazole derivative of formula D of the Reaction Scheme 2a (1.0 mmol) in EtOH (5 mL / mmol). The mixture was stirred under a hydrogen atmosphere overnight. The reaction was followed by CCD. The solution was mixed through celite and the solvent was removed under vacuum. The crude was purified (formula E of Reaction Esquema 2A) without further purification. 2N HCl solution (10.0 mmol) was added to a solution of the corresponding triazole derivative of formula E from Reaction Spindle 2A (1.0 mmol) in a solvent mixture (THF / CH3COOH 8: 1) (8 mL / mmol) at 0 ° C and the mixture was stirred for 5 minutes at room temperature. NaN02 (1.0 mmol) was then added in water (0.32 M) and then 3% H202 solution. The reaction was stirred at 0 ° C for 30 minutes and then for 1 hour at room temperature. Then, EtOAc was added and the mixture was extracted with water. The organic layers were dried with MgSO 4 and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 9: 1) to obtain the compound of formula F of Reaction Escape 2A (Yield 17%). Pd (C) (10-20% by weight) and NH4 + COO "(10-20 mmol) were added to a solution of the compound of formula F of Reaction Esquema 2A (1.0 mmol) in EtOH (5 mL / mmol). The mixture was stirred at 80 ° C overnight.The reaction was followed by CCD.The reaction was filtered through celite and the solvent was removed under vacuum.The crude material was purified by Biotage (Hexane / EtOAc 1: 1). ) to obtain a compound of formula F of Reaction Run 2A. main piece Mitsounobu reaction: The title compound (2 mmol), Bu3P (2.0 mmol) and TMAD (2.0 mmol) were added to a solution of the triazole derivative compound E from Reaction Estrus 2 (1.0 mmol) in THF / DCM mixture (1 : 1) (10 mL / mmol). The mixture was stirred at room temperature for 10-20 minutes. The reaction was followed by CCD. The solvent was removed under reduced pressure and then water and diethyl ether were added. The organic layer was separated and stirred with a 2N NaOH solution for 10 minutes. The mixture was extracted, the organic layer was dried with MgSO4, and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 91 :) to obtain compound F from Reaction Esquema 2. 2N KOH solution (10 mmol) was added to a solution of the triazole-derivative compound F from Reaction Strue 2 (1.0 mmol) in a mixture of EtOH / THF (1: 1) (10 mL / mmol) and the mixture was stirred. stirred at room temperature overnight. The reaction was followed by CCD. The solvent was removed under vacuum and then, water and EtOAc were added. 1N HCl solution was added until the pH is 5-7. The mixture was extracted, the organic layer was washed with water, separated and dried with MgSO 4, and concentrated in vacuo. Compound G of Reaction Scheme 2 was obtained.Synthesis of Example 13 Preparation 2 BnBr (72.7 mL, 0.61 mmol, 1.1 eg.) Was added and Ag20 (141.6 g, 0.61 mol, 1.1 eg.), To a solution of methyl glycolate (50 g, 0.56 mol) in EtOAc (300 mL) and the mixture was stirred at reflux overnight. The reaction was followed by CCD (Hexane / EtOAc 1: 1). The reaction was filtered through celite and the solvent was removed under vacuum. The oil was passed absorbed on instant silica. It was placed on the top of an instant silica pad (500 g) and was levigated with 20% ethyl acetate / hexane to give 75.8 g (75% yield) of a colorless oil.

Preparation 3 Preparation 2 (7.5 g, 41.6 mmol) was dissolved in EtOH (100 mL). Then, hydrazine monohydrate (6.05 mL, 124.9 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexane / EtOAc 4: 1). The solvent was removed under vacuum and the residue was dissolved in EtOAc and washed with water. The organic layer was dried and concentrated and the crude was used without further purification.

Preparation 4 4- (Trifluoromethyl) benzonitrile (14.2 g, 83.2 mmol) and potassium tert -butoxide (2.8 g, 25 mmol) were added to a 3-fold solution in MeOH (100 mL) and the mixture was stirred at reflux for 24 hours. hours. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The crude was quenched with water, the MeOH was removed in vacuo, and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried with MgSO 4 and concentrated in vacuo. The crude was purified by flash chromatography (Hexane / EtOAc 4: 1) to obtain 11.2 g (81% yield) of preparation 4 as a white solid.

KOH powder (0.37 g, 6.6 mmol), EtI was added (0.48 mL, 6.0 mmol) and BuNBr (0.19 g, 0.6 mmol) were added to a solution of Preparation 4 (1.0 g, 3.0 mmol) in THF (15 L), and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexane / EtOAc 4: 1). The crude was quenched with water and EtOAc was added. The aqueous layer was extracted with EtOAc (2x). The organic layer was separated, dried with MgSO 4, and concentrated in vacuo. The crude was purified by flash chromatography (Hexane / EtOAc 9: 1) to obtain 1.09 g (99% yield) of preparation 5 as a white solid.

Pd (C) (20% by weight) and NH4 + COO "(1.83 g, . 0 mmol) was added to a solution of Preparation 5 (1.05 g, 2.9 mmol) in EtOH (25 mL) and the mixture was stirred at 80 ° C for 6 hours. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The reaction was filtered through celite and the solvent was removed under vacuum to obtain 0.88 g of preparation 6 as a white solid which was used without further purification.

Preparation 7 Preparation 5 H = PC "3 Preparation 7 Main part The title compound (1.38 g, 5.8 mmol), Bu3P (1.44 L, 5.8 mmol) and TMAD (0.99 g, 5.8 mmol) were added to a solution of preparation 6 ( 0.88 g, 2.9 mmol) in a mixture of THF / DCM (1: 1) (15 + 15 mL) and the mixture was stirred at room temperature for 1 hour.The reaction was followed by CCD (hexane / EtOAc 1: 1) The solvent was removed under vacuum, then water and diethyl ether were added.The organic layer was separated and stirred with 2N NaOH solution for 10 minutes.The mixture was extracted and the organic layer was dried with MgSO4, and concentrated in vacuo. The crude was purified by Biotage [40 + S] (Hexane / EtOAc 9: 1) to obtain 0.99 g (70% yield) of preparation 7 as a white solid MS data (ER +) m / z 492.3 [M + H]. 350 mg (fraction B) of the impure compound were reserved. 2N KOH solution (10 mmol, 19.9 mmol) was added to a solution of Preparation 7 (0.98 g, 1.99 mmol) in a mixture of EtOH / THF (1: 1) (10 mL / mmol) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / EtOAc 1: 1). The solvent was removed under vacuum. Then water and EtOAc were added and the mixture was stirred for 2 minutes. The organic layer was isolated and 1N HCl solution was added over the aqueous phase until pH 5-7. The white solid was precipitated and washed with water. It was dried under vacuum to obtain 0.80 g (87% yield) of Example 13 (Purity 97%). MS data (ER +) m / z 464.2 [M + H]. Examples 12 and 14-34 were prepared by a similar procedure for the preparation of Example 13.

Reaction Reaction 3 General Procedure for Reaction Run 3 K2C? 3 (3.0 mmol) and the compound of formula A of spague 3 (1.0 mmol) were added to a solution of the bromo-ester derivative (compound of formula H of Reaction Run-3) (1.2 mmol). ) in MeCN (5 mL / mmol). The mixture was stirred at reflux overnight. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The solvent was removed under vacuum and then, water and EtOAc were added. The mixture was extracted, the organic layer was dried with MgSO 4 and concentrated in vacuo. The crude was purified by flash chromatography (Hexane / EtOAc 6: 1) to obtain compound B from Reaction Esquema 3. The ester of compound B from Reaction Ester B (1.0 mmol) was dissolved in EtOH (0.8 M). Then, hydrazine monohydrate (3.0 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexane / EtOAc 4: 1). The solvent was removed under vacuum. The residue was dissolved in EtOAc and washed with water. The organic layer was dried and concentrated. The crude was used without further purification. 4- (Trifluoromethyl) benzonitrile (2.0 ml) and potassium tert -butoxide (0.6 mmol) were added to a solution of the acylhydrazine compound of formula C of Reaction Estrus 3 (1.0 mmol) in EtOH (2.4 M). The mixture was stirred at reflux for 24 hours. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The crude was quenched with water, the MeOH was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried with MgSO 4, and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 6: 1) to obtain the compound of Formula F of Reaction Esquema 3 as a colorless oil. 2N KOH solution (10 mmol) was added to a solution of the triazole derivative compound of formula F of Reaction Esquema 3 (1.0 mmol) in EtOH / THF mixture (1: 1) (10 mL / mmol). The mixture was stirred at room temperature overnight. The reaction was followed by CCD. The solvent was removed under vacuum. Then, water and EtOAc were added. 1N HCl solution was added until pH 5-7. The mixture was extracted, the organic layer was washed with water, separated with MgSO 4 and concentrated in vacuo. The products of the compound of formula G of Reaction Scheme 3 are obtained as white solids.

Synthesis of Example 36 Preparation 8 main piece K2C03 (9.23 g, 66.99 mmol) and the master (5.0 g, 22.3 mmol) were added to a solution of commercially available bromoether derivative (2.54 mL, 26.8 mmol) in MeCN (100 mL) and the mixture was stirred at reflux for the night. The reaction was followed by CCD (hexane / EtOAc 4: 1). The solvent was removed under vacuum. Then, water and EtOAc were added. The mixture was extracted and the organic layer was dried with MgSO 4 and concentrated in vacuo. The crude was purified by flash chromatography (Hexane / EtOAc 19: 1) to obtain preparation 8 as a colorless oil (6.59 g).

Preparation 9 The preparation 8 (6.59 g, 22.3 mmol) was dissolved in EtOH (30 mL). Then, hydrazine monohydrate (4.32 mL, 89.2 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexane / EtOAc 4: 1). The solvent was removed under vacuum. The residue was dissolved in EtOAc and washed with water. The organic layer was dried and concentrated. The crude preparation 9 was used without further purification.

Preparation 10 4- (Trifluoromethyl) benzonitrile (4.72 g, 27.6 mmol) and potassium tert-oxide (0.93 g, 8.3 mmol) were added to a solution of preparation 9 of acylhydrazine (3.22 g, 10.9 mmol) in EtOH (50 mL). and the mixture was stirred at reflux for 24 hours. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The crude was quenched with water, the MeOH was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried with MgSO 4 and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 9: 1 to 6: 1) to obtain preparation 10 as a white solid (2.28 b obtained, 47% yield in two steps).

Example 36 2N KOH solution (2.7 mL, 4.5 mmol) was added to a solution of Preparation 10 (200 mg, 0.45 mmol) in a mixture of EtOH / THF (1: 1) (8 L) and the mixture was stirred at room temperature. atmosphere during the night. The reaction was followed by CCD. The solvent was removed under vacuum. Then water and EtOAc were added. 1N HCl solution was added until pH 5-6. The mixture was extracted and the organic layer was washed with water, separated, dried with MgSO 4, and concentrated in vacuo. Example 36 was obtained as white solids (164 mg, 87% yield). Examples 35, 37 and 38 were prepared by a similar procedure for the preparation of Example 36.

Reaction Reaction 4 General Procedure for Reaction Escape 4 4- (Trifluoromethyl) benzonitrile (3.0 ml) and potassium tert -butoxide (0.21 mmol) were added to a solution of a compound of formula A from Reaction Spindle 4 (1.5 mmol) in MeOH (5 mL) and the mixture was stirred at reflux overnight. An additional 0.2 equivivalents of potassium tert -butoxide was added and the reaction was stirred for 24 hours. The crude was quenched with water, the MeOH was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried with MgSO 4 and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 4: 1) to provide a compound of formula B of Reaction Estrus 4.

R = alkenyl group Alkylation of triazole: KOH powder (2.2 mmol), R-I (Br) (2.0 mmol) and BuNBr (0.2 mmol) were added to a solution of the corresponding triazole compound of formula B of the Reaction Run 4 (1.0 mmol) in THF (5 mL / mmol) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexane / EtOAc 4: 1). The crude was quenched with water and EtOAc was added. The aqueous layer was extracted with EtOAc (2x). The organic layer was separated, dried with MgSO4, and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 7: 1 and 4: 1) to obtain a compound of formula C of the Reaction Escape 4.

R = aryl group (Ph and p-CF3-Ph) Coupling reaction: Added aryllidine (1.0 mmol), K2C03 (2.0 mmol), Cu (OAc) 2 (0.01 mmol) and trans-1,2-diaminocyclohexane (0.07) mmol) was added to a solution of the corresponding triazole derivative compound of formula B of Reaction Scheme 4 (1.2 mmol) in anhydrous dioxane (5 mL / mmol) under N2. The mixture was stirred at 110 ° C overnight. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The reaction was filtered through celite and the organic layer was extracted with water. The aqueous layer was extracted with EtOAc (2x), the organic layer was separated, dried with MgSO, and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 9: 1) to obtain a compound of formula C from Reaction Escape 4.

Reaction Escape 4a R = aryl group (oF-Ph) K2CÜ3 (1.1 mmol) and 3,4-difluoro-nitrobenzene (1.0 mmol) were added to a solution of the corresponding triazole compound of formula B (1.0 mmol) in DMSO (20 mL / mmol ) and the mixture was stirred at 90 ° C overnight. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The crude was quenched with ice / water and DCM was added. A second extraction was extracted with 20% DCM / MeOH. The organic layers were combined, dried with MgSO 4, and concentrated in vacuo. The crude was purified by flash chromatography (Hexane / EtOAc 9: 1) to obtain a compound of formula Ba from Reaction Escape 4a. Pd (C) (10% by weight) was added to a solution of the triazole derivative (1.0 mmol) in alcohol (5 mL / mmol). The mixture was stirred under a hydrogen atmosphere overnight. The reaction was followed by CCD. The solution was filtered through celite and the solvent was removed under vacuum and the crude was used without further purification. 2N HCl solution (10.0 mmol) was added to a solution of the corresponding triazole compound Bb of the Reaction Run 4a (1.0 mmol) in a solvent mixture (THF / CH3COOH 8: 1) (8 mL / mml) at 0 ° C. The mixture was stirred 5 minutes at this temperature and NaN02 (1.0 mmol) was added in water (0.32 M) and then 3% H202 solution (0.56 mL). The reaction was stirred at 0 ° C for 30 minutes and 1 hour at room temperature. Then, EtOAc was added and the mixture was extracted with water. The organic layer was dried with MgSO 4 and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 9: 1) to obtain compound C from Reaction Escape 4a.

TFA (excess) was added to a solution of the compound of formula C of Reaction Estrus 4 (1.0 mmol) in CH2C12 (5 ml) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / EtOAc 1 :). The solvent and the residual TFA were moved in vacuo. The residue was dissolved in DCM and washed with a saturated solution of NaHC 3. The organic layer was dried with MgSO 4 and concentrated in vacuo. The compound of formula D of Reaction Spindle 4 was obtained. I2 (2.0 mmol) and AgS04 (2.0 mmol) were added to a solution of the corresponding triazole compound of formula D of Reaction Estrus 4 (1.0 mmol) in EtOH (8 mL / mmol) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The crude was quenched with water and EtOAc was added. The aqueous layer was extracted with EtOAc (2x). The organic layer was separated, dried with MgSO4, and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 7: 1 and 4: 1) to obtain a compound of formula E of the Reaction Escape 4. MeB (OH) 2 (3.0 mmol), CsF (3.0 mmol) and PdCl2 (dppf) (0.16 mmol), to a solution of the corresponding triazole compound of formula E of Reaction Scheme 4 (1.0 mmol) in anhydrous Dioxane (10 ml / mmol) under N2. The mixture was stirred at 80 ° C overnight. The reaction was followed by LC / MS. The reaction was cooled, filtered through celite and the solvent was removed under vacuum. The crude was purified by flash chromatography (7: 1 and 4: 1 Hexane / EtOAc mixtures) to obtain a compound of formula F of Reaction Run 4. TFA (excess) was added to a solution of the compound of Formula F of the Scheme. of Reaction 4 (1.0 mmol) in CH2C12 (5 ml) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / EtOAc 1: 1). The solvent and residual TFA were removed in vacuo. The residue was dissolved in DCM and washed with saturated NaHCO3 solution. The organic layer was dried with MgSO 4 and concentrated in vacuo. A compound of formula G of Reaction Spindle 4 was obtained.

Synthesis of Example 47 Preparation 11 Preparation 11 4- (Trifluoromethyl) benzonitrile (0.51 g, 3. 0 mmol) and potassium tert -butoxide (0.023 g, 0.21 mmol) were added to a solution of A above (0.5 g, 1.5 mmol) in MeOH (5 mL) and the mixture was stirred at reflux overnight. An additional 0.2 equivivalents of potassium tert -butoxide was added and the reaction was stirred for 24 hours. The crude oil was quenched with water.

The MeOH was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried with MgSO 4 and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 4: 1) giving 0.32 g (44%) of preparation 11 as a pale yellow oil. MS data (ER +) m / z 490.6 [M + H].

Preparation 12 KOH powder (0.14 g, 2.45 mmol), Mei (0.14 mL, 2.3 mmol) and Bu4NBr (0.05 g, 0.15 mmol) were added to a solution of preparation 11 (0.75 g, 1.5 mmol) in THF (5 mL). and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexane / EtOAc 4: 1). The crude was quenched with water and EtOAc was added. The aqueous layer was extracted with EtOAc (2x). The organic layer was separated, dried with MgSO 4 and concentrated in vacuo. The crude was purified by flash chromatography (Hexane / EtOAc 9: 1) to obtain 0. 51 g (66% yield) of preparation 12 as a white solid.

Preparation 13 I2 (2.0 mmol, 0.8 mmol) and AgS0 (0.25 g, 0.8 mmol) were added to a solution of Preparation 12 (0.25 g, 0.5 mmol) in EtOH (5 mL) and the mixture was stirred at room temperature overnight . The reaction was followed by CCD (Hexane / EtOAc 4: 1). The crude was quenched with water and EtOAc was added. The aqueous layer was extracted with EtOAc (2x). The organic layer was separated, dried with MgSO 4, and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 9: 1) to obtain 0.15 g (48% yield) of preparation 13 as a white solid.

Preparation 14 MeB (OH) 2 (0.04 g) was added, 0.71 mmol), CsF (0.11 g, 0.71 mol) and PdCl 2 (dppf) (0.03 g, 0.04 mmol), to a solution of Preparation 13 (0.15 g, 0.24 mmol) in anhydrous dioxane (2 mL) under N 2 and The mixture was stirred at 80 ° C overnight. The reaction was followed by LC / MS. The reaction was cooled, filtered through celite and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hexane / EtOAc 4: 1 mixtures) to obtain 0.09 g (77% yield) of preparation 14 as a white solid.

Example 47 TFA (excess) was added to a solution of preparation 14 (0.09 g, 0.17 mmol) in CH2C12 (5 mL) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / EtOAc 1: 1). The solvent and residual TFA were removed in vacuo. The residue was dissolved in DCM and washed with saturated NaHCO3 solution. The organic layer was dried with MgSO 4 and concentrated in vacuo. Example 47 was obtained as a solid, 0.05 g (92% yield). Examples 39-46 and 48-52 were prepared by a similar procedure for the preparation of Example 47.

Reaction Reaction 5 R in Reaction Scheme 5 is Rl or R32.

General Procedure for the Reaction Scheme I2 (1.1 mmol) and AgS0 (1.1 mmol) were added to a solution of the compound of formula A from Reaction Esquema 5 (1.0 mmol) in EtOH (8 mL / mmol) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The crude was quenched with water and EtOAc was added. The aqueous layer was extracted with EtOAc (2x). The organic layer was separated, dried with MgSO 4, and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 9: 1) to obtain a compound of formula B from Reaction Esquema 5. MeB (OH) 2 (3.0 mmol), CsF (3.0 mmol) and PdCl2 (dppf) were added ( 0.16 mmol), to a solution of the compound of formula B of Reaction Esquema 5 (1.0 mmol) in anhydrous Dioxane (10 ml / mmol) under N2. The mixture was stirred at 80 ° C overnight. The reaction was followed by LC / MS. The reaction was cooled, filtered through celite and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hexane / EtOAc 19: 1 mixtures) to obtain a compound of formula C from Reaction Run 5. The compound of formula C from Reaction Run 5 (1.0 mmol) was dissolved in EtOH (0.8 M) Then, hydrazine monohydrate (3.0 mmol) was added and the mixture was stirred at room temperature overnight. The residue was dissolved in EtOAc and washed with water. The organic layer was dried and concentrated and the crude was used without purification. 4- (Trifluoromethyl) benzonitrile (2.0 mol) and potassium tert-butoxide (0.6 mmol) were added to a solution of the acylhydrazine compound of formula D from Reaction Run 5 (1.0 mmol) in MeOH (2.4 M). The mixture was stirred at reflux for 24 hours.

The reaction was followed by CCD (hexane / EtOAc 4: 1). The crude was quenched with water, the MeOH was removed in vacuo, and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried with MgSO 4 and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 4: 1 and 2: 1) to obtain a compound of formula E of Reaction Esquema 5. TFA (excess) was added to a solution of the compound of Formula E of Reaction Estrus. (1.0 mmol) in CH2C12 (5 ml) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / EtOAc 1: 1). The solvent and residual TFA were removed in vacuo. The residue was dissolved in DCM and washed with saturated NaHCO3 solution. The organic layer was dried with MgSO 4 and concentrated in vacuo. A compound of formula F of Reaction Spindle 5 was obtained as a pure solid. KOH powder (2.2 mmol), RI (Br) (2.0 mmol) and Bu4NBr (0.2 mmol) were added to a solution of the corresponding triazole derivative compound of formula E from Reaction Esquema 5 (1.0 mmol) in THF (5 mL mmol) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexane / EtOAc 4: 1). The crude was quenched with water and EtOAc was added. The aqueous layer was extracted with EtOAc (2x), the organic layer was separated, dried with MgSO, and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 7: 1 and 4: 1) to obtain a compound of formula G of Reaction Esquema 5 as a white solid. TFA (excess) was added to a solution of the compound of Formula G of Reaction Estrus 5 (1.0 mmol) in CH2C12 (5 mL) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / EtOAc 1: 1). The solvent and residual TFA were removed in vacuo. The residue was dissolved in DCM and washed with saturated NaHCO3 solution. The organic layer was dried with MgSO 4 and concentrated in vacuo. A compound of formula H of Reaction Spindle 5 was obtained as a pure solid.

Synthesis of Example 54 Preparation 15 preparation 15 I 2 (18.2 g, 71.4 mmol) and AgSO (22.2 g, 71.14 mmol) were added to a solution of the corresponding triazole derivative (compound A above) (20 g, 64.4 mmol) in EtOH (65 mL) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The crude was quenched with water and EtOAc was added. The aqueous layer was extracted with EtOAc (2x). The organic layer was separated, dried with MgSO 4, and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 9: 1) to obtain preparation 15 as a white solid (m = 15.8 g, yield 56%).

Preparation 16 MeB (OH) 2 (3.48 g, 58.2 mmol), CsF (13.8 g, 91.0 mmol) and PdCl2 (dppf) (4.75 g, 5.82 mmol) were added to a solution of Preparation 15 (15.8 g, 35.4 mmol) in anhydrous Dioxane (40 mL4) under N2, and the mixture was stirred at 80 ° C overnight. The reaction was followed by LC / MS. The reaction was cooled, filtered through celite and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hexane / EtOAc 19: 1 mixtures) to obtain 7.75 g (66% yield) of preparation 16 as a white solid.

Preparation 17 Preparation 16 (7.75 g, 24.04 mmol) was dissolved in EtOH (50 mL). Then, hydrazine monohydrate (4.66 mL, 96.2 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexane / EtOAc 9: 1). The solvent was removed under vacuum. The residue was dissolved in EtOAc and washed with water. The organic layer was dried and concentrated. Preparation 17 was used without further purification.

Preparation 18 4- (Trifluoromethyl) benzonitrile (8.2 g, 48.08 mmol) and potassium tert -butoxide (1.62 g, 14.42 mmol) were added to a solution of preparation 17 (24.04 mmol) in EtOH (50 mL) and the mixture stirred at reflux for 48 hours. The reaction was followed by CCD (Hexane / EtOAc 4: 1). The crude was purified with water and the MeOH was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried with MgSO, and concentrated in vacuo. The crude was purified by flash chromatography (Hexane / EtOAc 4: 1 and 2: 1) to obtain 2.5 g (22% yield) of preparation 18.

Preparation 19 KOH powder (0.065 g, 1.16 mmol), PrI (0.10 mL, 1.04 mmol) and BuNBr (0.033 g, 0.10 mmol) were added to a solution of Preparation 18 (0.25 g, 0.52 mmol) in THF (5 mL). and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexane / EtOAc 4: 1). The crude was quenched with water and EtOAc was added. The aqueous layer was extracted with EtOAc (2x). The organic layer was separated, dried with MgSO, and concentrated in vacuo. The crude was purified by flash chromatography (Hexane / EtOAc 9: 1) to obtain 0.13 g (48% yield) of preparation 19.

Example 54 TFA (excess) was added to a solution of Preparation 19 (0.09 g, 0.17 mmol) in CH2C12 (5 mL) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / EtOAc 1: 1). The solvent and residual TFA were removed in vacuo. The residue was dissolved in DCM and washed with saturated NaHCO3 solution. The organic layer was dried with MgSO 4 and concentrated in vacuo. Example 54 was obtained as a solid, 0.06 g (72% yield). Example 53 was prepared by a similar procedure for the preparation of Example 54.

Reaction Reactor 6 HO BnBr / AgzO / BOAC B commercially available MeOH? BuOK MeOH Pd oyNH ^ COOVEtOH OH. THF / EtOH R in Reaction Run 6 is Rl or R32 Reaction Run 6a Reaction Reactor 6b General Procedure for the Reaction Route 6 BnBr (72.7 ml, 0.61 mol, 1.1 eq) and Ag20 were added (141.6 mol, 1.1 eg) was added to a solution of methyl glycolate (50 g, 0.56 mol) in EtOAc (300 ml) and the mixture was stirred at reflux overnight. The reaction was followed by CCD (Hexane / EtOAc 1: 1). The reaction was filtered through celite and the solvent was removed under vacuum. The adsorbed oil was passed on flash silica and placed at an instant silica celite pad (500 g) and levigated with 20% ethyl acetate / hexane to give 75.8 (75% yield) of compound A from Esguema of Reaction 6.

The benzyl derivative compound of formula A of Reaction Streak 6 (1.0 mmol) was dissolved in EtOH (0.8 M) and then hydrazine monohydrate (3.0 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was followed by TLC (hexane / EtOAc 4: 1). The solvent was removed under vacuum. The organic layer was dried and concentrated the crude was used without further purification. 4- (Trifluoromethyl) benzonitrile (2.0 mol) and potassium tert-butoxide (0.6 mmol) were added to a solution of the acylhydrazine compound of formula B from Reaction String 6 (1.0 mmol) in MeOH (2.4 M) of a mixture. stirred at reflux for 24 hours. The reaction was followed by CCD (Hexanes / EtOAc 4: 1). The crude was quenched with water, the MeOH was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried with MgSO 4, and extracted in vacuo. The crude was purified by Biotage (Hexanes / EtOAc 4: 1) and Compound C was obtained from Reaction Escape 6. R = Me or MeOCH2CH2 Aligilation of Triazole: KOH powder (2.2 mmol), RI (Br) ( 2.0 mmol) and BuNBRr (0.2 mmol) were added to a solution of the corresponding triazole compound (C) of Reaction Estrus 6 (1.0 mmol) in THF (5 mL / mmol) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexanes / EtOAc 4: 1). The crude was quenched with water and EtOAc was added. The aqueous layer was extracted with EtOAc (2x). The organic layer was separated, dried with MgSO 4 and concentrated in vacuo. The crude was purified by Biotage (Hexane / EtOAc 4: 1) to obtain the compound of formula D of Reaction Escape 6. Pd (C) (10-20% by weight) and NH4 + COO "(10-20 mmol) were added to a solution of the triazole compound of formula D (1.0 mmol) in EtOH (5 ml / mmol) and the mixture was stirred at 80 ° C overnight. The reaction was followed by CCD. The reaction was filtered through celite and the solvent was removed under vacuum. The crude was purified by Biotage (Hexane / EtOAc 1: 1) to obtain the compound of formula E from Reaction Escape 6. NaH (2.1 mmol, 60%) was added to a solution of the triazole derivative compound of formula E of the digest of reaction 6 (1.0 mmol) in anhydrous DMF (10 ml) at 0 ° C, the mixture was stirred at room temperature for 15 minutes, cooled to 0 ° C, and benzyl bromide (compound F of the reaction 6) (1.5 mmol) in anhydrous DMF 85 ML). The reaction was stirred at room temperature for 30 minutes, MeOH was added, and then water was added. The MeOH was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by Biotage (Hexane / EtOAc 4: 1) to obtain the compound of formula G of reaction enzyme 6. 2N KOH solution (10 mmol) was added to a solution of the triazole derivative compound of formula G of reaction scheme 6 (1.0 mmol) in EtOH / THF mixture. (1: 1) (10 ml / mol) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD. The solvent was removed under vacuum and then water and EtOAc were added. A 1N HCl solution was added until pH 5-7. The mixture was extracted and the organic layer was washed with water, separated, dried with MgSO, and concentrated in vacuo. The products were obtained from the compound of formula H of reaction enzyme 6 as white solids.

Synthesis of Example 55 Preparation 19 75% yield Commercially available Preparation 19 BnBr (27.7 ml, 0.61 mol, 1.1 g) and Ag20 (141.6 g, 0.61 mol, 1.1 g) were added to a solution of methyl glycolate (50 g, 0.56 mol) in EtOAc ( 300 ml) and the mixture was stirred at reflux overnight. The reaction was followed by CCD (Hexanes / EtOAc 1: 1). The reaction was filtered through celite and the solvent was removed under vacuum. The oil is passed adsorbed on silica gel. It was placed on top of an instant silica pad (500 g) and was levigated with 20% ethyl acetate / hexane to give 75.8 (75% yield) of preparation 19 as a colorless oil.

Preparation 20 Preparation 19 (7.5 g, 41.6 mmol) was dissolved in EtOH (100 ml). Then hydrazine monohydrate was added (6.05 mL, 124.9 mmol) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexane / EtOAc 4: 1). The solvent was removed under vacuum. The residue was dissolved in EtOAc and washed with water. The organic layer was dried and concentrated. Preparation 20 was used without further purification.

Preparation 21 4- (Trifluoromethyl) -benzonitrile (142 g, 83. 2 mmol) and potassium tert-butoxide (2.8 g, 25 mmol) were added to a prep solution in MeOH (100 mL) and the mixture was stirred at reflux for 24 hours. The reaction was followed by CCD (hexane / EtOAc 4: 1). The crude was quenched with water, the MeOH was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried with MgSO 4, and concentrated in vacuo. The crude was purified by flash chromatography (hexane / EtOAc 4: 1) to obtain 11.2 g (81% yield) of preparation 21 as a white solid.

Preparation 22 KOH powder (0.27 g, 4.8 mmol), Mei (0.28 mL, 4.5 mmol) and Bu4NBr (0.09 g, 0.3 mmol) were added to a solution of Preparation 21 (1.0 g, 3.0 mmol) in THF- (15 mL) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (hexanes / EtOAc 4: 1). The crude was quenched with water and EtOAc was added. The aqueous layer was extracted with EtOAc (2x). The organic layer was separated, dried with MgSO, and concentrated in vacuo. The crude was purified by Biotage (hexane / EtOAc 4: 1) to obtain preparation 22 (1.04 g).

Preparation 23 Pd (C) (10-20% by weight) and NH0COO "(1.89 g, 30 mmol) were added to a solution of preparation 22 (1.04 g, 3.0 mmol) in EtOH (15 mL) and the mixture was stirred at 80 C during the night The reaction was followed by CCD The reaction was filtered through celite and the solvent was removed under vacuum The crude was purified by Biotage (hexane / EtOAc 1: 1) to obtain preparation 23 (0.59 g, 76% yield).

Preparation 24 Preparation 23 70% yield Preparation 24 NaH (0.091 g, 2.29 mmol, 60%) was added to a preparation solution 23 (0.28 g, 1.09 mmol) in anhydrous DMF. (10 ml) at 0 ° C and the mixture was stirred at room temperature by minutes. Again it was cooled to 0 ° C and compound A benzyl bromide (0.68 g, 1.63 mmol) in anhydrous DMF (5 ml) was added and the reaction was stirred at room temperature for 30 minutes. MeOH was added and then water was added. The MeOH was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by Biotage (Hexane / EtOAc 4: 1) to obtain preparation 24 as white solids (0.39 g 70% yield).

Example 55 2N of a KOH solution (1.05 mL, 2.1 mmol) was added to a solution of Preparation 24 (0.1 g, 0.21 mmol) in an EtOH / THF (1: 1) mixture (2 mL) and the mixture was stirred at room temperature. Atmosphere during the night. The reaction was followed by CCD. The solvent was removed under vacuum and then, water and EtOAc were added. 1N HCl was added until pH 5-7. The mixture was extracted and the organic layer was washed with water, separated, dried with MgSO 4, and concentrated in vacuo. Example 55 was obtained as white solids (65 mg, 69% yield).

Example 56 was prepared by a similar procedure for the preparation of example 55.

Reaction Reaction 7 EDC 4- (trnTuorometHr H OBT benzylhydrazine piri ina DCM BBr3 DCM CPC N aOH MeOH Preparation 25 H ^ 'CH, OR Sodium hydride (369 mg, 0.2 mmol) was suspended in DMF (25 ml) at 0 ° C, and then 4-methoxyphenol (1.15 g, 9.2 mmol) was added in one portion and the reaction was allowed to warm up. Room temperature during the night. The reaction was quenched with 1N HCl and extracted with ethyl acetate. The organic layers were combined, dried over MgSO, and evaporated. The residue was purified via chromatography on silica gel (30% ethyl acetate in hexanes) to give 983.1 mg of preparation 25 as a clear, thick oil (57.2%). MS = 225 (M + H +); 242 (M + NH4 +).

Preparation 26 Preparation 26 (983 mg, 4.4 mmol) was dissolved in methanol (10 mL) and 1N NaOH (10 mL) was added thereto. It was stirred at room temperature for 12 hours. Then, the solvent was evaporated, the residue was dissolved in 1N HCl (20 ml), and extracted with ethyl acetate. The organics were combined, dried over MgSO4 and evaporated. This crude product was used (767.5 mg, 89%) without further purification. MS = 195 (M-H "); 214 (M + NH 4 +).

Preparation 27 Preparation 26 (100 mg, 0.5 mmol) was dissolved in dichloromethane (10 ml) and EDC / 117 mg, 0.6 mmol) was added followed by HOBT (83 mg, 0.6 mmol) and stirred for 5 minutes. Then, 4- (trifluoromethyl) benzhidrazine (104 mg, 0.5 mmol) was added in one portion followed by pyridine (0.124 mL, 1.5 mmol) and stirred at room temperature overnight. After this time, the reaction was washed with saturated sodium bicarbonate solution and 1N HCl. The organics were dried over MgSO4 and evaporated. The residue was purified via chromatography on silica gel (50% ethyl acetate in hexanes) to give 127.8 mg of preparation 27 as a white solid (65.6%). MS = 383 (M + H +); 381 (M-H ~).

Preparation 28 Preparation 27 (127 mg, 0.33 mmol) was dissolved in toluene (5 mL). To this was added Lawesson reagent (134 mg, 0.33 mmol) and the reaction was heated to reflux for 2 hours. After this time, the reaction was cooled and diluted with 20 ml of ethyl acetate. It was washed with saturated bicarbonate solution and the organics were dried over MgSO4 and evaporated. The residue was purified via silica gel chromatography (15% ethyl acetate in hexanes) to give 103.8 mg of Preparation 28 as a white solid (82.2%) MS = 381 (M + H +).

Preparation 29 The preparation 28 (100 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL). This was then cooled to 0 ° C and boron tribromide (0.788 ml, 0.79 mmol) was added. After 2 hours, the reaction was quenched via saturated bicarbonate and extracted with 20 ml of ethyl acetate. The organics were dried over MgSO4 and evaporated. This gave 87.2 mg of preparation 29 as a whitish solid (98.4%). MS = 337 & 338 (M + H +).

Preparation 30 w 2- (4-Hydroxy-2-methyl-phenoxy) -2-methyl-propionic acid ethyl ester (73.6 mg, 0.31 mmol) was dissolved in DMF. To this was added sodium hydride (12.4 mg, 0.31 mmol) and stirred at room temperature for 5 minutes. After this time, preparation 29 (87 mg, 0.26 mmol) was added in one portion and the reaction was continued for 2 hours. The reaction was quenched with ammonium chloride and extracted with ethyl acetate. The organics were dried over MgSO4 and evaporated. The residue was purified via chromatography on silica gel (15% ethyl acetate in hexanes) to give 59.7 mg of preparation 30 as a clear oil (46.8%). MS = 495 (M + H +).

Example 57 racemic Preparation 30 was dissolved (59 mg, 0.12 mmol) in methanol (2 mL). To this, 1N of NaOH solution (2 ml) was added. After 12 hours, the reaction was brought to pH = 6 with 1 N of HCl solution and extracted with ethyl acetate. The organics were dried MgSO4 and evaporated. The residue was purified via silica gel chromatography (50% ethyl acetate in hexanes) then reverse phase HPLC @ 140 ml / min for 30 minutes on a Symmetric column 50 x 250 mm, mm, C18) to give 7.1 mg of Example 57 as a white solid (12.7%). MS = 467 (M + H +).

Reaction Scheme 8 phenol ADDP BitjP tolueno F, C NaOH "9 MeOH F OH N-N M H_3CC r CμH_3 yy N ° -N? 4? H3yC CH3? Preparation 31 4- (Trifluoromethyl) benzhydrazide (5 g, 24.5 mmol) was placed in an eguided round bottom flask with a short path reflux condenser. To this was added trimethyl chloroformate (4 ml, 36.7 mmol) followed by p-toluene sulphonic acid (46.6 mmg, 0.24 mmol). It was heated to 100 ° C and the methanol was distilled. After 2 hours, no methanol was collected, the system pressure decreased to 300 microns to remove the trimethyl orthoformate. The residual solid was cooled and dissolved in ethyl acetate. It was washed with saturated bicarbonate solution and the organics were combined, dried over MgSO4 and evaporated. The crude product (5.2 g, 99%) was used without further purification. MS = 215 (M + H +).

Preparation 32 The preparation 31 (500 mg, 2.3 mmol) was dissolved in THF and cooled to -78 ° C. To this, t-BuLi (1.5 ml, 1.7 M sol.) Was added and stirred for 30 minutes. After this time, acetaldehyde (0.157 ml, 2.8 mmol) was added and the reaction allowed to slowly warm to room temperature for 6 hours. After this time, the reaction was quenched with a saturated ammonium chloride solution and then extracted with ethyl acetate. The combined organics were dried over MgSO and evaporated. The residue was purified via silica gel chromatography (20% ethyl acetate in hexanes) to give 24 mg of preparation 32 as a white solid (3.9%).

Preparation 33 Preparation 32 (24 mg, 0.09 mmol) was dissolved in toluene (2 ml) and 2- (4-hydroxy-2-methyl-phenoxy) -2-methyl-propanoic acid methyl ester (26.5 mg, 0-6 mg) was added. 11 mmol). Nitrogen was bubbled in this mixture for 15 minutes. After this time, ADDP (3.51 mg, 0.135 mmol) was added followed by Bu3P (0.034 ml, 0.135 mmol) and the reaction was stirred for 18 hours at room temperature. After this time, the reaction was diluted in 20 ml of ethyl acetate and washed with brine. The organics were dried over MgSO4 and evaporated. The residue was purified via chromatography on silica gel (20% ethyl acetate in hexanes) to give 24.4 mg of preparation 33 as a white solid (54.9%). MS = 479 (M + H +). racemic Preparation 33 (59 mg, 0.12 mmol) in methanol (2 ml) was dissolved. To this, 1N of a NaOH solution (2 ml) was added. After 12 hours, the reaction was brought to pH = 6 with 1N HCl solution and extracted with ethyl acetate. The organics were dried over MgSO4 and evaporated. The residue was purified via silica gel chromatography (50% ethyl acetate in hexanes) then reversed phase HPLC (40-90% gradient @ 140 ml / min for 30 minutes on a Symmetric column 50 x 250 mm, mm, C18) to give 8.6 mg of Example 58 as a white solid (9.5%). MS = 451 (M + H +).

Example 59 Example 59 can be made by one of ordinary skill in the art using the same procedure as in Example 57 using 2- (4-hydroxymethyl-phenoxy) -2-methyl-propionic acid ethyl ester (162 mg, 0.67 mmol) as the nucleophile and 2-bromomethyl-5- (4-trifluoromethyl-phenyl) - [1, 3, 4] thiadiazole (200 mg, 0.62 mmol) as the electrophile (as described in Preparation 30) and then perform the saponification as described in Example 57. After purification via chromatography on silica gel (20% ethyl acetate in hexanes), 60.2 mg (21.5%) of Example 59 is obtained as a thick oil. MS = 451 (M + H " Example 60 Example 60 can be prepared by one skilled in the art using the same procedure as in Example 57 using 2-Methyl-2- (4-methylaminomethyl-phenoxy) -propionic acid ethyl ester (171 mg, 0.67 mmol) as the nucleophile and 2-bromomethyl-5- (4-trifluoromethyl-phenyl) - [1, 3, 4] thiadiazole (200 mg, 0.62 mmol) as the electrophile (as described in preparation 30) and then the saponification was performed as described in Example 57. After purification via chromatography on silica gel (10% methanol in dichloromethane), 75.3 mg (26.3%) of Example 60 is obtained as a thick oil. MS = 464 (M + H ").

Example 61 Example 61 can be prepared by one of ordinary skill in the art, using the same procedure as in Example 57 using 2- (4-Etylaminomethyl-phenoxy) -2-methyl-propionic acid ethyl ester (180.6 mg, 0.67 mmol) as the nucleophile and 2-bromomethyl-5- (4-trifluoromethyl-phenyl) - [1, 3, 4] thiadiazole (200 mg, 0.62 mmol) as the electrophile (as described in preparation 30) and then the Saponification as described in Example 57. After purification via chromatography on silica gel (10% methanol in dichloromethane), 24.3 mg (8.3%) of Example 61 is obtained as a thick oil. EN = 478 (M-H ").

Preparation 34 The preparation 31 (500 mg, 2.3 mmol) was dissolved in THF and cooled to -78 ° C. To this was added t-BuLi (1.5 ml of sol.) And stirred for 30 minutes. After this time, propionaldehyde (0.202 ml, 2.8 mmol) was added and the reaction was slowly allowed to warm to room temperature for 6 hours. After this time, the reaction was quenched with a saturated ammonium chloride solution and then extracted with ethyl acetate. The combined organics were dried over MgSO4 and evaporated. The residue was purified via chromatography on silica gel (20% ethyl acetate in hexanes) to give 99.8 mg of preparation 34 as a white solid (15.7% The preparation 34 (99 mg, 0.36 mmol) was dissolved in toluene (5 ml) and 2- (4-hydroxy-2-methyl-phenoxy) -2-methyl-propionic acid ethyl ester (105 mg, 0.43 mmol) was added. ). Nitrogen was bubbled in this mixture for 15 minutes. After this time, ADDP (139 mg, 0.54 mmol) was added followed by Bu3P (111.5 mmol, 0.54 mmol) and the reaction was stirred for 18 hours at room temperature. After this time, the reaction was diluted with 20 ml of ethyl acetate and washed with brine. The organics were dried over MgSO4 and evaporated. The residue was purified via chromatography on silica gel (20% ethyl acetate in hexanes) to give 63.0 mg of preparation 35 as a white solid (34.8%). MS = 493 (M + H +).

Example 62 racemic Preparation 35 was dissolved (63 mg, 0.13 mmol) in methane (2 ml). To this was added a 1N NaOH solution (2 ml). After 12 hours the reaction was brought to pH = 6 with a 1N HCl solution and extracted with ethyl acetate. The organics were dried over MgSO4 and evaporated. The residue was purified via silica gel chromatography (50% ethyl acetate in hexanes) then reverse phase HPLC (40-90% gradient @ 140 min / for 30 minutes on a C18 symmetry column 50 x 250 mm, mm ) to give 9.7 mg of Example 62 as a white solid (16.3%). MS = 465 (M + H +).

Reaction Scheme 9 NaOH EtOHfl- Preparation 36 Preparation 36 p-Trifluoromethyl bezoyl chloride (11.3 ml, 76 mmol) was added at 0 ° C to a solution of acylhydrazine (compound 1 above) (13.7 g, 76 mmol) in CH2C12 (200 ml) and pyridine (20 ml) for 15 minutes. minutes and the reaction was stirred for 30 minutes. Then, it was poured into 5 N HCl (200 ml). The solution was extracted with Et20 (250 ml) and EtOAc (250 ml). The combined organic extracts were washed with H20 (200 ml) followed by brine (200 ml), dried over Na2SO4, filtered and concentrated. The crude semi-solid was triturated with 10% H20 / hexanes, and the desired Preparation 36 (23.4 g, 88%) was precipitated as a white solid. aH NMR (CDC13) d 10.64 (s, 1 H), 10.07 (s, 1 H), 8.09 (m, 2 H), 7.93 (m, 2 H), 7.40 (m, 5 H), 4.64 (s, 2 H), 4.11 (s, 2 H).

Preparation 37 A solution of Preparation 36 (12.0 g, 34.1 mmol) and Lawesson's reagent (16.5 g, 40.9 mmol) in toluene (200 mL) was heated at reflux for 4 hours, then cooled to room temperature and poured into H20 (400 ml). The mixture was extracted with Et20 (200 ml) and EtOAc (400 ml). The organic extracts were combined with brine (250 ml), dried over Na 2 SO 4, filtered and concentrated. Purification of the crude product by LCMS (0% to 10% 15% to 20% EtOAc / hexanes gave preparation 37 (11.2 g, 93%) as a clear oil, 2 H NMR (CDC13) d 8.10 (d, J = 8.4 Hz, 2 H), 7.75 (d, J = 8.4 Hz, 2 H), 7.37 (m, 5 H), 4.99 (s, 2 H), 4.70 (s, 2 H).

Preparation 3¡ A solution of BBr3 (42 mL, 1 M of CH2C12, 42 mmol) was added over 15 minutes to a solution at 0 ° C of Preparation 37 (9.8 g, 27.9 mmol) in CH2C12 (120 mL). After an additional 15 minutes, the contents were poured into saturated NaHCO3 (500 ml). The mixture was extracted with Et20 (250 mL) and EtOAc (300 mL). The combined organic extracts were washed with brine (250 ml), dried over Na 2 SO, filtered and concentrated to give a white solid. The crude product was triturated with 10% Et20 / hexanes, the desired Preparation 38 (7.0 g,> 95%) was precipitated as a white solid. XE NMR (CDC13) d 8.09 (d, J = 8.4 Hx, 2 H), 7.60 (d, J = 8.4 Hz, 2 H), 5.16 (s, 2 H), 2.40-2.60 (br s, 1 H) .

Preparation 39 Preparation 39 Nitrogen gas was bubbled into a solution of Preparation 38 (0.125 g, 0.28 mmol) and phenol compound (0.119 g, 0.50 mmol) in toluene (5 mL) for 10 minutes. The solution was cooled to 0 ° C and tri-n-butyl phosphine was added (0.180 mL, 0.72 mmol) followed by (1, 1 ') -azodicarbonyl-dipiperidine (ADDP) (0.182 g, 0.72 mmol). After 5 minutes, the reaction was allowed to warm to room temperature and was stirred for 16 hours. Then, the reaction mixture was poured into saturated NaHC 3 (25 ml). The mixture was extracted with Et20 (25 mL) and EtOAc (25 mL). The combined organic extracts were washed with brine (25 ml), dried over Na 2 SO 4, filtered and concentrated. Purification of the crude product by LCMS (0% to 5% to 8% to 12% EtOAc / hexanes) provided preparation 39 (0.138 g, x%) as a white foam. ^ NMR (CDC13) d 8.11 (d, J = 8.4 Hz, 2 H), 7.77 (d, J = 8.4 Hz, 1 H), 6.72 (s, 1 H), 6.65 (m, 1 H), 6.56 (d, J = 3.2 Hz, 1 H) , 5.48 (s, 2 H), 4.27 (g, J = 7.2 Hz, 2 H), 2.19 (s, 3 H), 1.55 (s, 6 H), 1.32 (t, J = 7.2 Hz, 3 H) .

Example 63 A solution of Preparation 39 (0.138 g, 0.29 mmol) in EtOH (5 mL) and 2 N NaOH (1 mL) was heated at 40 ° C for 1 hour. The mixture was poured into 1N HCl (20 ml) and extracted with Et20 (20 ml) and EtOAc (2 x 20 ml). The combined organic extracts were washed with brine (25 ml), dried over Na 2 SO, filtered and concentrated. Purification of the crude product by column chromatography (35% EtOAc / 2% HOAc in hexanes) gave Example 59 (0.102 g, 77%) as a white solid. LRMS 453.1 (M ++ H).

Preparation 40 Preparation 40 The reaction was run in accordance with preparation 39. The reaction of preparation 38 (0.125 g, 0.48 mmol) and phenol compound 3 (above) (0.112 g, 0.50 mmol) yielded Preparation 40 (0.124 g, 55% ) like a white foam. XH NMR (CDC13) d 8.08 (d, J = 8.2 Hz, 2 H), 7.74 (d, J = 8.2 Hz, 2 H), 6.89 (m, 2 H), 6.75 (m, 2 H), 5.47 ( s, 2 H), 4.23 (g, J = 7.2 Hz, 2 H), 1.52 (s, 6 H), 1.27 (t, J = 7.2 Hz, 3 H).

The reaction was run in accordance with example 63. Hydrolysis of preparation 40 (0.124 g, 0.27 mmol) provided Example 60 (0.082 g, 69%) as a white foam. LRMS 439.1 (M ++ H).

Reaction Scheme 10 Preparation 41 HCl (g) was bubbled through a 0 ° C solution of p-trifluoromethylbenzonitrile (5.50 g, 3.21 mmol) in EtOH (9.4 mL, 161 mmol) and toluene (50 mL) for 30 minutes. The cold bath was removed and the solution was kept at room temperature for 16 hours. The concentration of the mixture provided the intermediate imidate salt, which was added to o-xylenes (165 ml). Compound 1 acylhydrazine (method for preparation 36) (5.78 g, 32.1 mmol) was added as a solution in o-xylenes (10 ml). Et3N (4.47 ml, 32.1 mmol) was added dropwise over 30 minutes, the solution was stirred for 2 hours, heated to reflux for 2.5 hours, cooled to room temperature and maintained for 16 hours. The solution was poured into NaHCO3. saturated (250 ml) and extracted with EtOAc (2 x 200 ml). The combined organic extracts were washed with brine (250 ml), dried over Na 2 SO 4, filtered and concentrated. Purification of the crude product by chromatography (0% to 15% to 20% to 25% to 35% EOAc / hexanes) provided preparation 41 (0.53 g, 5%) as a white solid. XH NMR (CDC13) d 7.79 (d, J = 8.0 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.30-7.40 (m, 5 H), 4.83 (s, 2 H), 4.70 (s, 2 H).

Preparation 42 A solution of Preparation 41 (0.53 g, 1.59 mmol) and 10% of Pd-C (0.10 g) in MeOH (30 ml) and THF (10 ml) at 40 psi H2 (g) was exposed at 40 ° C. 24 hours. Casting the mixture with N2 (g) followed by filtration through celite provided a clear solution, which was concentrated to provide preparation 42 (0.24% g, 62%) as a white solid. aH NMR (CDC13) d 8.18 (d, J = 8.0 Hz, 2 H), 7.70 (d, J = 8.0 Hz, 2 H), 5.00 (s, 2 H).

Preparation 43 Preparation 43 was produced from preparation 42 (0.050 g, 0.20 mmol) and phenol 2 (0.051 g, 0.21 mmol) in accordance with preparation 39, provided preparation 43 (0.072 g, 76%) as a clear solid. XH NMR (CDC13) d 8.20 (d, J = 8.4 Hz, 2 H), 7.78 (d, J = 8.4 Hz, 2 H), 6.85 (s, 1 H), 6.68 (m, 2 H), 5.27 ( s, 2 H), 4.25 (g, J = 7.2 Hz, 2 H), 2.22 (s, 3 H), 1.54 (s, 6 H), 1.28 (t, J = 7.2 Hz, 3 H).

Example 65 Example 65 was produced from preparation 43 in accordance with the procedure of working up Example 63, providing Example 65 (0.070 g,> 95%) as a white solid. LRMS 455.1 (M ++ H). Example 66 was prepared by a method according to Reaction Escape 4 and Example 67 was prepared by a method according to Reaction Escape 2.

Examples 68-73 were prepared by the method described in Reaction Run 2 and the Examples 74-76 by the method described in Reaction Escape 6a and / or 6b.

Reaction Reactor 11 General Procedure for Reaction Escape 11 Compound A hydrazide was suspended (100 mmol) in trimethyltortoformate (150 mmol) and p-toluenesulfonic acid monohydrate (1.5 mmol) in an eguided round bottom flask with standard distillation apparatus. It was heated to 90 ° C until the formation of a precipitate was observed, then at 120 ° C. The methanol was distilled. The reaction was monitored by HPLC and CCD (Hex / AcOEt 1: 1). The yellow oil was dissolved in AcOEt and washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude was purified by Si02 chromatography (Hex / AcOEt 9: 1 to 7: 3) to obtain a compound of formula B from Reaction Run 11. The nBuLi (1.6 M in hexanes) was added dropwise (10 mmol) under an atmosphere. N2 a cooled solution (-78 ° C) of compound B of oxadiazole (10 mmol) in THF (33 ml). After 40 minutes, MgBr2.Et20 (10 mmol) was added, the cold bath was heated to -45 ° C and the resulting suspension was stirred at -45 ° C for an additional 1.5 hours. The aldehyde (9 mmol) in THF (11 mL) was added, the reaction temperature increased to -20 ° C and stirred for an additional 2.5 hours at this temperature. The reaction was monitored by HPLC and CCD (Hex / AcOEt 8: 2). The crude material was quenched with a solution of NH4C1 and AcOEt was added. The aqueous layer was extracted twice with AcOEt. The organic layer was separated, washed with water, brine, dried with MgSO 4, filtered and concentrated in vacuo. The crude material was purified by Si02 chromatography (Hex / AcOEt 95: 5 to 85:15) to obtain a compound of formula C of Reaction Scheme 11. Reaction Mi sounobii: A solution of oxadiazole C (1.0 mmol) was added and phenol (compound D) (2 mmol) in toluene (20 ml), degassed several times, BU3P (2.0 mmol) and ADDP (2.0 mmol) at 0 ° C. The mixture was stirred at room temperature overnight. The reaction was followed by CCD. The solvent was removed under vacuum, the residue was triturated with diethyl ether and the precipitate obtained was filtered. The filtrate was washed with 2N NaOH solution, water, brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by Si02 chromatography (Hexane / AcOEt 95: 5 to 85:15) to obtain compound E from Reaction Estrus 11. Hydrolysis. A 2N solution of KOH (1.5 ml) was added to a solution of oxadiazole C (1.0 mmol) in an EtOH / THF (1: 1) mixture (40 ml) and the mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hex (AcOEt 1: 1) and HPLC, AcOEt and water were added and the pH was adjusted to 6 by the addition of a 6N HCl solution.The two phases were separated, the aqueous layer was extracted twice With AcOEt, the organic layer was washed with water, brine, dried over MgSO, filtered and concentrated in vacuo The crude was purified by ISCO (Hex-TFA 0.05% / acetone 9: 1 to 85:15) to obtain the Acid compound F of Reaction Scheme 11.

Preparation of the H2 compound H1 H2 p-Benzyloxyphenol (300 mmol) was dissolved in CH3CN (750 mL), Cs2CO3 (360 mmol) was added in portions, followed by the bromine derivative. The resulting mixture was refluxed overnight. It was cooled, filtered through celite plug, and concentrated in vacuo. Purification by Si02 chromatography (Hex / AcOEt 8: 2) to obtain compound Hl in 94% yield. Pd-C (10% by weight) was added to a solution of Hl (282 mmol) in EtOH (940 mL). The mixture was stirred under an H2 atmosphere overnight. It was filtered through a plug of Celite, the solvent was removed and purified by Biotage (Hex / AcOEt 7: 3) to obtain the compound H2 in 64% yield.

Preparation of compound H4 H3 H4 The starting aldehyde (45 mmol) was dissolved in THF: EtOH (95: 5 ml), cooled to 0 ° C, and NaBH4 was added in portions until the starting material was not detected by CCD. It was quenched at 0 ° C with 1N HCl and AcOEt was added. The pH was adjusted to 6. The two phases were separated, extracted twice with AcEOt. They were washed with water, brine, dried over MgSO4, filtered and concentrated under vacuum. They were purified by Si02 chromatography to obtain alcohol H3 in 95% yield. Pd-C (10% by weight) was added to a solution of H3 (42.7 mmol) in EtOH (430 mL). The mixture was stirred under H2 atmosphere at room temperature for 6 hours. It was filtered through a plug of Celite, the solvent was removed and purified by Si02 chromatography (Hex / AcOEt 7: 3) to obtain compound H4 in 76% yield.

Preparation of compound H7 NaBHt TH F- EtOH H7 The thiol (100 mmol) was dissolved in MeOH (170 mL), cooled to 0 ° C and I 2 (0.5 mmol) and NaHCO 3 (2.8 mmol) were added in portions. The resulting mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was purified by Si02 chromatography to obtain compound H5 in 83% yield. The disulfide H5 (70 mmol) was dissolved in CH2C12 (110 ml), Cs2CO3 (3.5 mmol) was added, stirred for 10 minutes and after adding bromine derivative (210 mmol). It was refluxed overnight. The reaction was followed by CCD (Hexane / AcOEt 7: 3). It was cooled to room temperature, filtered through a plug of Celite, concentrated in vacuo and the residue was purified by Si02 chromatography (Hexane to Hexane / AcOEt 4: 1) to obtain compound H6 in 51% yield.

H6 (6 mmol) was dissolved in THF: EtOH (16: 5 ml), NaBH4 was added in portions at 0 ° C until the starting material was not detected. It was quenched with a 1N HCl solution at 0 ° C and AcOEt was added. The pH was adjusted to 4. The two phases were separated, extracted twice with AcOEt. They were washed with water, brine, dried over MgSO, filtered and concentrated. They were purified by Si02 chromatography (Hex to Hex / AcOEt 95: 5) to obtain H7 in 97% yield.

Preparation 52 Commercially available Preparation 52 The hydrazide (5 g) in trimethylortoformate (4.0 ml) and p-toluenesulfonic acid monohydrate (47 mg) was suspended in an eguipated round bottom flask with a standard distillation apparatus. It was heated to 90 ° C until the formation of a precipitate was observed, then at 120 ° C. The methanol was distilled to obtain a yellow oil. The yellow oil was dissolved in AcOEt and washed with water, brine, dried with MgSO 4 and concentrated in vacuo. The crude was purified by Si02 chromatography (Hex / AcOEt 9: 1 to 7: 3) to obtain preparation 52 as a white solid (95%).

Preparation 53 NBuLi (1.51 ml, 1.7 M in pentane) was added dropwise, under N2 atmosphere to a cooled solution (-78 ° C) of preparation 52 (500 mg) in THF (20 ml). After 40 min, MgBr2.Et20 (10 mmol) was added, the cold bath was warmed to -45 ° C and the resulting suspension was stirred at -45 ° C for an additional 1.5 hours. Aldehyde (0.175 ml) in THF (10 ml) was added, the reaction temperature was increased to -20 ° C and stirred for 2.5 hours at this temperature. The crude material was quenched with an NHC1 solution and AcOEt was added. The aqueous layer was extracted twice with AcOEt. The organic layer was separated, washed with water, brine, dried with MgSO 4, filtered and concentrated in vacuo. The crude material was purified by Si02 chromatography (Hex / AcOEt 95: 5 to 85:15) to obtain preparation 53 (22%).

Preparation 54 Mitsounobu reaction: To a solution of preparation 53 (24 mg) and phenol (26.5 mg) in toluene (2 ml) was added, degassed several times, Bu3P (0.035 ml) and ADDP (35 mg) at 0 ° C. . The mixture was stirred at room temperature overnight. The solvent was removed under vacuum, the residue was triturated with diethyl ether and the precipitate obtained was filtered. The filtrate was washed with a 2N NaOH solution, water, brine, dried over MgSO4, and concentrated in vacuo. The crude was purified by Si02 chromatography (Hexane / AcOEt 95: 5 to 85:15) to obtain preparation 54 (55%).

Example 77 A 2N solution of KOH (1.5 ml) was added to a solution of preparation 54 (24 mg) in an EtOAH / THF (1: 1) mixture (4 ml) and the mixture was stirred at room temperature overnight. AcOEt and water were added and adjusted to pH 6 by the addition of a 1N HCl solution. The two layers were separated, the aqueous layer was extracted twice with AcOEt, the organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by Si02 / Hexane / AcOEt chromatography 95: 5 to 85:15) to obtain Example 77 (90%).

Examples 78, 81, 84, 85 and 88-90 were prepared using a similar procedure to prepare Example 77.

Reaction Run 12 two stages 73-59% THF-EtOH KOH General Procedure for Reaction Scheme 12 The commercial ester starting material (10 mmol) was added to a suspension of phenol A (10 mmol) and K2C03 in CH3CN (10 mL). The mixture was refluxed overnight. The reaction was followed by CCD (Hexane / AcOEt 9: 1). It was cooled, filtered through a plug of Celite and the solvent was removed under vacuum. The crude material was purified by Si02 chromatography (Hexane to Hex / AcOEt 9: 1) to obtain a compound of formula B from reaction stent 12. Methyl ester B was dissolved (10 mmol) in EtOH (12.5 ml). Then, hydrazine monohydrate (40 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was followed by CCD (Hexane / AcOEt 9: 1). The solvent was removed under vacuum. The residue was dissolved in AcOEt and washed with water. The organic layer was dried over MgSO4 and concentrated. The material was used without further purification. Hydrazide C was dissolved (10 mmol) in THF (25 ml). Et3N was added at 0 ° C and the resulting solution was stirred for 5 minutes, then the acid chloride (11 mmol) was added at -30 ° C dropwise. The mixture was stirred at this temperature for 45 minutes and then at room temperature overnight. The reaction was monitored by HPLC and CCD (Hex / AcOEt 1: 1). The crude material was quenched with water and AcOEt was added. The organic layer was separated, dried with MgSO 4, and concentrated in vacuo. The crude material was purified by Si02 chromatography (Hex (AcOEt 9: 1 to 7: 3) to obtain a compound of formula D of reaction enzyme 12. Compound D was dissolved (10 mmol) in toluene (100 ml), The Lawesson reagent (20.0 mmol) was added.The mixture was refluxed for 4 hours.The reaction was followed by CCD (Hexane / AcOEt 4: 1) .The solvent was removed under vacuum.The residue was purified by Si02 chromatography ( Hex to Hex / AcOEt 85:15) to obtain a compound of formula E in Reaction Run 12. 2N of a KOH solution (1.5 ml) was added to a solution of thiadiazole E (1.0 mmol) in an EtOH / THF mixture (1: 1) (40 ml) and the mixture was stirred at room temperature overnight The reaction was followed by CCD / Hex / AcOEt 1: 1) and HPLC. AcOEt and water were added and the pH adjusted to 6 by the addition of a 6N HCl solution. The two phases were separated, the aqueous layer was extracted twice with AcOEt, the organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by ISCO (hex-TFA 0.05% / acetone 9: 1 to 85:15) to obtain the acid F from Reaction Esquema 12.

Experimental Procedure for Example 91 Preparation 55 The commercial starting material (167 mg) was added to a suspension of phenol A (224 mg) and K2C03 in CH3CN (10 ml).

The mixture was refluxed overnight. It was cooled, filtered through a plug of Celite and the solvent was removed under vacuum. The crude material was purified by Si02 chromatography (Hexane to Hex / AcOEt 9: 1) to obtain preparation 55 in a yield of 95%.

Preparation 56 The preparation 55 (300 mg) was dissolved in EtOH (12.5 ml). Then, hydrazine monohydrate (190 mg) was added. The mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was dissolved in AcOEt and washed with water. The organic layer was dried over MgSO4 and concentrated. The crude material was used without further purification.

Preparation 57 Preparation 58 Preparation 57 The preparation 56 (300 mg) was dissolved in TFH (25 ml). Et3N was added at 0 ° C and the resulting solution was stirred for 5 minutes, then commercially available acid chloride (160 mg) was added at -30 ° C dropwise. The mixture was stirred at this temperature for 45 minutes and then at room temperature overnight. The crude material was quenched with water and AcOEt was added. The organic layer was separated, dried with MgSO 4 and concentrated in vacuo. The crude material was purified by Si02 chromatography (Hex / AcOEt 9: 1 to 7.3) to obtain preparation 57 which provided 60% for the two steps.

Preparation 58 Preparation 57 was prepared (127 mg) in toluene (5 ml) and Lawesson reagent (134 mg) was added. The mixture was refluxed for 4 hours. The solvent was removed under vacuum and the residue was purified by Si02 chromatography (Hex to Hex / AcOEt 85:15) to obtain preparation 58 in 60% yield.

Example 91 A 2N solution of KOH (1.5 mL) was added to a solution of Preparation 58 (24 mg) in EtOH / THF (1: 1) mixture (4 mL) and the mixture was stirred at room temperature overnight. AcOEt and water were added and the pH adjusted to 6 by the addition of a 1N HCl solution. The two phases were separated, the aqueous layer was extracted twice with AcOEt, the organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by Si02 chromatography to obtain Example 91 (90%). Example 94 was prepared using a similar procedure to prepare Example 91.

Reaction Scan 13 Essentially available Experimental Procedure for the Reaction Escape 13 Hydrazide (100 ml), trimethylortoformate (150 mmol) and toluene sulfonic acid monohydrate (1.5 mmol) were added to a round-bottomed eguipated flask with a standard distillation apparatus. It was heated to 90 ° C until a precipitate was obtained, then it was added at 120 ° C. The methanol was distilled to obtain an oil. The reaction was monitored by HPLC and THC (Hex / AcOEt 1: 1). The oil was dissolved in AcOEt and washed with water, brine, dried with MgSO 4 and concentrated in vacuo. The crude was purified by Si02 chromatography (Hex / AcOEt 9: 1 to 7: 3) to obtain an oxazole compound of formula A from Reaction Run 13. The nBuLi (1.6 M in hexane) was added dropwise (10 mmol) under an atmosphere of N2 to a cooled solution (-78 ° C) of the oxazole (10 mml) in THF (33 ml). After 40 minutes, MgBr2.Et20 (10 mmol) was added, the cold bath was heated to -45 ° C and the resulting suspension at -45 ° C for an additional 1.5 hours. The aldehyde (9 mmol) in THF (11 ml) was added, the reaction temperature was raised to -20 ° C and stirred for an additional 2.5 hours at this temperature. The reaction was monitored by HPLC and CCD (Hex / AcOEt 8: 2). The crude material was quenched with a solution of NH4C1 and AcOEt was added. The aqueous layer was extracted twice with AcOEt. The organic layer was separated, washed with water, brine, dried with MgSO 4, filtered and concentrated in vacuo. The crude material was purified by Si02 chromatography (Hex / AcOEt 95: 5 to 85:15) to obtain a compound of formula B from Reaction Ester 13. To a solution of oxadiazole B (1.0 mmol) and the bromine derivative C (1.1 mmol) in CH3CN (2.5 ml), Cs2CO3 (1.3 mmol) was added, and the resulting mixture was stirred at room temperature. The reaction was followed by CCD (Hexane / AcOEt 4: 1). It was filtered through a celite plug. The solvent was removed under vacuum. The crude was purified by Si02 chromatography (Hexane / AcOEt 95: 5 to 85:15) to obtain a compound D from Reaction Esquema 13. A 2N solution of KOH (1.5 ml) was added to a solution of oxadiazole D (1.0 mmol) in EtOH / THF mixture (1: 1) (40 ml) and the mixture was stirred at room temperature overnight. The reaction was monitored by CCD (Hex / AcOEt 1: 1) and CLAR. AcEOt and water were added and the pH adjusted to 6 by the addition of a 6N HCl solution. The two phases were separated, the aqueous layer was extracted twice with AcOEt, the organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo The crude was purified by ISCO (Hex-TFA 0.05% / acetone 9: 1 to 85:15) to obtain the E acid from Reaction Esquema 13.

Preparation of the Bromine Derivative Preparation of compound H9 H8 H9 Phenol (154 mmol) was dissolved in EtOH (513 mL), K2CO3 (600 mmol) and MgSO4 were added and then the bromine derivative (231 mmol). The resulting mixture was refluxed overnight. It was cooled, filtered through a plug of Celite, concentrated in vacuo. Purification by Si02 chromatography (Hex / AcOEt 8: 2) to obtain compound H8 in 53% yield. H8 (13 mmol) was dissolved in CH2C12 (130 ml) at 0 ° C, CBr was added and then PPh3 in portions. The mixture was stirred at 0 ° C for 2 hours. The reaction was followed by CCD (Hex (AcOEt 4: 1) The solvent was removed The residue was purified by Si02 chromatography (Hexane / AcOEt 9: 1) to obtain H9 in 95% yield.

Experimental Procedure for Example 97 Preparation 59 Preparation 59 The hydrazide (5 g) in trimethylortoformate (4.0 ml) and p-toluenesulfonic acid monohydrate (47 mg) was suspended in an eguipated round bottom flask with a standard distillation apparatus. It was heated to 90 ° C until the formation of a precipitate was observed, then at 120 ° C. The method was distilled to obtain a yellow oil. The yellow oil was dissolved in AcOEt and washed with water, brine, dried with MgSO 4 and concentrated in vacuo. The crude was purified by Si02 chromatography (Hex / AcOEt 9: 1 to 7: 3) to obtain preparation 59 as a white solid (95%).

Preparation 60 NBuLi (1.51 mol, 1.7 M in pentane) was added dropwise, under N2 atmosphere, to a cooled solution (-78 ° C) of oxadiazole (500 mg) in THF (20 ml). After 40 minutes, MgBr2.Et20 (10 mmol) was added, the cold bath was heated to -45 ° C and the resulting suspension was stirred at -45 ° C for an additional 1.5 hours. Butyric aldehyde (0.157 ml) in THF was added (10 ml), the reaction temperature was raised to -20 ° C and stirred for an additional 2.5 hours at this temperature. The crude material was quenched with an NH4C1 solution and AcOEt was added. The aqueous layer was extracted twice with AcOEt. The organic layer was separated, washed with water, brine, dried with MgSO 4, filtered and concentrated in vacuo. The crude material was purified by Si02 chromatography (Hex / AcOEt 95: 5 to 85:15) to obtain preparation 60 (25%).

Preparation 61 Preparation 60 Preparation 61 To a solution of preparation 60 (80 mg) and the bromine derivative (217 mg) in CH3CN (5 ml), Cs2CO3 (213 mg) was added, and the resulting mixture was stirred at room temperature during the night. It was filtered through a plug of Celite. The solvent was removed under vacuum. The crude was purified by Si02 chromatography (Hexane / AcOEt 95: 5 to 85:15) to obtain preparation 61 in 90% yield.

Example 97 A 2N solution of KOH (1.5 ml) was added to a solution of preparation 61 (24 mg) in an EtOH / THF mixture. (1: 1) (4 ml) and the mixture was stirred at room temperature overnight. AcOEt and water were added and the pH adjusted to 6 by the addition of a 1N HCl solution. The two phases were separated, the aqueous layer was extracted twice with AcOEt, the organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by Si02 chromatography to obtain Example 97 (85%). Example 100 was prepared using a similar procedure to prepare example 97 Reaction Escape 14 toluene, reflow fara X = S) Experimental Procedure for Reaction Escape 14 For W = O: The commercially available hydrazide (1 g) was made paste in DCM and then the acid chloride was added (1.1 g) followed by triethylamine (2 g). It was stirred under nitrogen at room temperature for 12 hours. Then the reaction was quenched with 1N HCl and extracted with DCM. The organic layer was dried over MgSO4 and evaporated. The recrystallized solid was recrystallized from EtOAc.

This material was dissolved in pyridine and tosylate chloride (1.5 g.) Was added and the mixture was refluxed for 18 hours. The reaction cooled, diluted with ethyl acetate, and washed with 1N HCl, saturated bicarbonate and water. The organics were dried over MgSO4 and evaporated. The residue was purified via column chromatography (20% ethyl acetate in hexanes) to obtain the compound of formula A in reaction styrene 14. This material was dissolved in DCM and cooled to 0 ° C. BBr (3 eg) was added for 10 minutes. The reaction was allowed to warm to room temperature for 2 hours. The reaction was diluted with ethyl acetate and washed with saturated bicarbonate and 1N HCl. The organic was dried over MgSO4 and evaporated. The solid was dissolved in DCM and PBr3 (1.2 eg) was added. This was stirred at room temperature for 2 hours, washed with water, the organics were dried over MgSO 4 and evaporated to give the compound of formula B or reaction line 14 without purification.

For W = S; Hydrazide (1 g.) Was made paste in DCM and acid chloride (1.1 g.) Was added followed by triethylamine (2 eg). This was stirred at room temperature for 12 hours. The reaction was quenched with 1N HCl and extracted with DCM. The organic layer was dried over MgSO4 and evaporated. The solid was recrystallized from EtOAc. This material was dissolved in pyridine, tosylate chloride (1.5 eg) was added, and the mixture was refluxed for 18 hours. The reaction was cooled, diluted with ethyl acetate and washed with 1N HCl, saturated bicarbonate and water. The organics were dried over MgSO4 and evaporated. The residue was purified via column chromatography (20% ethyl acetate in hexanes) to obtain the compound of formula A of reaction rod 14. The material was dissolved in DCM and cooled to 0 ° C. BBr3 (3 eg) was added for 10 minutes. Then, the reaction was allowed to warm to room temperature for 2 hours. The reaction was diluted with ethyl acetate and washed with saturated bicarbonate and 1N HCl. The organic was dried over MgSO4 and evaporated.

Synthesis of compound D: The title of the appropriate amine was dissolved (compound of formula C) in DMF and cooled to 0 ° C. NaH (1 eg) was added thereto and stirred for 30 minutes. Compound B was added (0.9 g) and the reaction allowed to warm slowly to room temperature. After the consumption of the starting material was finished, the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organics were dried over MgSO4 and evaporated. The residue was purified via column chromatography (20% ethyl acetate in hexanes), to give the compound of formula D of Reaction Spindle 14.

Synthesis of compound E: 1N NaOH solution (1.5 mL) was added to a solution of the compound of formula D (1.0 mmol) in a mixture of MeOH / THF (1: 1) (40 mL) and the mixture was stirred at room temperature. atmosphere during the night. The reaction was followed by CCD (Hex / AcOEt 1: 1) and HPLC. AcOEt and water were added and the pH was adjusted to 6 by the addition of a 1N HCl solution. The two phases were separated, the aqueous layer was extracted twice with AcOEt, the organic layer was washed with water, brine, dried over MgSO, filtered and concentrated in vacuo. This residue was then purified via column chromatography (30% ethyl acetate in hexanes) to give product E.

Experimental Procedure for Example 104 Preparation 62 4-Trifluoromethylbenzhydrazine (1 g) was made in DCM (25 ml) and benzyloxyacetyl chloride (0.837 ml) was added to this mixture, followed by triethylamine (1.37 ml). This was stirred under nitrogen at room temperature for 12 hours. Then, the reaction was quenched with 1N HCl and extracted with DCM. The organic layer was dried over MgSO4 and evaporated. The solid was recrystallized from EtOAc (93%). This material was dissolved in toluene and Lawsen reagent (3 g) was added and the mixture was refluxed for 18 hours. Then, the reaction was cooled and diluted with ethyl acetate and washed with 1 N HCl, sodium bicarbonate and water. The organics were dried over MgSO4 and evaporated. This residue was purified via column chromatography (20% ethyl acetate in hexanes) to give preparation 62 as a pale yellow solid (80%).

Preparation 63 v The preparation 62 (100 mg) was dissolved in DCM (5 ml) and cooled to 0 ° C. It was added to this BBr3 (0.788 ml) for 10 minutes. The reaction was allowed to warm to room temperature for 2 hours. The reaction was diluted with ethyl acetate and washed with saturated bicarbonate and 1N HCl. The organic was dried MgSO4 and evaporated to give preparation 63 as a whitish solid (98%).

Preparation 64 The title compound (429 mg) was dissolved in acetonitrile (20 ml) and cooled to 0 ° C. To this CSCO3 (1 g) was added, and preparation 63 (500 mg) and the reaction was allowed to slowly warm to room temperature. After finishing the consumption of the starting material, the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic was dried over MgSO and evaporated. The residue was purified via column chromatography (20% ethyl acetate in hexanes) to give preparation 64. (62%).

Example 104 A solution of 2N KOH (1.5 mL) was added to a solution of Preparation 64 (24 mg) in a mixture of EtOH / THF (1: 1) (4 mL) and the mixture was stirred at room temperature overnight. AcOEt and water were added and the pH was adjusted to pH 6 by the addition of a 1N HCl solution. The two phases were separated, the aqueous layer was extracted twice with AcOEt, the organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by Si02 chromatography (Hexane / AcOEt 95: 5 to 85:15) to give example 104 (80%). Examples 105-112 were prepared using a similar procedure to prepare Example 104.

Example 113 Lysine salt of Example 3C 7 mL of MeOH was added to a vial containing 203 mg of Example 3c and heated to about 60 ° C. Then, 0.5 mL of L-lysine (in water) was added to an eguivalence of 1 molar. It was cooled to room temperature. It was evaporated to dryness under nitrogen. 7 mL of isopropyl alcohol was added resulting in a solid suspension. The vial was heated to approximately 80 ° C. Water was added until soluble (2 mL total). The vial was allowed to cool to room temperature overnight and the solid was isolated by vacuum filtration. Thermal: Start 227.8 ° C.

EXAMPLE 114 Example 3C (2.00 g, 0.00455 m) was made paste in 20.0 mL of IPA and heated to 70 ° C. The hot opaque / turbid solution was filtered and rinsed with 1.5 mL of IPA, and the resulting filtrate was heated to 70 ° C. In a separate vessel, L-lysine (681 mg, 0.00466 mg, 1.0 eg, 97% Aldrich) was suspended in water (2.00 mL) and briefly heated to 50 ° C in a water bath to dissolve it to a clear solution. . The L-lysine solution was added dropwise to the free acid solution at 70 ° C for 35 minutes. The slurry was stirred for an additional 5 hours at 70 ° C, then removed from the hot and allowed to cool to room temperature for 1 hour. The resulting suspension was further cooled in an ice bath for one hour, filtered, rinsed with cold IPA and dried under vacuum / 40 ° C overnight to give the L-lysine salt of Example 3C as a white crystalline solid. (2.44 g, 91% by weight of yield). Thermal: Start 227.6 ° C.

Example 115 Example 114 (0.50 g, 0.00087 m) was suspended in MeOH (13 L) and water (3.0 mL) and heated to 60 ° C. The solution was concentrated under vacuum, which resulted in the removal of approximately 6.0 g by weight of the solvent. The solution was heated to 60 ° C and IPA (10 mL) was added by dripping for 10 minutes, maintaining the temperature at 60 ° C during the addition. The solution was concentrated again, which results in the removal of approximately 8.4 g of solvent. Then additional IPA (10 mL) was added per drop for 10 minutes at 60 ° C. The suspension was concentrated under vacuum, which resulted in the removal of approximately 4.9 g of solvent, and a final amount of IPA (5 mL) (hot) was added over 5 minutes. The suspension was heated briefly to 60 ° C, allowed to cool to room temperature, then cooled with ice water for 1 hour. It was filtered, rinsed with IPA, and dried overnight under vacuum at 40 ° C to obtain a white crystalline product (404 mg: CLAR: 97.4% area, 81% by weight, 86.6% CLAR% area corrected yield) . Thermal: Start 220.19 ° C.

Example 116 The HCl salt of Example 3C (2.00 g, 0.0043 m) was made paste (the free base form could probably be used) in water (15 mL), CH2C12 (15 mL) and MeOH (5 mL). 5N NaOH (1.80 mL, 2.1 eq.) Was added until pH = 11. The layers were separated and the aqueous layer was extracted with additional CH2C12 (15 mL). The organic layers were unloaded and combined. Fresh CH2C12 (15 mL) was added to the aqueous, and 1N HCl (15 mL) was added with vigorous stirring. The layers were separated, the aqueous layer was extracted with additional CH2C12 (15 mL) and the organic layers were combined. EtOAc (5 mL) and MeOH (5 mL) were added to the turbid organic layer to prevent premature crystallization of the HCl salt, then the organic layer was dried with Na 2 SO 4, filtered, rinsed and concentrated under vacuum to a weight of 11. mg of milky solution. The solution was seeded with starting material and stirred at room temperature as the product crystallizes. It was filtered and rinsed with CH2C12 then dried overnight under vacuum / room temperature to give the birefringent solid. (669 mg, 33% yield by weight, 38% corrected HPLC yield, HPLC: 98.1% area purity). Thermal: Start 162.44 ° C.

Separation of racemic mixtures The isomers of racemic mixtures of examples were separated by HPLC.

BIOLOGICAL TESTING Linkage and Cotransfection Studies The in vitro potency of compounds in the modulations of PPAROÍ receptors is determined by the procedures detailed below. The DNA dependent link (ABCD link) is carried out using SPA technology with PPAR receptors. PPARα agonists linked with tritium are used with radioligands to generate displacement curves and IC50 values with compounds of the invention. Transfection assays are carried out in CV-1 cells. The reporter plasmid contained an acylCoA (AOX) PPRE oxidase and a TK promoter upstream of the luciferase reporter cDNA. Appropriate PPARs are constitutively expressed using plasmids which contain the CMV promoter. For PPARa, interference by PPAR? endogenous in CV-1 cells is in an emission. To eliminate such interference, a GAL4 guimer system is used in which, the DNA binding domain of the transfected PPAR is replaced by GAL4 ague, and the GAL4 response element is used in place of the AOX PPRE. The co-transfection efficiency is determined in relation to the PPARa agonist reference molecules. The efficiencies are determined by computer setting in a concentration response curve, or in some cases, at a single high concentration of agonist (10 μM). These studies are carried out to evaluate the ability of the compounds of the invention to bind and / or activate various nuclear transcription factors, particularly huPPARa ("hu" indicates "human"). These studies provide in vitro data which refers to the efficacy and selectivity of the compounds of the invention. In addition, the binding and cotransfection data for compounds of the invention are compared with the corresponding data for marketed compounds that act on huPPARa. The cotransfection and binding efficiency values for compounds of the invention which are especially useful for modulating a PPAR receptor are, < 100 nM and > 50%, respectively.

Evaluation of Triglyceride Reduction and Elevation of HDL Cholesterol in HuapoAI Transgenic Mice The compounds of the present invention are studied to determine the effects of triglyceride and HDL levels in human apoAI mice. For each compound tested, they were acclimated in individual cages for two weeks with standard feed diet (Purina 5001) and water provided at will, male mice of seven to eight weeks of age, transgenic for human apoAI (C57BL / 6-tgn ( apoal) lrub, Jackson Laboratory, Bar Harbor, ME). After acclimation, mice and food were weighed and assessed to the test groups (n = 5) with randomization by body weight. Mice were dosed daily by forced oral feeding for 8 days using a 1-1 / 2 inch (2.54-1.27 centimeter) gauge needle feed needle (Popper &Sons). The vehicle for the controls, the test compounds and the positive control (fenofibrate 100 mg / kg) is 1% carboxymethylcellulose (w / v) with 0.25% tween 80 (w / v). All mice are dosed daily between 6 and 8 a.m with a dosage volume of 0.2 ml. Prior to termination, animals and diets are weighed and the change in body weight and feed is calculated. Three hours after the last dose, the mice are euthanized with C02 and the blood is removed (0.5 -1.0 ml) by cardiac puncture. After sacrifice, the liver, heart and epididymal fat pad are excised and weighed. The blood is allowed to coagulate and the serum is separated from the blood by centrifugation. Cholesterol and triglycerides are measured colorimetrically using commercially repeated reagents (e.g., as available from Sigma # 339-1000 and Roche # 450061 by triglycerides and cholesterol, respectively). These procedures are modified from published work (McGowan M. W. et al., Clin Chem 29: 538-542, 1983).; Allain C. C. et al., Clin Chem 20: 470-475,1974. The commercially available standards for triglycerides and total cholesterol, respectively, the commercial quality control plasma and samples, are measured in duplicate using 200 μl of the reagent. An additional aliquot of the sample is added to a well containing 200 μl of water, providing a blank for each specimen. The plates are incubated at room temperature in a plate shaker and the absorbance is read at 500 nm and 540 nm for triglycerides and total cholesterol, respectively. The values for the positive controls are always within the expected range, and the coefficient of variation for the samples is below 10%. All samples from the experiment are tested at the same time to minimize inter-assay variability. The serum lipoproteins are separated and the cholesterol quantified by fast protein lipoprotein chromatography (FPLC) coupled in an on-line detection system. The samples are applied to a size exclusion column of Superosa 6 HR (Amersham Pharmacia Biotech) and eluted with EDTA-saline buffered with phosphate at 0.5 ml / min. The cholesterol reagent (Roche Diagnostics Chol / HP 704036) at 0.16 ml / min, is mixed with the column effluent through a connection T and the mixture is passed through a id tube tube reactor of 15 mx 0.5 mm submerged in a bath of ice water 37 ° C. The colored product produced in the presence of cholesterol is monitored in the flow stream at 505 nm and the analog voltage of the monitor is converted to a digital signal for collection and analysis. The change in voltage corresponding to the change in cholesterol concentration is plotted against time and the area under the curve corresponding to the elution of very low density lipoprotein (VLDL), low density lipoprotein (LDL) and lipoprotein. High density (HDL), is calculated using Perkin Elmer Turbochrome software. Serum Triglyceride Levels in Mice Dosed with a compound of the invention, they are compared with the mice that receive the vehicle, to identify compounds which could be particularly useful for lowering triglycerides. In general, triglycerides decrease more than or equal to 30% (thirty percent), compared to the control that follows a dose of 30 mg / kg, which suggests a compound that may be especially useful for lowering triglyceride levels . The percentage increase in HDLc serum levels in mice receiving a compound of the invention is compared to mice receiving vehicle to identify compounds of the invention which could be particularly useful for raising HDL levels. In general, an increase greater than or equal to 25% (twenty-five percent) increase in HDLc levels after a dose of 30 mg / kg suggests a compound that may be essentially useful in raising HDLc levels. It may be particularly desirable to select compounds of this invention which lower triglyceride levels as they increase HDLc levels. However, compounds that either decrease triglyceride levels or increase HDLc levels may also be desirable.

Evaluation of Glucose Levels in db / db mice The effects on plasma glucose associated with the administration of various dose levels of different compounds of the present invention and the rostralgroup PPAR agonist rosiglitazone (BRL49653) or the PPAR alpha agonist fenofibrate are studied. , and control for male db / db mice. Five five-week-old male diabetic (db / db) mice [e.g., C57BIKs / j-m + / + Lepr (db), Jackson Laboratory, Bar Harbor, ME] or slender broodlings of the same bait, are housed 6 Cage with food and water available at all times. After a period of acclimatization of 2 weeks, the animals are individually identified by indentations in the ear, weighed and bled via the vein of the tail for determination of the initial glucose levels. Blood is collected (100 μm) from non-fasted animals, by wrapping each mouse in a towel, cutting the tip of the tail with a scarf and obtaining blood from the tail in a heparinized capillary tube. The sample is discharged into a heparinized microteiner with separate gel and retained on ice. The plasma is obtained after centrifugation at 4 ° C and the glucose is measured immediately. The remaining plasma is frozen until the end of the experiment, when glucose and triglycerides are tested in all samples. The animals are grouped based on initial glucose levels and body weights. Beginning the next morning, the mice are dosed daily by forced oral feeding for 7 days. The treatments are test compounds (30 mg / kg), a positive control agent (30 mg / kg) or vehicle [1% carboxymethylcellulose (w / v) Tween 80 at 0.25% (w / v); 0.3 ml / mouse]. On day 7, the mice are heavy and bled (vein of the tail) 3 hours after dosing.

Twenty-four hours after the 7th. dose (that is, the day 8), the animals are bled again (vein of the tail).

Samples obtained from conscious animals at day 0, 7 and 8 are tested for glucose. After 24 hours of bleeding, the animals are weighed and dosed for the final time. Three hours after dosing at day 8, the animals are anesthetized by inhalation of isoflurane and blood is obtained via cardiac puncture (0.5-0.7 mmol). The whole blood is transferred to serum separator tubes, frozen in ice, and allowed to coagulate. The serum is obtained after centrifugation at 4 ° C and frozen until analysis to determine the levels of the compound. After sacrifice by cervical dislocation, the liver, heart and epididymal fat pad are excised and weighed. Glucose is measured colorimetrically using commercially-obtained reagents. According to the manufacturers, the procedures are modified from published works (McGowan, M. W., Artiss, J. D., Strandbergh, D. R. &; Zak, B. Clin Chem, 20: 470-5 (1974) and Keston, A. Specific colorimetric enzymatic analytical reagents for glucose. Abstract of papers 129th Meeting ACS, 31C (1956). ); and dependent on the release of one mole of hydrogen pide per mole of analyte, coupled with a first reaction color described by Trinder (Trinder, P. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor.) Ann Clin Biochem , 6:24 (1969)). The absorbance of the dye produced is linearly related to the analyte in the sample. The standard for commercially available glucose, commercially available quality control plasma, and samples (2 or 5 μl / well), are measured in duplicate using 200 μl of reagent. An additional sample aliquot, pipetted into a third well and diluted in 200 μl of water, provided a blank for each specimen. The plates are incubated at room temperature for 18 minutes to determine glucose in a plate shaker (DPC Micromix 5) and the absorbance is read at 500 nm in a plate reader. The mixing absorbances are compared with a standard curve (100-800 for glucose). The values for the quality control sample are always within the expected range and the coefficient of variation for the samples is below 10%. All samples from one experiment are tested at the same time to minimize inter-assay variability.

Evaluation of the Effects of the Compounds of the Present Invention on the Body Weight of Mice Ay, Adipose Mass, Glucose and Insulin Levels Mice A? Female female A mice are individually housed, maintained under standardized conditions (22 ° C, 12 h light cycle: dark), and provided free access for food and water throughout the duration of the study. At twenty weeks of age, mice are randomly assigned to control vehicle and treated groups, based on body weight and body fat content as assessed by DEXA scan (N = 6). The mice are then dosed via oral forced feeding with either vehicle or a compound of this invention (50 mg / kg), one hour after the initiation of the light cycle (eg, about 7 A.M.) for 18 days. Body weights are measured daily through the study. At day 14, the mice are maintained in individual metabolic chambers by indirect calorimetric assessment of energy expenditure and fuel utilization. On day 18, the mice are again subjected to DEXA screening for post-treatment measurement of body composition. Dosage results p.o of compound for 18 days in body weight, fat mass and thin table are evaluated and it is suggested which compounds of this invention can be especially useful for maintaining desirable weight and / or promoting thin mass to fat mass. The indirect calorimetric measurements that reveal a significant reduction in the respiratory quotient (QR) in animals treated during the dark cycle [0.864 + 0.013 (Control) against 0.803 + 0.007 (Treaty); p < 0.001], is indicative of an increased utilization of fat during the active cycle of the animals (dark) and can be used to select especially desired compounds of this invention. Additionally, treated animals that exhibit significantly higher rates of energy consumption than the control animals suggest that such compounds of this invention may be especially desired.

KK / Ay male mice KK / Ay male mice are lightly housed, maintained under standardized conditions (22 ° C, 12 hours light cycle: dark), and provided free access to food and water throughout the duration of the study. At twenty-two weeks of age, mice are randomly assigned to treated and vehicle control groups, based on plasma glucose levels. The mice are then dosed via oral forced feeding with either vehicle or a compound of this invention (30 mg / kg) one hour after the start of the light cycle (7 A.M.) for 14 days. Plasma glucose levels, triglycerides, and insulin are assessed at day 14. Dosage results p.o. of the compound for 14 days in plasma glucose, triglycerides and insulin, are evaluated to identify compounds of this invention which may be especially desired.

Method to stimulate the Effect of decreasing LDL cholesterol, total cholesterol and triglycerides Male Syrian hamsters (Harían Sprague Dawley), weighing 80-120 g, are placed on a diet rich in high-fat cholesterol, for two to three weeks prior to use. Feeding and water are provided at will through the course of the experiment. Under these conditions, hamsters become hypocholesterolemic, showing plasma cholesterol levels between 180-280 gm / dL. (Hamsters are fed normal food that has a total plasma cholesterol level between 100-150 mg / dL). Hamsters with high plasma cholesterol (180 mg / dl and above) are randomized into treatment groups based on their total cholesterol level using the GroupOptimizeV211.xls program. A compound of this invention is dissolved in an aqueous vehicle (which contains CMC with Tween 80), so that each hamster receives once a day, approximately 1 ml of the solution by forced feeding at doses of 3 and 30 mg / kg of body weight. Fenofibrate (Sigma Chemical, prepared as a suspension in the same vehicle), is given as a known alpha-agonist control, at a dose of 200 mg / kg, and the blank control is the vehicle alone. Dosing is done daily in early morning for 14 days.

Quantification of plasma lipids: On the last day of the test, the hamsters are bled (400 μl) of suborbital sinus, while they are under isoflurane anesthesia 2 hours after dosing. Blood samples are collected in frozen heparinized micro-tubes in an ice bath. The plasma samples are separated from the blood cells by brief centrifugation. The total cholesterol and triglycerides are determined by means of enzymatic tests carried out automatically in the Monarch (Instrumentation Laboratory) team, followed by the manufacturer's procedure. Plasma lipoproteins (VLDL, LDL and HDL) are resolved by injecting 25 μl of the combined plasma samples in an FPLC system eluted with phosphate buffered saline at 0.5 ml / min through a column of Super 6 HR 10/30 column (Pharmacia), maintained at room temperature. The detection and characterization of the isolated plasma lipids are carried out by post-column incubation of the effluent with a Cholesterol / HP reagent (for example, Roche Lab System, infused at 0.12 ml / min) in a spot reaction coil, maintained at 37 ° C. The intensity of the color formed is proportional to the cholesterol concentration and is measured photometrically at 505 nm. The administration effect of a compound of this invention for 14 days is suitable for the percentage reduction in the LDL level with reference to the vehicle group. Especially desired compounds are markedly more potent than fenofibrate in LDL lowering efficacy. The compounds of this invention which decrease LDL greater than or equal to 30% (thirty percent), compared to the vehicle, can be especially desired. The effects of lowering triglycerides and total cholesterol of a compound of this invention are also studied. Data for reduction in triglyceride and total cholesterol levels after treatment with a compound of this invention for 14 days are compared with the vehicle to suggest compounds that may be particularly desired. The known control fenofibrate does not show significant efficacy under the same experimental conditions.

Method to Stimulate the Fibrinogen Decrease Effect of PPAR Modulators Zucker Fat Rat Model: The life phase of the study in the fibrinogen decrease effect of compounds of this invention is part of the life phase procedures for the anti-diabetic studies of the same compounds. At the last day (14th) of the treatment period, with the animals placed under surgical anesthesia, ~ 3 ml of blood is collected by cardiac puncture, in a syringe containing citrate buffer. The blood sample is frozen and centrifuged at 4 ° C to isolate the plasma which is stored at ~ 70 ° C prior to the fibrinogen assay.

Quantification of Plasma Fibrinogen in Rats: Fibrinogen levels in rat plasma are quantified using a commercial assay system which consists of a coagulation instrument, following the manufacturer's protocol. In essence, 100 μl of plasma is sampled from each specimen and a 1/30 dilution is prepared with buffer. The diluted plasma is incubated at 37 ° C for 240 seconds. Fifty microliters of thrombin solution of coagulation reagent (provided by the manufacturers of the instrument in a standard concentration), are then added. The instrument monitors coagulation time, a function of the concentration of fibrinogen quantified with reference to standard samples. Compounds that decrease the levels of fibrinogen higher than the vehicle may be especially desirable. The cholesterol and triglyceride lowering effects of the compounds of this invention are also studied in Zucker rats.

Method for Stimulating the Anti-Appetite Weight Gain and Anti-Appetite Effects of Compounds of this Invention Fourteen-day study in Rat Models1 Zucker or Rat2 ZDF male Zucker fat rat, non-diabetic (Charles River Laboratories, Wilmington, MA), or male ZDF rats (Genetic Models, Inc., Indianapolis, IN) of comparable age and weight, are acclimated for 1 week prior to treatment. The rats are in normal food and water is provided at will throughout the course of the experiment. The compounds of this invention are dissolved in an aqueous vehicle, so that each rat receives approximately 1 ml of the solution per forced feeding once a day at doses of 0.1, 0.3 and 3 mg / kg of body weight. Fenofibrate (Sigma Chemical, prepared as a suspension in the same vehicle), a known alpha agonist, is given at a dose of 300 mg / kg, as well as the vehicles are controls. Dosing is done daily early in the morning for 14 days. Over the course of the experiment, body weight and feed intake are monitored. Using this assay, the compounds of this invention are identified to determine which can be associated with a significant reduction in weight.

Method for stimulating the activation of the delta receptor PPAR in vivo This method is particularly useful for measuring the activation of the PPAR delta receptor in vivo of the compounds of this invention which are determined to possess significant in vitro activity by such isoform of the receptor on the PPAR isoform spectrum. Male PPARa null mice (129s4 SvJae-PPARa <tml Goz <Jackson Laboratories) mice aged 8-9 weeks, are maintained in 5001 Purina feed with at-will water for at least one week prior to use. Feeding and water are provided at will through the course of the experiment. Using the GroupOptimizeV211.xls program, the mice are randomized into treatment groups of five animals, each based on their body weight. The compounds of this invention are suspended in an aqueous vehicle of 1% carboxymethylcellulose (w / v) and 0.25% Tween 80, so that each mouse receives approximately 0.2 ml of the solution per forced feeding per dose approximately once a day. They vary from 0.2 to 20 mg / kg of body weight. A control group of mice is included in each experiment, by means of which they are dosed in parallel with the vehicle alone. Dosing is done daily early in the morning for 7 days. At the last day of dosing, mice are euthanized by asphyxia with C02 3 hours after the final dose. Blood samples are collected by cardiac extraction in centrifugal tubes containing EDTA and frozen in ice. The liver samples are collected by necropsy and are instantly frozen in liquid nitrogen and stored at -80 ° C. For isolation of liver RNA, five to ten mg of frozen liver are placed in 700 μl of Ix nucleic acid lysis solution (Applied Biosystems, Foster City, CA) and homogenized using a hand tissue masher (Biospec Products Inc. , Bartlesville, OK). The homogenate is filtered through an ABI tissue pre-filter (Applied Biosystems Inc., Foster City, CA) and collected on a deep cavity plate at an ABI 6100 nucleic acid preparation station (Applied Biosystems Inc., Foster City, CA). The filtered homogenate is then loaded onto an RNA isolation plate and the DNA-filter-DNA tissue method is run on the ABI 6100. The isolated RNA is levigated in 150 μl of water-free RNase. To assess the quality, 9 μl of the isolated RNA solution is loaded on a 1% TBE agarose gel, and the RNA is visualized by fluorescence of ethidium bromide. Complementary DNA (cDNA) is synthesized using the ABI High Capacity File Kit (Applied Biosystems Inc., Foster City, CA). Briefly, a Master Mix of reverse transcriptase was prepared, in accordance with the manufacturer's protocol for the appropriate number of samples(RT buffer, dNTP, Random primers, MultiScribe RT (50 U / μl), RNase free of water). For each reaction, 50 μl of RT Master Mix was added to 50 μl of isolated RNA in a PCR tube which was incubated in a thermal cycler (25 ° C for 10 minutes, followed by 37 ° C for 2 hours). The resulting cDNA preparation is diluted 1: 100 in dH20 for real-time PCR analysis. Also, a standard cDNA curve is diluted 1:20, 1: 100, 1: 400, 1: 2000, 1: 10,000, for use in final quantification. A Real Time PCR Master Mix to determine the expression of the mouse Cyp4Al gene, is mixed to contain: "IX Tagman Universal PCR Master Mixer (Applied Biosystems Inc., Foster City, CA)" Front primer at final concentration of 6 micromolar; Qiagen / Operon Technologies, Alameda, C?) "Reverse primer at final concentration of 6 micromolar (Qiagen / Operon Technologies, Alameda, CA)" Probe at final concentration of 0.15 micromolar (5 '6-FAM and 3' Tamra-Q; Qiagen / Operon Technologies, Alameda, CA) "RNase free of water at 10 microliters.

A master mix of real-time PCR for the expression of the 18S ribosomal RNA control gene is mixed to contain "RPC IX Tagman Universal Main Mixer (Applied Biosystems Inc., Foster City, CA)" ribosomal RNA control reagents TagMan® probe / primer 0.34 micromolar # 4308329 Applied Biosystems Inc., Foster City, CA) "RNase water-free at 10 microliters.

For real-time PCR analyzes, 6 ul of the respective Main Mix solution was added (either Cyp4Al or 18S) and 4 ul of either diluted cDNA or standard curve samples, to individual cavities of a 384-well plate (n = 2 by standards, n = 4 by unknown). The reactions were performed using the ABI 799 HT standard universal TR-RCP cyclization protocol. The data was analyzed using SDS 2.1 (Applied Biosystems Inc., Foster City, CA). The standard deviation and average quantity were calculated automatically for each individual sample, in accordance with the standard curve values. Using Microsoft Excel 2000, the mean values for each group of the five individual mice were calculated. The average value of each group treated with compound is divided by the average value of the group treated with vehicle. The times of induction on the vehicle group, is determined by valuing the vehicle group to the value of 1.0, and the times of change of the average value for each group, is expressed as times of induction against vehicle (1.0). The data is plotted using Jandel SigmaPlot 8.0.

Monkey Studies Efficacy Studies The compounds of the invention can be examined in a dyslipidemic rhesus monkey model. After an oral dose escalation study for 28 days in nondiabetic, obese rhesus monkeys, a determination of HDL elevation was made with each dose and compared with pretreatment levels. LDL cholesterol is also determined with each dose. C-reactive protein levels are measured and compared to determine pretreatment levels. The compound of Formula I can be shown to elevate plasma HDL cholesterol levels in an African Green Monkey model, in a manner similar to agüella described above in rhesus monkeys. The two groups of monkeys are placed in a dose escalation study which consists of a week of baseline measurements, 9 weeks of treatment (vehicle, compound of formula 1) and four weeks of emptying. During the baseline, the monkeys in three groups are administered by vehicle once daily for seven days. The test compound of Formula I is administered in vehicle once daily for three weeks, then at a higher concentration (the double dose may be desired), once daily for three weeks, and then at an even higher concentration.

(It may be desired to double the most recent dose) once daily for three weeks. Upon completion of treatment, monkeys in both groups are vehicle-administered once daily and monitored for an additional six weeks. The animals are fasted at night and then sedated by measurements of body weight and blood collection at weeks 1 (vehicle), 2, 3, 4, 6, 7, 9, 10, 12 and 14 of the study.

Parameters to be measured, for example: Body weight Total plasma cholesterol HDL LDL Triglycerides Insulin Glucose Parameters PK to weeks 4, 7, and 10 (concentration of plasma drug in the last week of each dose) ApoAI ApoAII ApoB ApoCIII Liver enzymes ( SGTP, SGT, DGT) Complete blood count In addition, other measurements can be made, as appropriate, and consistent with the declared study design.

EQUIVALENTS While this invention has been particularly shown and described with reference to the preferred embodiments thereof, it will be understood by those skilled in the art, that various changes may be made in the form and detail thereof, without departing from the scope of the invention. encompassed by the appended claims.

Claims (84)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property.

1. A compound of formula I: (I) and pharmaceutically acceptable stereoisomers, salts, solvates and hydrates thereof, characterized by: (a) R 1 is selected from the group consisting of hydrogen, Ci-Ca alkoyl, Ci-Cs alkenyl, C 8 -C 8 heteroalyl, aryl C0-4 alkoyl, C 1 -C 4 aryl heteroalyl, heteroaryl-alkylaryl-C and C 3 -C 6 cycloal-guilaryl-C 0-2 alkylaryl wherein C 6 -C 8 alkenyl, C 7 -C 8 alkenyl, C 0 -C aryl alkynyl -C4, aryl-heteroalguyl Ci-4, heteroaryl-alkoyl C0-4, cycloal-guilayl C3-C6-alkoyl C0-2, are each optionally substituted with one to three substituents independently selected from R1 '; (b) R1 ', R26, R27, R28 and R31 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C6-C6 alkoyl, C6-C6-COOR12 alkoyl, alkoxy C? -C6, haloalkyl Ci-Ce, haloalicyloxy C? -C6, cycloalkyl C3-C7, aryloxy, aryl-alkoyl C0-C4, heteroaryl, heterocycloalguilo, C (0) R13, C00R14, OC (0) R15, OS ( 0) 2R16, N (R17) 2, NR18C (0) R19, NR20SO2R21, SR22, S (0) R23, S (0) 2R24, and S (0) 2N (R25) 2; R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each independently selected from the group consisting of hydrogen, C6-C6 alkoyl and aryl; (c) V is selected from the group consisting of C0-C8 aligyl and C? -4 heteroalyl; (d) X is selected from the group consisting of a single bond, O, S, S (0) 2 and N; (e) U is an aliphatic linker wherein a carbon atom of the aliphatic linker is optionally replaced with O, NH or S, and wherein such an aliphatic linker is optionally substituted with one to four substituents each independently selected from R30; (f) W is N, O u S; (g) Y is selected from the group consisting of C, O, S, NH and a single bond; (h) E is C (R3) R4) A or A and wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C1-C5-allylnitrile, carboxamide, sulfonamide and acylsulfonamide; wherein the sulfonamide, acylsulfonamide and tetrazole are each, optionally substituted with one to two groups independently selected from R7; (ii) each R7 is independently selected from the group consisting of hydrogen, haloalkyl C? -C6, aryl alkoyl Co-C and algayl C? -C6; (iii) R3 is selected from the group consisting of hydrogen, C3-C5 alkoxy and C5-C5 alkoxy; and (iv) R 4 is selected from the group consisting of H, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, aryloxy, C 3 -C 6 cycloalkyl and C 0 -C 4 aryl aligyl, and R 3 and R 4 are optionally combined to form a C 3 cycloalkyl C4, and wherein alkenyl, alkoxy, aryloxy, cycloalguyl, and aryl-alkenyl are each optionally substituted with one to three substituents each independently selected from R26; i) R8 is selected from the group consisting of hydrogen, C? -C4 alkenyl, C? ~ C4 alkenyl, and halo; (j) R9 is selected from the group consisting of hydrogen, C1-C4 alkoyl, C al-C4 alkenyl, halo, aryl-alkoyl Co-C4, heteroaryl, C?-C6 allyl and OR29, and wherein aryl-C0- C4 alkenyl, heteroaryl, are each optionally substituted with one to three independently selected from R27; R29 is selected from the group consisting of hydrogen and C al-C4 algayl; (k) RIO, Rll, are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C al-C6-alkoyl, C?-C6-alicylenyl, C al-C6-C00R12-alkoyl, C0-C6 alkoxy, Ci-Cß haloalipyl, C? -C6 haloalicyloxy, C3? C7 cycloal keyl, C0-4 aryl alkoyl, C? -4 aryl heteroaroal guyl, Co-4 heteroaryl algayl, C3-C6 cycloal kebayl alkoyl C0 -2, aryloxy, C (0) R13 ', COOR14', 0C (0) R15 ', OS (0) 2R16', N (R17 ') 2, NR18'C (0) R19', NR20 'S02R21', SR22 ', S (0) R23', S (0) 2R24 ', and S (O) 2N (R25') 2; and where aril-alguyl C0-4, aryl-heteroalguyl Cj.-C4, heteroaryl-C0- alkoyl and C3-C6-cycloal-guilayl-alguyl Co ~ 2, are each optionally substituted with one to three, independently selected from R28; and wherein RIO and Rll are optionally combined to form a fused bicyclic ring of 5 to 6 elements with the phenyl to which they are attached; (1) R12 ', R12", R13', R14 ', R15', R16 ', R17', R18 ', R19', R20 ', R21', R22 ', R23', R24 ', and R25', are each independently selected from the group consisting of hydrogen, C al-C6 alkoyl and aryl; (m) R30 is selected from the group consisting of Ci-Ce alkoyl, aryl-alkoyl Co-4, aryl-heteroalguilo C? ~ 4, heteroaryl-C0-4 alkyloyl and C3-C6-cycloal-guilaryl-C0-2 alkyloyl, and wherein C6-C6 alkoyl, aryl-Coyl-4-aryl, C6-aryl-heteroal-guyl, C0-4-heteroaryl-alkoyl and C3-C6-cycloal-guilaryl -alcoyl C0-2, each optionally substituted from one to three substituents each independently selected from R31; (n) R32 is selected from the group consisting of hydrogen, halo, C-C6 algayl, Ci-Ce haloalguyl, and alguiloxo Ci-Ce; and (o) is optionally a bond to form a double bond at the indicated position 2. A compound as claimed in claim 1, characterized by the compound having the formula: and pharmaceutically acceptable stereoisomers, salts, solvates and hydrates thereof characterized by: (a) R1 is selected from the group consisting of hydrogen, C?-C8 alkenyl, C?-C8 alkenyl, arylguiloby Co Co4, aryl heteroalguyl C? -C, C6-C4 heteroaryl allyl and C3-C6 cycloalkylaryl_C6 alkyl, and, wherein C? -C8 alkyl, C? -C8 alkenyl, C0-C aryl alkoyl, C? - aryl heteroalguyl, C0-4 heteroaryl alkoyl, C3-C6 cycloal-guilayl-C0-2 alkeyl, each optionally substituted with one to three substituents independently selected from R1 '; (b) R1 ', R26, R27, R28 and R31 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C6-C6 alkoyl, C6-C6-COOR12 alkoyl, alkoxy C? ~ Ce, haloalkyl C? -C6, haloalicyloxy C? -C6, cycloalguile C3-C, aryloxy, aryl-alkoyl Co-C4, heteroaryl, heterocycloalguyl, C (0) R13, C00R14, 0C (0) R15, 0S (0) 2R16, N (R17)

2, NR18C (0) R19, NR20SO2R21, SR22, S (0) R23, S (0) 2R24, and S (O) 2N (R25) 2; R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each independently selected from the group consisting of hydrogen, C6-C6 alkoyl and aryl; (c) V is selected from the group consisting of alguilo Co-Cs and heteroalguilo C? -; (d) X is selected from the group consisting of a single bond, O, S, S (0) 2 and N; (e) U is an aliphatic linker wherein a carbon atom of the aliphatic linker is optionally replaced with O, NH or S, and wherein such an aliphatic linker is optionally substituted with one to four substituents each independently selected from R30; (f) Y is selected from the group consisting of C, NH and a single bond; (g) E is C (R3) R4) A or A and wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C-C6-allylnitrile, carboxamide, sulfonamide and acylsulfonamide; wherein the sulfonamide, acylsulfonamide and tetrazole are each, optionally substituted with one to two groups independently selected from R7; (ii) each R7 is independently selected from the group consisting of hydrogen, haloalguil C? -C6, aryl algayl Co-C4 and alguilo C? -C6; (iii) R3 is selected from the group consisting of hydrogen, C?-C5 alkoyl and C?-C alkoxy; and (iv) R4 is selected from the group consisting of H, C? -C5 alkoyl, C? -C alkoxy, aryloxy, C3-C6 cycloal keyl and C0-C4 aryl aligyl, and R3 and R4 are optionally combined to form a cycloalguilo C3-C, and wherein alkenyl, alkoxy, aryloxy, cycloalguyl and aryl-alkenyl are each optionally substituted with one to three substituents each independently selected from R26; (h) R8 is selected from the group consisting of hydrogen, C? -C alkyl, C? -C4 alkenyl, and halo; (i) R9 is selected from the group consisting of hydrogen, C? -C4 alkenyl, C? -C4 alkenyl, halo, C0-C4 aryl-alkoyl, heteroaryl, C? -C6 allyl and OR29, and wherein aryl-C0 -C alkenyl, heteroaryl, are each optionally substituted with one to three independently selected from R27; R29 is selected from the group consisting of hydrogen and C al-C4 algayl; (j) RIO, Rll, are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C al-C6-alkoyl, C?-C6-alicylenyl, C al-C6-COOR-12 algayl, alkoxy Co-Cβ, haloalguilo C? -Cd, haloalguiloxi C? -C6, cycloalguilo C3-C7, aril-alguilo C0-4, aril-heteroaroalguilo C? -4, heteroaril-alguilo C0-4, cycloalguilaril C3-C6-alguilo C0-2, aryloxy, C (0) R13 ', COOR14', OC (0) R15 ', 0S (0) 2R16', N (R17 ') 2 ,. NR18'C (0) R19 ', NR20' S02R21 ', SR22', S (0) R23 ', S (0) 2R24', and S (0) 2N (R25 ') 2; and wherein C 0-4 aryl alkoyl, C 1 -C 4 aryl heteroalyl, C 0-4 heteroaryl alkoyl, and C 3 -C 6 cycloalkylaryl alkoxy Co-2, are each optionally substituted with one to three, independently selected from R 28; and wherein RIO and Rll are optionally combined to form a fused bicyclic ring of 5 to 6 elements with the phenyl to which they are attached; (k) R12 ', R12", R13', R14 ', R15', R16 ', R17', R18 ', R19', R20 ', R21', R22 ', R23', R24 ', and R25', are each independently selected from the group consisting of hydrogen, C al-Ce alkoyl and aryl; (1) R30 is selected from the group consisting of C6-C6 alkoyl, C0-4 aryl-alkoyl, C1-4 aryl-heteroal-guyl, heteroaryl-alkoyl Co-4 and C3-C6 cycloal-guilayl-C0-2 algayl, and wherein C al-C6 alkoyl, arylguiloby Co-, aryl-Cal -4 heteroalkyl, heteroaryl-alkoyl Co- and C3-C6 cycloal-guilayl-alkenyl Co-2, are each optionally substituted with one to three substituents each independently selected from R31; (m) R32 is selected from the group consisting of a bond, hydrogen, halo, C?-C6-alkoyl, C halo-Cdhaloalkyl, and Cx-Ce alkoxyloxy; and (n) is optionally a link to form a double bond in the indicated position.

3. A compound as claimed in claim 1, characterized in that the compound is of the formula le: you and pharmaceutically acceptable stereoisomers, salts, solvates and hydrates thereof characterized by: (a) R1 is selected from the group consisting of hydrogen, C?-C8 alkenyl, C?-C8 alkenyl, C?-8 heteroalyl, aryl alkoyl Co-4 aryl-heteroalguilo C? -C, heteroaryl-alkoyl Co-C4 and cycloalguilaryl C3-C6-alguilo C0-2, and, where C? -C8 alguilo, alguenilo C? -8, aril-alguilo Co- C4, C? -4 aryl heteroalyl, heteroaryl-alkenyl Co-4, C3-C6 cycloal-guilayl-alkenyl Co ~ 2, are each optionally substituted with one to three substituents independently selected from Rl '; (b) R1 ', R26, R27, R28 and R31 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C6-C6 alkoyl, C6-C6-COOR12 alkoyl, alkoxy C? ~ C ?, C halo-C6 haloal-guyl, C?-C6-haloal-yloxy, C3-C7-cycloal-guyl, aryloxy, aryl-alkoxy Co-C4, heteroaryl, heterocycloal-guyl, C (0) R13, COOR14, 0C (0) R15, OS (0 ) 2R16, N (R17) 2, NR18C (0) R19, NR20SO2R21, SR22, S (0) R23, S (0) 2R24, and S (O) 2N (R25) 2; R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each independently selected from the group consisting of hydrogen, C6-C6 alkoyl and aryl; (c) V is selected from the group consisting of alkoxy Co-C8 and heteroalguilo C? -4; (d) X is selected from the group consisting of a single bond, O, S, S (0) 2 and N; (e) U is an aliphatic linker wherein a carbon atom of the aliphatic linker is optionally replaced with 0, NH or S, and wherein such an aliphatic linker is optionally substituted with one to four substituents each independently selected from R30; (f) Y is selected from the group consisting of C, 0, S, NH and a single link; (g) E is C (R3) R4) A or A and wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C? -C6 alkylnitrile, carboxamide, sulfonamide and acylsulfonamide; wherein the sulfonamide, acylsulfonamide and tetrazole are each, optionally substituted with one to two groups independently selected from R7; (ii) each R7 is independently selected from the group consisting of hydrogen, C6-C6 haloal-guyl, C0-C4 aryl, and C6-C6 algayl; (iii) R3 is selected from the group consisting of hydrogen, C? -C5 alkoyl and C? -C5 alkoxy; and (iv) R4 is selected from the group consisting of H, C? -C5 alkoyl, C? -C5 alkoxy, aryloxy, C3-C6 cycloal keyl and C0-C4 aryl aligyl, and R3 and R4 are optionally combined to form a cycloalguilo C3-C3, and wherein alkenyl, alkoxy, aryloxy, cycloalguyl and aryl-alkenyl are each optionally substituted with one to three substituents each independently selected from R26; (h) R8 is selected from the group consisting of hydrogen, C? -C4 alkenyl, C? -C4 alkenyl, and halo; (i) R9 is selected from the group consisting of hydrogen, C? -C4 alkenyl, C? -C alkenyl, halo, C0-C4 aryl-alkoyl, heteroaryl, C? -C6 allyl and OR29, and wherein aryl-C0 -C4 alkenyl, heteroaryl, are each optionally substituted with one to three independently selected from R27; R29 is selected from the group consisting of hydrogen and C al-C4 algayl; (j) RIO, Rll, are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C al-C6-alkoyl, C?-C6-alicylenyl, C al-C6-C00R12-alkoyl, alkoxy Co-Cd, haloalguilo C? -Cg, haloalguiloxi C? -Ce, C3-C7 cycloalkyl, aryl-C0- alkyl, aryl-heteroaroalguilo C? -4, heteroaryl-algayl Co-4, cycloalguilaryl C3-C6-alguilo C0 -2, aryloxy, C (0) R13 ', C00R14', 0C (0) R15 ', OS (0) 2R16', N (R17 ') 2, NR18'C (0) R19', NR20 'S02R21', SR22 ', S (0) R23', S (0) 2R24 ', and S (0) 2N (R25') 2; and where aril-alguyl C0-4, aryl-heteroalguil C? -C4, heteroaryl-C0-4 aligyl and C3-C6-cycloal-guilayl-C0-2 aligyl, are each optionally substituted with one to three, independently selected from R28; and wherein RIO and Rll are optionally combined to form a fused bicyclic ring of 5 to 6 elements with the phenyl to which they are attached; (k) R12 ', R12", R13', R14 ', R15', R16 ', R17', R18 ', R19 ', R20', R21 ', R22', R23 ', R24', and R25 ', are each independently selected from the group consisting of hydrogen, C al-Cd alkoyl and aryl; (1) R30 is selected from the group consisting of C6-C6 alkoyl, C0-4 aryl-alkoyl, C4-4 aryl-heteroal-guyl, C0-4 heteroaryl-alkoyl and cycloal-guilaryl C3-Cd-C0-2 alkoxy, and wherein C al-C al alkoyl, Co ~ 4 arylalguyl, C ar - aryl-heteroalguyl, C0-4-heteroaryl-alkoyl and C C-C6-cycloal-guilayl-C al-2-alkoyl are each optionally substituted from one to three substituents each independently selected from R31; (m) R32 is selected from the group consisting of a bond, hydrogen, halo, C?-C6-alkoyl, C?-C6-haloal-guyl, and C C-Cß-alkyloxy; and (n) is optionally a link to form a double bond in the indicated position.

4. A compound as claimed in claim 1, characterized in that the compound is of formula Ib: where W1 is S or O.

5. A compound according to claim 5, characterized in that W1 is S.

6. A compound according to claim 5, characterized in that W1 is O.

7. A compound as claimed according to any one of claims 4, 5 or 6, characterized by when Y is O, then U is aliphatic linker C? -C4, wherein a C 1 -C 4 alkenyl carbon is replaced with O and wherein the aliphatic linker is optionally substituted with one to four substituents each independently selected from R30.

8. A compound as claimed in any of claims 1, 2, 3 or 7, characterized by the compound is of Formula III: and pharmaceutically acceptable stereoisomers, salts, solvates and hydrates thereof characterized by: (a) R1 is selected from the group consisting of hydrogen, C?-C8 alkyl, C?-C8 alkenyl, C?-8 heteroaligyl, C0-4 alkylaryl-C6-4 heteroaryl, C0-C4 heteroaryl-alkeyl and C3-C6-cycloal-guilayl-alkenyl Co-2, and, wherein C? -C8 alkenyl, C? -C8 alkenyl, aryl-alkynyl Co-? C4, C? -4 aryl-heteroalguyl, C0-4 heteroaryl algayl, C3-Cg cycloal-guilayl-algayl Crj-2, are each optionally substituted with one to three substituents independently selected from R1 '; (b) R1 ', R26, R27, R28 and R31 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C al-Cd alkoyl, C al-C6-COOR 12 alkoxy, alkoxy C? ~ Cs, haloalkyl C? -C6, haloalkyloxy C? -C6, cycloalguile C3-C7, aryloxy, aryl-alkoyl Co-C4, heteroaryl, heterocycloalguyl, C (0) R13, C00R14, 0C (0) R15, OS (0) 2R16, N (R17) 2, NR18C (0) R19, NR20SO2R21, SR22, S (0) R23, S (0) 2R24, and S (0) 2N (R25) 2; R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each independently selected from the group consisting of hydrogen, C6-C6 alkoyl and aryl; (c) V is selected from the group consisting of alkoxy Co-C8 and heteroalguilo C? -4; (d) X is selected from the group consisting of a single bond, 0, S, S (0) 2 and N; (e) U is an aliphatic linker wherein a carbon atom of the aliphatic linker is optionally replaced with 0, NH or S, and wherein such an aliphatic linker is optionally substituted with one to four substituents each independently selected from R30; (f) Y is selected from the group consisting of C, 0, S, NH and a single bond; (g) E is C (R3) R4) A; wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C 1 -C 6 -annitrile, carboxamide, sulfonamide and acylsulfonamide; wherein the sulfonamide, acylsulfonamide and tetrazole are each, optionally substituted with one to two groups selected independently from R7; (ii) each R7 is independently selected from the group consisting of hydrogen, C6-C6 haloal-guyl, C0-C4 aryl, and C6-C6 algayl; (Iii) R3 is selected from the group consisting of hydrogen, C al-C5 alkoyl and C?-Cs alkoxy; and (iv) R 4 is selected from the group consisting of H, C al-C5 alkoyl, C?-C alkoxy, aryloxy, C 3 -C 6 cycloalkyl and C 0 -C 4 aryl, and R 3 and R4 are optionally combined to form a C3-C4 cycloalguil, and wherein alkenyl, alkoxy, aryloxy, cycloalguyl, and aryl-alkenyl are each optionally substituted with one to three substituents each selected 20 independently of R26; with the proviso that when Y is O then R4 is selected from the group consisting of C al-C5-alkoxy, C?-Cs alkoxy, aryloxy, C3-C6 cycloal-guyl and C0-C4 aryl-alkoyl, and R3 and R4 optionally combined to form a C3_C4 cycloalguil, and wherein alkenyl, alkoxy, cycloalguyl and aryl-alkenyl are each optionally substituted with one to three of each independently selected from R26; (h) R8 is selected from the group consisting of hydrogen, C? -C4 alkenyl, C? -C4 alkenyl, and halo; (i) R9 is selected from the group consisting of hydrogen, C? -C4 algayl, C? -C4 alkenyl, halo, C0-C4 aryl-alkoyl, heteroaryl, C? -C6 allyl and OR29, and wherein aryl-Co ~ C4 alkyl, heteroaryl, are each optionally substituted with one to three independently selected from R27; R29 is selected from the group consisting of hydrogen and C al-C4 algayl; (j) RIO, Rll, are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C6-C6 aligyle, C6-C6-alkynyl, C6-C6-C00R12-alkoyl, alkoxy Co-Cd, haloalguilo 'C? -C6, haloalguiloxi C? -C6, cycloalguilo C3-C7, aril-algilo C0-4, aril-heteroaroalguilo C? -4, heteroaril-alguilo C0-4, cycloalguilaril C3-C6-alguilo C0-2, aryloxy, C (0) R13 ', COOR14', OC (0) R15 ', 0S (0) 2R16', N (R17 ') 2, NR18'C (0) R19', NR20 'S02R21' , SR22 ', S (0) R23', S (0) 2R24 ', and S (0) 2N (R25') 2, and wherein aryl-C0-4 alkylaryl, aryl-heteroalguyl C? -C4, heteroaryl- C4-C6-alkeyl and C3-C6-cycloal-guilary ~ Cn-2 aligyl are each optionally substituted with one to three, independently selected from R28; RIO and Rll are optionally combined to form a fused bicyclic ring of 5 to 6 elements with the phenyl to which they are attached; (k) R12 ', R12", R13', R14 ', R15', R16 ', R17', R18 ', R19', R20 ', R21', R22 ', R23', R24 ', and R25', are each independently selected from the group consisting of hydrogen, C6-C6 alkoyl and aryl; (1) R30 is selected from the group consisting of C6-C6-alkoyl, C0-4-aryl-allyl, aryl-heteroalguyl C? -4, C0-4 heteroaryl-alkoyl and C3-C6 cycloal-guilayl-C0-2 algayl, and wherein C? -C6 alkenyl, CoA4 arylalkyl, C? - aryl heteroalkyl, Co-4 heteroaryl alkenyl and C3-C6 cycloal-guilaryl ~ alyl Co-2, are each optionally substituted from one to three substituents each independently selected from R31; (m) R32 is selected from the group consisting of a bond, hydrogen, halo, C? -Ce alkyl, C? -C6 haloalkyl, and C? -C6 alkyloxy; and (n) is optionally a link to form a double bond in the indicated position.

9. A compound as claimed in any of claims 1 to 8, characterized in that X is 0.

10. A compound as claimed in any of claims 1 to 8, characterized by X is S.

11. A compound as claimed in any of claims 1 to 10, characterized in that Y is O.

12. A compound as claimed in accordance with any of claims 1 to 10, characterized by Y is C.

13. A compound as claimed according to any one of claims 1 to 10, characterized by section Y is S.

14. A compound as claimed in any of claims 1 to 13, characterized by two "" on the ring of five elements. they are each united to form double bonds in the designated locations.

15. A compound as claimed in any of claims 1 to 14, characterized in that E is (C (R3) (R4) A.

16. A compound as claimed in accordance with any of claims 1 to 15, characterized by A is COOH.

17. A compound as claimed in accordance with any one of claims 1 to 16, characterized by RIO is haloalguilo.

18. A compound as claimed in claim 17, characterized by RIO is CF3.

19. A compound as claimed according to any one of claims 1 to 16, characterized by RIO is haloalkyloxy.

20. A compound as claimed in any of claims 1 to 16, characterized in that RIO and Rll are each independently selected from the group consisting of hydrogen, halo, oxo, C al-C6-alkoyl, C al-C6-alkoyl. -COOR12 '', C6-C6 alkoxy, C6-C6 haloal-guyl and C6-C6-haloalyloxy.

21. A compound as claimed according to any one of claims 1 to 16, characterized in that RIO and Rll are each independently selected from the group consisting of C? -C2 alkenyl.

22. A compound as claimed according to any one of claims 1 to 16, characterized in that RIO is selected from the group consisting of C3-C7 cycloal-guyl, aryl-alkoyl Co-4, aryl-heteroalguyl C? _4, heteroaryl-alguyl C0-4, C3-C6 cycloalguilaryl-C0-2 alkyl and aryloxy.

23. A compound as claimed in any of claims 1 to 22, characterized in that R1 is optionally substituted C2-C3 arylalkyl.

24. A compound as claimed in any of claims 1 to 23, characterized in that R8 and R9 are each independently selected from the group consisting of hydrogen and C-C3 alkenyl.

25. A compound as claimed in any of claims 1 to 22 and 24, characterized by R1, V, R3 and R4 are each independently selected from the group consisting of C al-C2 alkenyl.

26. A compound as claimed in any of claims 1 to 22 and 24, characterized by R1, R3 and R4 are each independently selected from the group consisting of hydrogen and C al-C2 alkoyl.

27. A compound as claimed in any of claims 1 to 24 or claim 26, characterized in that V is a bond.

28. A compound as claimed in any one of claims 1 to 24, characterized in that V is selected from the group consisting of alkoyl Co-C ?.

29. A compound as claimed according to any one of claims 1 to 28, characterized in that U is C? -C3 alkyl.

30. A compound as claimed in any of claims 1 to 29, characterized by ü is saturated.

31. A compound as claimed in any of claims 1 to 22 or 24 to 30, characterized in that R1 is C6-C6 heteroalyl.

32. A compound as claimed in any one of claims 1 to 31, characterized in that a carbon atom of the aliphatic linker is replaced with an O.

33. A compound as claimed in any one of claims 1 to 31. , characterized by U is an aliphatic linker which has a carbon replaced by N.

34. A compound as claimed in any of claims 1 to 31, characterized by U is an aliphatic linker having one carbon replaced by S.

35. A compound as claimed in any of claims 1 to 34, characterized by aliphatic linker is substituted with one to three substituents each independently selected from R30.

36. A compound as claimed in claim 35, characterized by aliphatic linker is substituted with one or two substituents each independently selected from R30.

37. A compound as claimed in any of claims 1 to 36, characterized in that each R30 is independently selected from the group consisting of C6-C6-alkoyl.

38. A compound as claimed in any of claims 1 to 37, characterized in that each R30 is independently selected from the group consisting of C2-C3 alkenyl.

39. A compound as claimed in any one of claims 1 to 36, characterized in that R30 is independently selected from the group consisting of aryl-alkoyl Co-4, aryl-heteroalguilo C? -C4, hetero-alguilo C0-4 and C3-C6 cycloal-guilaryl-algayl Co ~ 2 - . 2-

40. A compound as claimed according to claim 39, characterized by "Y" is O and E is -CH2COOH.

41. A compound as claimed according to any one of claims 1 to 40, characterized in that U is substituted with methyl.

42. A compound as claimed in any of claims 1 to 41, characterized by U is methylene.

43. A compound as claimed in any of claims 1 to 16 and 22 to 42, characterized in that RIO and Rll combine to form a fused ring of 6 elements.

44. A compound as claimed in accordance with any of claims 1-3, 8-13, 15-24 and 36-41, characterized by is represented by the following structural formula IV:

45. A compound as claimed in accordance with any of claims 1-3, 8-13, 15-24, 26, 36-41, characterized by the following is represented by the following structural formula V:

46. A compound as claimed according to any one of claims 1-3, 8-13, 15-24, 26, 36-41, characterized by the following is represented by the following structural formula VI:

47. A compound as claimed in any of claims 1-3, 8-13, 15-24, 26, 36-41, characterized by the following structural formula VIII is represented:

48. A compound as claimed in accordance with any of claims 1-3, 8-13, 15-24, 26, 36-41, characterized by a is represented by structural formula IX:

49. A compound as claimed in claim 1 to 48, characterized by X and Y are substituted in a 1,4 position, such that X and Y are substituted with each other.

50. A compound as claimed in claim 1 to 48, characterized by X and Y are substituted in a 1,3 position, such that X and Y are meta substituted.

51. A compound as claimed in claim 1, characterized by a compound of the formula: or a pharmaceutically acceptable salt, solvate or hydrate thereof.

52. A compound as claimed in any of claims 1 to 50, characterized by X is a bond.

53. A compound as claimed in claim 1, characterized in that it is 2-Methyl-2- acid. { 4- [3- (5-naphthalen-2-ylmethyl-2 H- [1, 2, 4] triazol-3-yl) -phenoxy} propionic 54.

A compound as claimed in any of claims 1 to 53, characterized in that it is in the S conformation.

A compound as claimed in any of claims 1 to 53, characterized by being in the conformation. R.

56. A pharmaceutical composition, characterized by comprising as an active ingredient, at least one compound as claimed in claim 1 to 55 together with a pharmaceutically acceptable carrier or diluent.

57. A method for modulating a peroxisome proliferator activated receptor, characterized by comprising the step of contacting the receptor with at least one compound as claimed in any of claims 1 to 55.

58. A method for treating diabetes mellitus in a mammal, characterized by comprising the step of administering to a mammal in need thereof, a therapeutically effective amount of at least one compound according to claims 1 to 55.

59. A method for treating a metabolic disorder in a mammal , characterized by comprising a therapeutically effective amount of at least one compound according to claims 1 to 55.

60. A method according to claim 59, characterized in that the mammal in need thereof is diagnosed as suffering from metabolic disorder.

61. A method for selectively modulating a delta PPAR receptor, characterized by comprising administering a compound as claimed in claim 1 to 55, to a mammal in need thereof.

62. The manufacture of a medicament for use in the treatment and / or prevention of a metabolic disorder, wherein the compound is a compound as claimed in any one of claims 1 to 55.

63. A method for treating atherosclerosis in a mammal, characterized by comprising the step of administering to a mammal in need thereof, a therapeutically effective amount of at least one compound according to claims 1 to 55.

64. A compound as claimed in accordance with any one of the claims. 1 to 55, characterized by being used as a pharmacist.

65. A method for treating or preventing the progression of a cardiovascular disease in a mammal in need thereof, characterized by administering a therapeutically effective amount of at least one compound as claimed according to any one of claims 1 to 55.

66. A method as claimed in claim 65, characterized in that the mammal is diagnosed as being in need of such treatment.

67. A compound as claimed in any of claims 1 to 55, characterized by radio-etching.

68. A compound, characterized by it, is described by any of the examples in this document.

69. All methods described herein, for preparing the compounds represented by Structural Formula I.

70. A compound as claimed in any of claims 1, 4, 5, 6, 9-13, 15-24, 26 or 36-41, characterized by is represented by structural formula X:

71. A compound as claimed in any of claims 1, 5, 7, 9-13, 15-24, 26, 36-41, characterized in that it is represented by structural formula XI:

72. A compound as claimed according to any one of claims 1, 4, 5, 6, 9-13, 15-24, 26 or 36-41, characterized by is represented by structural formula XII:

73. A compound as claimed according to any one of claims 1, 5, 7, 9-13, 15-24, 26, 36-41, characterized by is represented by structural formula XIII:

74. A compound as claimed in claim 45, characterized in that the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or hydrate thereof.

75. A compound as claimed in claim 46, characterized in that the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or hydrate thereof.

76. A compound as claimed in claim 46, characterized in that the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or hydrate thereof.

77. A compound as claimed in claim 48, characterized in that the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or hydrate thereof.

78. A compound as claimed in claim 70, characterized in that the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or hydrate thereof.

79. A compound as claimed in claim 71, characterized in that the compound is selected from the group consisting of: Or a pharmaceutically acceptable salt, solvate or hydrate thereof.

80. A compound as claimed in claim 72, characterized in that the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or hydrate thereof.

81. A compound as claimed in claim 73, characterized in that the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or hydrate thereof.

82. A pharmaceutical formulation, characterized by comprising a compound as claimed in any of claims 1 to 55, claims 70 to 81, 83 or 84 and at least one pharmaceutically acceptable excipient or carrier.

83. A compound as claimed in any of claims 1, 2, 3, 8, 12-26, 39, 40 and 43, characterized by the structural formula:

84. A compound as claimed in claim 1, of the formula la: (the) and pharmaceutically acceptable stereoisomers, salts, solvates and hydrates thereof characterized by: (a) R1 is selected from the group consisting of hydrogen, C?-C8 alkenyl, C?-C8 alkenyl, C?-C8 heteroaligyl, C0-4 heteroalguyl-C?-C4 aryl and C al-C6 alkylaryl-heteroaryl and C C-C6-cycloalkylaryl-C alquilo-2 alkyl, and, wherein C?-C8 alkyl, C?-C8 alkenyl, aryl-C C-alkyl C4, aryl-heteroalguyl C? -4, heteroaryl-alkoyl CO-, cycloal-guilayl C3-C6-alkenyl Co-2, are each optionally substituted with one to three substituents independently selected from RI '; (b) R1 ', R26, R27, R28 and R31 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C6-C6 alkoyl, C6-C6-COOR12 alkoyl, alkoxy C? ~ Cß, haloalkyl C? -C6, haloalkyloxy C? -Cd, cycloalkyl C3 ~ C7, aryloxy, aryl-alkoyl Co-C4, heteroaryl, heterocycloalguyl, C (0) R13, COOR14, OC (0) R15, 0S (0) 2R16, N (R17) 2, NR18C (0) R19, NR20SO2R21, SR22, S (0) R23, S (0) 2R24, and S (O) 2N (R25) 2; R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each independently selected from the group consisting of hydrogen, C-Ce alkyl and aryl; (c) V is selected from the group consisting of C0-C8 aligyl and heteroalguyl C? -; (d) X is selected from the group consisting of a single bond, 0, S, S (0) 2 and N; (e) U is an aliphatic linker wherein a carbon atom of the aliphatic linker is optionally replaced with 0, NH or S, and wherein such an aliphatic linker is optionally substituted with one to four substituents each independently selected from R30; (f) Y is selected from the group consisting of C, 0, S, NH and a single bond; (g) E is C (R3) R4) A or A and wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C6-C6-allylnitrile, carboxamide, sulfonamide and acylsulfonamide; wherein the sulfonamide, acylsulfonamide and tetrazole are each, optionally substituted with one to two groups independently selected from R7; (ii) each R7 is independently selected from the group consisting of hydrogen, haloalkyl C? -C6, aryl algayl C0-C and algayl C? -C6; (iii) R3 is selected from the group consisting of hydrogen, C al-C al alkoxy and C?-C5 alkoxy; and (iv) R 4 is selected from the group consisting of H, C?-C5 alkoyl, C?-C5 alkoxy, aryloxy, C 3 -C 6 cycloalkyl and C 0 -C 4 aryl alkoyl, and R 3 and R4 are optionally combined to form a C3-C cycloalkyl, and wherein alkenyl, alkoxy, aryloxy, cycloalguyl, and aryl-alkenyl are each optionally substituted with one to three substituents each independently selected from R26; (h) R8 is selected from the group consisting of hydrogen, C? -C4 alkenyl, C? -C4 alkenyl, and halo; (i) R9 is selected from the group consisting of hydrogen, C? -C4 alkenyl, C? -C4 alkenyl, halo, C0-C4 aryl-alkoyl, heteroaryl, C? -C6 allyl and OR29, and wherein aryl-Co -C alkenyl, heteroaryl, are each optionally substituted with one to three independently selected from R27; R29 is selected from the group consisting of hydrogen and C al-C4 algayl; (j) RIO, Rll, are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C? -Ce alkoyl, C? -C6 alicylenyl, C? -C6-COOR12 algayl, C0-C6 alkoxy, C6-C6 haloal-guyl, C6-C6-haloalyloxy, C3-C7-cycloal-guyl, C0-4-aryl-allyl, C-4 aryl-heteroaroal-guyl, C0-4-heteroaryl-allyl, C3-C6-cycloal-guilayl-algayl C0-2, aryloxy, C (0) R13 ', C00R14', 0C (0) R15 ', OS (0) 2R16', N (R17 ') 2, NR18'C (0) R19 ', NR20' S02R21 ', SR22', S (0) R23 ', S (0) 2R24', and S (0) 2N (R25 ') 2; and wherein C 0-4 aryl alkoyl, C 1 -C 4 aryl heteroalyl, C 0-4 heteroaryl alkoyl, and C 3 -C 6 cycloal-guilayl-C 0-2 alkeyl are each optionally substituted with one to three, independently selected from R 28; and wherein RIO and Rll are optionally combined to form a fused bicyclic ring of 5 to 6 elements with the phenyl to which they are attached; (k) R12 ', R12", R13', R14 ', R15', R16 ', R17', R18 ', R19 ', R20', R21 ', R22', R23 ', R24', and R25 ', are each independently selected from the group consisting of hydrogen, C-Cd alkoyl and aryl; (1) R30 is selected from the group consisting of C6-C6 alkoyl, C0-4 aryl-C4-4 aryl-heteroalkyl, C0-4 heteroaryl-alkoyl and C3-C6 cycloal-guilary-C0-2 alkyl, and wherein alkyl C? -Ce, arylalkyl Co-, aryl-heteroalkyl C? -4, heteroarylC0-4 alkyl and C3-C6 cycloalkylaryl-C0-2 alkeyl, are each optionally substituted from one to three substituents each selected independently of R31; (m) R32 is selected from the group consisting of a bond, hydrogen, halo, C6-C6 algayl, haloal-guyl C? -C6, and alguilox C? -Ce; and (n) is optionally a link to form a double bond in the indicated position.