MX2007003323A

MX2007003323A - Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors

Info

Publication number: MX2007003323A
Application number: MXMX/A/2007/003323A
Authority: MX
Inventors: Jianmin Fu; Vishnumurthy Kodumuru; Shaoyi Sun; Rajender Kamboj; Zaihui Zhang; Serguei Sviridov; Shifeng Liu; Duanjie Hou; Nagasree Chakka; Vandna Raina
Original assignee: Nagasree Chakka; Jianmin Fu; Duanjie Hou; Rajender Kamboj; Vishnumurthy Kodumuru; Shifeng Liu; Vandna Raina; Shaoyi Sun; Serguei Sviridov; Xenon Pharmaceuticals Inc; Zaihui Zhang
Priority date: 2004-09-20
Filing date: 2007-03-20
Publication date: 2008-10-03

Abstract

Methods of treating an SCD-mediated disease or condition in a mammal, preferebly a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I):where x, y, G, J, K, L, M, W, R2, R3, R5, R5a, R6, R6a, R7, R7a, R8and R8aare difined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.

Description

HETEROCICLIC DERIVATIVES AND THEIR USE AS THERAPEUTIC AGENTS FIELD OF THE INVENTION The present invention relates generally to the field of stearoyl-CoA desaturase inhibitors, such as heterocyclic derivatives, and to uses for said compounds in the treatment and / or prevention of various human diseases, including those mediated by the enzymes stearoyl-CoA desaturase ( SCD), preferably SCD1, especially diseases related to elevated lipid levels, cardiovascular diseases, diabetes, obesity, metabolic syndrome and the like.

BACKGROUND OF THE INVENTION The acyl desaturases enzymes catalyze the formation of double bonds in fatty acids derived either from dietary sources or from de novo synthesis in the liver. Mammals synthesize at least three fatty acid desaturases of different chain length specificity that catalyze the addition of double bonds at the delta-9, delta-6, and delta-5 positions. Stearoyl-CoA desaturases (SCDs) introduce a double bond in the Cg-do position of saturated fatty acids. The preferred substrates are palmitoyl-CoA (16: 0) and stearoyl-CoA (18: 0), which are converted to palmitoyl-CoA (16: 1) and oleoyl-CoA (18: 1), respectively. The resulting monounsaturated fatty acids are substrates for incorporation into phospholipids, triglycerides, and cholesteryl esters. Numerous mammalian SCD genes have been cloned. For example, two genes have been cloned from rat (SCD1, SCD2) and four SCD genes have been isolated from mouse (SCD1, 2, 3, and 4). Although the basic biochemical role of SCD has been known in rats and mice since the 1970s. (Jeffcoat, R et al, Elsevier Science (1984), Vol.4, page 85-112, Antueno, RJ, Lipids (1993), Vol.28, No. 4, pp. 285-290), Only recently has been directly involved in human disease processes. A single SCD gene, SCD1, has been characterized in humans. SCD1 is described in Brownle et al., Published PCT Patent Application, WO 01/62954, the disclosure of which is incorporated herein by reference in its entirety. A second human SCD isoform has been recently identified, and because it has little sequence homology with the alternating rat or mouse isoforms. SCD5 or hSCD5 have been mentioned (published PCT patent application, WO 02/26944, incorporated herein by reference in its entirety). To date, non-small molecules, drug-like compounds that specifically inhibit or modulate SCD activity, are known. Historically, certain long chain hydrocarbons have been used to study the activity of SCD. The known examples include a fatty acids, cyclopropenoid fatty acids, and certain conjugated linoleic acid isomers. Specifically, it is believed that cis-12 linoleic acid, trans-10 conjugates inhibit the enzymatic activity of SCD and reduces the abundance of SCD1 mRNA while linoleic acid cis-9, trans-11 conjugated does not. Fatty acids of cyclopropenoids, such as those found in cotton and esterulate seeds, are also known to inhibit SCD activity. For example, acid (8- (2-octylcyclopropenyl) octanoic acid) stearic acid and 7- (2-octylcyclopropenyl) heptanoic acid) malvalic acid) are 16 and 18 carbon atoms derivatives of esterculoyl and malvaloyl fatty acids, respectively , which have cyclopropene rings in their C9-C10 position. It is believed that these agents inhibit the enzymatic activity of SCD by direct interaction with the enzyme, thus inhibiting delta-9 desaturation. Other agents that can inhibit SCD activity include thia-fatty acids, such as 9-thiostearic acid (also called 8-nonthioioctanoic acid) and other fatty acids with a sulfoxy moiety. These known modulators of delta-9 desaturase activity are not useful for treating diseases and disorders linked to the biological activity of SCD1. None of the known SCD inhibitor compounds are selective for SCD or delta-9-desaturases, when they also inhibit other desaturases and enzymes. Thia-fatty acids, conjugated linoleic acids and cyclopropene fatty acids (malvonic and sterulic acid) are neither useful at reasonable physiological doses, nor are they specific inhibitors of the biological activity of SCD1, on the contrary they show cross inhibition of other desaturases, in particular delta-5 and delta-6 desaturases by means of the fatty acids of cyclopropene. The absence of small molecule inhibitors of SCD enzymatic activity is an important medical and scientific disappointment because the evidence is now mandatory that the SCD activity is directly involved in the process of common human diseases. See, for example, Attie A. D. et al., "Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia", J. Lipid Res. (2002), Vol. 43, No. 1 1, p. 1899-907; Cohen, P. et al., "Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss", Science (2002), Vol. 297, No. 5579, p. 240-3, Ntambi, J. M. et al., "Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity", Proc. Nati Acad. Sci. U.S.A. (2002), Vol. 99, No. 7, p. 1 1482-6. The present invention solves this problem by introducing new classes of compounds that are useful in the modulation of SCD activity and the regulation of lipid levels, especially plasma lipid levels, and which are useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, especially diseases related to high lipid levels, cardiovascular diseases, diabetes, obesity, metabolic syndrome and the like.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate stearoyl-CoA desaturase activity and pharmaceutical compositions comprising said derivatives are also encompassed. Accordingly, in one aspect, the invention provides compounds of Formula (I): wherein x and y are each independently 0, 1, 2 or 3; G is -N (R4) -, - O-, -S (O) - (where t is 0, 1 or 2), -C (R4) = o - C (R4) = C (R4); J and K are each independently N or C (R10); L and M are each independently -N =, -N (R4) - 'or -N (R4) =, provided that when G is -C (R4) = or -C (R4) = C (R4) -, L and M can not be both -C (R4) =; W is a direct bond, -N (R1) C (0) N (R1) -, -OC (0) N (R1) -, - N (R1) C (O) N (R1) -, -O-, -N (R1) -, -S (0) t- (where t is 0, 1, or 2), -N (R1) S (O) p- (where p is 1 or 2). -S (0) pN (R1) - (where p is 1 or 2), -C (O) -, -OS (0) 2N (R1) -, -OC (O) -, -C (0) 0 - oN (R) C (0) 0-, each R1 is independently selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms and aralkyl of 7 to 19 carbon atoms; R2 is selected from the group consisting of alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 carbon atoms, alkoxyalkyl of 2 to 12 atoms carbon, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 19 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms, and heteroarylalkyl of 2 to 12 carbon atoms; or R2 is a multianular structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings can be fused together; R3 is selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl from 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 19 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms and heteroarylalkyl of 3 to 12 carbon atoms; or R3 is a multianular structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings can be fused together; each R4 is independently selected from hydrogen, fluorine, chlorine, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, haloalkyl, cyano, nitro or -N (R9) 2; or two adjacent R4 groups, together with the carbon to which they are attached, can form an aryl, heteroaryl or heterocyclyl ring system; R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R5 and R5a together, R6 and R6a together, or R7 and R7a together, or R8 and R8a together are an oxo group; or one of R5, R5a, R6 and R6a together with one of R7, R7a, R8 and R8a form a direct bond or an alkylene bridge, while the remaining R5, R5a, R6, R6a, R7, R7a, R8, and R8a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; each R9 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R10 is independently selected from hydrogen, fluorine, chlorine, alkyl of 1 to 12 carbon atoms or alkoxy of 1 to 12 carbon atoms. a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition of the same or a prodrug thereof. It is understood that the scope of the invention in relation to the compounds of Formula (I) described above is not intended to encompass compounds specifically described and / or claimed in previous publications, including, but not limited to, the compounds specifically described in the following publications: Patent Application Published by PCT, WO 03/076400 Patent Application Published by PCT, WO 03/066604; Patent Application Published by PCT, WO 01/019822; Patent Application Published by PCT, WO 99/021834; Patent Application Published by PCT, WO 99/020606; Patent Application Published by PCT, WO 98/001446; Patent Application Published by PCT, WO 94/012495; European Published Patent Application, 0 300 526; European Published Patent Application, 0 156 433; European Published Patent Application, 0 055 583; European Published Patent Application, 0 009 655, U.S. Pat. No. 5,719,154; Y U.S. Patent No. 5,494,908. In another aspect, the invention provides methods of treating a disease or condition mediated by SCD in a mammal, preferably a human, wherein the methods comprise administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention as set forth previously. In another aspect, the invention provides compounds or pharmaceutical compositions useful in the treatment, prevention and / or diagnosis of a disease or condition related to the biological activity of SCD such as diseases encompassed by cardiovascular disorders and / or metabolic syndrome (including dyslipidemia). , insulin resistance and obesity). In another aspect, the invention provides methods of preventing or treating a disease or condition related to elevated lipid levels, such as plasma lipid levels, especially triglycerides or high cholesterol levels, in patients affected with such high levels, which comprise administering to said patient a therapeutically and prophylactically effective amount of a composition as described herein. The present invention also concerns new compounds having therapeutic effectiveness for reducing levels of lipids in an animal, especially triglyceride and cholesterol levels. In another aspect, the invention provides pharmaceutical compositions comprising the compounds of the invention as discussed above, and pharmaceutically acceptable excipients. In one embodiment, the present invention concerns a pharmaceutical composition comprising a compound of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate the level of triglycerides, or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when an animal is preferably administered to a mammal, more preferably to a human patient. In one embodiment of said composition, the patient has a high plasma level of lipids, such as triglycerides or high cholesterol, before administration of said compound and said compound is present in an amount effective to reduce said level of lipids. In another aspect, the invention provides methods for treating a patient to, or protecting a patient from developing, a disease or condition mediated by stearoyl-CoA desaturase (SCD), said methods comprising administering to a patient afflicted with said disease or condition , or at risk of developing said disease or condition, a therapeutically effective amount of a compound that inhibits SCD activity in a patient when administered. In another aspect, the invention provides methods for treating a range of diseases involving lipid metabolism using compounds identified by the methods described herein. Accordingly, a range of compounds having said activity, based on a screening test, are described herein. to identify, from a library of test compounds, a therapeutic agent that modulates the biological activity of said SCD and is useful in the treatment of a disorder or human condition related to serum levels of lipids, such as triglycerides, VLDL, HDL, LDL, and / or total cholesterol.

DETAILED DESCRIPTION OF THE INVENTION Definitions Certain chemical groups mentioned herein are preceded by an abbreviated notation indicating the total number of carbon atoms found in the indicated chemical group. For example: C7-C2-alkyl describes an alkyl group, as defined above, having a total of 7 to 12 carbon atoms, and C4-C12-cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the abbreviated notation does not include the carbons that may exist in substituents of the described group. Accordingly, as used in the specification and appended claims, unless otherwise specified, the following terms have the indicated meaning: "Methoxy" refers to the radical -OCH3. "Ciano" refers to the radical -CN. "Nitro" refers to the radical -NO2.

"Trifluoromethoxy", refers to the radical -CF3. "Oxo" refers to the substituent = 0. "Tioxo", refers to the substituent = S. "Alkyl" refers to a straight or branched chain hydrocarbon radical consisting solely of carbon and hydrogen atoms, not containing unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1, 1- dimethylethyl (t-butyl), and the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloaqyl, heterocyclyl, heteroaryl, -OR 4 , -OC (0) -R14, -N (R1) 2, -C (0) R14, -C (0) OR14, -C (0) N (R14) 2, -N (R14) C (O) OR16, -N (R14) C (O) R16, -N (R14) (S (0) tR16) (where t is 1 to 2), -S (0) OR16 (where t is 1 or 2), - S (0) tR16 (where t is 0 to 2), and -S (0), N (R1) 2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more groups selected from halo or haloalkyl), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and wherein each of the above substituents is unsubstituted unless otherwise indicated way. "Alkyl of 1 to 3 carbon atoms" refers to an alkyl radical as defined above containing one to three carbon atoms. The alkyl radical of 1 to 3 carbon atoms may be optionally substituted as defined for an alkyl group. "Alkyl of 1 to 6 carbon atoms" refers to an alkyl radical as defined above containing one to six carbon atoms. The alkyl radical of 1 to 6 carbon atoms can be optionally substituted as defined for an alkyl group. "Alkyl of 1 to 12 carbon atoms" refers to an alkyl radical as defined above containing one to twelve carbon atoms. The alkyl radical of 1 to 12 carbon atoms may be optionally substituted as defined for an alkyl group. "Alkyl of 2 to 6 carbon atoms" refers to an alkyl radical as defined above containing two to six carbon atoms. The alkyl radical of 2 to 6 carbon atoms may be optionally substituted as defined for an alkyl group. "Alkyl of 3 to 6 carbon atoms" refers to an alkyl radical as defined above containing three to six carbon atoms. The alkyl radical of 1 to 6 carbon atoms can be optionally substituted as defined for an alkyl group. "Alkyl of 3 to 12 carbon atoms" refers to an alkyl radical as defined above containing three to twelve carbon atoms. carbon. The alkyl radical of 3 to 12 carbon atoms may be optionally substituted as defined for an alkyl group. "Alkyl of 6 to 12 carbon atoms" refers to an alkyl radical as defined above containing six to twelve carbon atoms. The alkyl radical of 6 to 12 carbon atoms may be optionally substituted as defined for an alkyl group. "Alkyl of 7 to 12 carbon atoms" refers to an alkyl radical as defined above containing seven to twelve carbon atoms. The alkyl radical of 7 to 12 carbon atoms may be optionally substituted as defined for an alkyl group. "Alkenyl" refers to a straight or branched chain hydrocarbon radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms, carbon and which is attached to the rest of the molecule by a single bond, for example, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like . Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl , heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR14, -OC (0) -R14, -N (R14) 2, -C (0) R14, -C (O) OR14, -C (O) N (R4) 2 , -N (R14) C (O) OR16, -N (R14) C (O) R16, -N (R14) (S (O) tR16) (where t is 1 to 2), -S (0) OR16 (where t is 1 to 2), -S (0), R16 (where t is 0 to 2), and -S (O) tN (R14) 2 (where t is 1 to 2) wherein each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and wherein each of the above substituents is unsubstituted. "Alkenyl of 3 to 12 carbon atoms" refers to an alkenyl radical as defined above containing three to twelve carbon atoms. The alkenyl radical of 3 to 12 carbon atoms may be optionally substituted as defined for the alkenyl group. "Alkenyl of 2 to 12 carbon atoms" refers to an alkenyl radical as defined above containing two to twelve carbon atoms. The alkenyl radical of 2 to 12 carbon atoms may be optionally substituted as defined for the alkenyl group. "Alkylene" and "alkylene chain" refers to a branched or straight chain divalent hydrocarbon that binds the rest of the molecule to a radical group, which consists only of carbon and hydrogen, which does not contain unsaturation and which has from one to eleven carbon atoms, preferably having from one to eight carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain may be attached to the rest of the molecule and to the radical group through a carbon in the chain or through any of two carbons in the chain. The alkylene chain can be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, OR14, -OC (O) -R14, -N (R14) 2, -C (O) R14, -C ( 0) OR14, -C (0) N (R14) 2, -N (R14) C (0) OR16, -N (R14) C (0) R16, -N (R14) (S (0) tR16) ( where t is 1 to 2), -S (O) OR16 (where t is 1 or 2), -S (0) tR16 (where t is 0 to 2), and -S (0) tN (R14) 2 ( where t is 1 to 2) wherein each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more groups selected from halo or haloalkyl), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and wherein each of the above substituents is unsubstituted unless otherwise indicated. "Alkenylene" and "alkenylene chain" refers to a branched or straight chain divalent hydrocarbon which binds the rest of the molecule to a radical group, consisting only of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, for example, ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is fixed to the rest of the molecule through a single bond and to the radical group through a double bond. The fixation points of the alkenylene chain to the rest of the molecule and to the radical group may be through a carbon or of any two carbons in the chain. The alkenylene chain may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, OR14, -OC (O) -R14, -N (R14) 2, -C (0) R14, -C (O) OR14, -C (O) N (R1) 2, -N (R1) C (0) OR16, -N (R14) C (0) R16, -N (R14) (S (0) tR16) (where t is 1 to 2), -S (O) OR16 ( where t is 1 or 2), -S (O) tR16 (where t is 0 to 2), and -S (O) tN (R14) 2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl , haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more groups selected from halo or haloalkyl), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and wherein each of the above substituents is unsubstituted unless otherwise indicated. "Alkylene bridge" refers to a straight or branched divalent hydrocarbon bridge joining two different carbons of the same ring structure, consisting only of carbon and hydrogen, which does not contain unsaturation and has from one to twelve carbon atoms, which it preferably has one to eight carbons, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene bridge can join any two carbons in the ring structure. "Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above. The alkyl part of the alkoxy radical can be optionally substituted as defined above for an alkyl radical. "Alkoxy of 1 to 6 carbon atoms" refers to an alkoxy radical as defined above it contains one to six carbon atoms. The alkyl part of the alkoxy radical of 1 to 6 carbon atoms may be optionally substituted as defined above for an alkyl group. "Alkoxy of 1 to 12 carbon atoms" refers to an alkoxy radical as defined above containing one to twelve carbon atoms. The alkyl part of the alkoxy radical of 1 to 12 carbon atoms may be optionally substituted as defined above for an alkyl group. "Alkoxy of 3 to 12 carbon atoms" refers to an alkoxy radical as defined above containing three to twelve carbon atoms. The alkyl part of the alkoxy radical of 3 to 12 carbon atoms may be optionally substituted as defined above for an alkyl group. "Alkoxyalkyl" refers to a radical of the formula -Ra-O-Ra wherein each Ra is independently an alkyl radical as defined above. The oxygen atom can be bonded to any carbon in one or more alkyl radical. Each alkyl part of the alkoxyalkyl radical may be optionally substituted as defined above for an "Alkoxyalkyl group of 2 to 12 carbon atoms", refers to an alkoxyalkyl radical as defined above containing two to twelve carbon atoms. Each alkyl part of the alkoxyalkyl radical of 2 to 12 carbon atoms can be optionally substituted as defined previously for an alkyl group. "Alkoxyalkyl of 3 carbon atoms" refers to an alkoxyalkyl radical as defined above containing three carbon atoms. Each alkyl part of the alkoxyalkyl radical of 3 carbon atoms may be optionally substituted as defined above for an alkyl group. "Alkoxyalkyl of 3 to 12 carbon atoms" refers to an alkoxyalkyl radical as defined above containing three to twelve carbon atoms. Each alkyl part of the alkoxyalkyl radical of 3 to 12 carbon atoms may be optionally substituted as defined above for an alkyl group. "Alkylene sulfonyl" refers to a radical of the formula -S (0) 2Ra where Ra is an alkyl group as defined above. The alkyl part of the alkylsulfonyl radical can be optionally substituted as defined above for an alkyl group. "Alkylsulfonyl of 1 to 6 carbon atoms", refers to an alkylsulfonyl radical as defined above having one to six carbon atoms. The alkylsulfonyl group of 1 to 6 carbon atoms may be optionally substituted as defined above for an alkylsulfonyl group. "Aryl" refers to the aromatic monocyclic or multicyclic hydrocarbon ring system consisting solely of hydrogen and carbon and containing from 6 to 19 carbon atoms, preferably from 6 to 10 carbon atoms. carbon, where the ring system can be partially or totally saturated. Aryl groups include, but are not limited to, groups such as fluorenyl, phenyl, and naphthyl. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as an "aralkyl") means that it includes aryl radicals optionally substituted by one or more substituents selected from the group consisting of of: alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R15-OR14, -R15-OC (O) -R14, -R15- N (R14) 2, -R15-C (O) R14, -R15-C (O) 0R14, -R 5-C (0) N (R) 2, -R15-N (R4) C (0) OR16, -R 5 -N (R1) C (O) R16, -R15-N (R1) (S (O) tR16) (where t is 1 to 2), -R15-S (0) OR16 (where t is 1 or 2), -R 5-S (0) tR16 (where t is 0 to 2), and -R15-S (O) tN (R 4) 2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R15 is independently a straight or a straight or branched alkylene or alkenylene chain; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and wherein each of the above substituents is unsubstituted. "Aralkyl" refers to a radical of the formula -RaRb where Ra is an alkyl radical as defined above and Rb is one or more aryl radicals as defined above, for example benzyl, diphenylmethyl and the like. The aryl part of the aralkyl radical can be optionally substituted as described above for an aryl group. The alkyl part of the aralkyl radical can be optionally substituted as defined for the alkyl group. "Aralkyl of 7 to 12 carbon atoms" refers to an aralkyl group as defined above containing seven to twelve carbon atoms. The aryl part of the aralkyl radical of 7 to 12 carbon atoms can optionally be substituted as described above for an aryl group. The alkyl part of the aralkyl radical of 7 to 12 carbon atoms may be optionally substituted as defined above for an alkyl group. "Aralkyl of 7 to 19 carbon atoms" refers to an aralkyl group as defined above containing seven to ten and nine carbon atoms. The aryl part of the aralkyl radical of 7 to 19 carbon atoms can optionally be substituted as described above for an aryl group. The alkyl part of the aralkyl radical of 7 to 19 carbon atoms may be optionally substituted as defined above for an alkyl group. "Aralkyl of 13 to 19 carbon atoms" refers to an aralkyl group as defined above containing thirteen to ten and nine carbon atoms. The aryl part of the aralkyl radical of 13 to 19 carbon atoms can optionally be substituted as described above for an aryl group. The alkyl part of the aralkyl radical of 13 to 19 carbon atoms may be optionally substituted as defined above for an alkyl group. "Aralkenyl" refers to a radical of formula -RcRb where Rc is an alkenyl radical as defined above and Rb is one or more aryl radicals as defined above, which may be optionally substituted as described above. The aryl part of the aralkenyl radical may be optionally substituted as described above for an aryl group. The alkenyl part of the aralkenyl radical may be optionally substituted as defined above for an alkenyl group. "Aryloxy" refers to a radical of the formula -ORb where Rb is an aryl group defined above. The aryl part of the aryloxy radical can be optionally substituted as defined above. "Aryl-alkyl of 1 to 6 carbon atoms, refers to the formula -Rh-R, where Rh is an unbranched alkyl radical having one to six carbons and R, is an aryl group attached to the terminal carbon of the alkyl radical. "Cycloalkyl" refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, preferably having from three to twelve carbon atoms, and which is saturated or unsaturated and is attached to the rest of the molecule by a single bond, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Unless specifically stated otherwise in the specification, the term "cycloalkyl" includes cycloalkyl radicals which are optionally substituted by one or more substituents selected from the group consisting of: alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R15-OR14, - R 5-OC (0) -R 14, -R 15 -N (R 14) 2, -R 15 -C (O) R 14, -R 15 -C (O) OR 14, -R 15 -C (0) N (R 14) 2, -R15-N (R14) C (0) OR16, -R15-N (R14) C (O) R16, -R15-N (R14) (S (0) tR16) (where t is 1 to 2), - R 5-S (0) OR16 (where t is 1 or 2), -R15-S (O) tR16 (where t is 0 to 2), and -R15-S (0) tN (R14) 2 (where t is 1 to 2) wherein each R 4 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and wherein each of the above substituents is unsubstituted. "Cycloalkyl of 3 to 6 carbon atoms" refers to a cycloalkyl radical as defined above having three to six carbon atoms. The cycloalkyl radical of 3 to 6 carbon atoms may be optionally substituted as defined above by a cycloalkyl group. "Cycloalkyl of 3 to 12 carbon atoms" refers to a cycloalkyl radical as defined above having three to twelve carbon atoms. The cycloalkyl radical of 3 to 12 carbon atoms can to be optionally substituted as defined above by a cycloalkyl group. "Cycloalkylalkyl" refers to a radical of the formula -RaRd, where Ra is an alkyl radical as defined above and Rd is a cycloalkyl radical as defined above. The cycloalkyl part of the cycloalkyl radical can be optionally substituted as defined above by a cycloalkyl radical. The alkyl part of the cycloalkyl radical can be optionally substituted as defined above by an alkyl radical. "Cycloalkylalkyl of 4 to 12 carbon atoms" refers to a cycloalkylalkyl radical as defined above having four to twelve carbon atoms. The cycloalkylalkyl radical of 4 to 12 carbon atoms may be optionally substituted as defined above by a cycloalkylalkyl group. "Halo" refers to bromine, chlorine, fluorine or iodine. "Haloalkyl", refers to an alkyl radical, as defined above, which is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1- fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl part of the haloalkyl radical may be optionally substituted as defined above by an alkyl group. "Haloalkenyl" refers to an alkenyl radical, defined and defined above, which is substituted by one or more halo radicals, as defined above, for example, 2-bromoethenyl, 3-bromoprop-1-enyl, and the like. The alkenyl part of the haloalkenyl radical can optionally be substituted as defined for an alkyl group. "Heterocyclyl" refers to a non-aromatic ring radical of 3 to 18 stable elements consisting of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which may include bridged or fused ring systems; and the nitrogen atoms. carbon, sulfur in the heterocyclyl radical can optionally be oxidized; the nitrogen atom can optionally be quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of said heterocyclyl radicals include, but we are limited to dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl , tetrahydrofuryl, trityanil, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless the specification is specifically stated otherwise, the term "heterocyclyl" includes heterocyclyl radicals as defined above which may optionally be substituted by one or more substituents selected from the group consisting of: alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R15-OR14, -R15-OC (O) -R14, -R15-N ( R14) 2, -R15-C (0) R14, -R15-C (0) OR14, -R15-C (0) N (R14) 2, -R15-N (R14) C (0) OR16, -R15 -N (R 4) C (0) R 16, -R 15 -N (R 14) (S (O) t R 16) (where t is 1 to 2), -R 15-S (0) OR 16 (where t is 1 or 2) ), -R15-S (O) tR16 (where t is 0 to 2), and -R15-S (O) tN (R14) 2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl, alkenyl , haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R15 is independently a straight or a straight or branched alkylene or alkenylene chain; and each R16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and wherein each of the above substituents is unsubstituted. "Heterocyclyl of 3 to 12 carbon atoms" refers to a heterocyclyl radical as defined above having three to twelve carbon atoms. Heterocyclyl of 3 to 12 carbon atoms may be optionally substituted as defined above by a heterocyclyl group. "Heterocyclylalkyl" refers to a radical of the formula -RaRe where Ra is an alkyl radical as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a heterocyclyl containing nitrogen, the heterocyclyl may be fixed to the alkyl radical at the nitrogen atom. The alkyl part of the heterocyclylalkyl radical it may be optionally substituted as defined above for an alkyl group. The heterocyclyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for a heterocyclyl group. "Heterocyclylalkyl of 3 to 12 carbon atoms" refers to a heterocyclylalkyl radical as defined above having three to twelve carbons. The heterocyclylalkyl radical of 3 to 12 carbon atoms may be optionally substituted as defined above for a heterocyclylalkyl group. "Heteroaryl" refers to an aromatic ring radical of 5 to 13 elements consisting of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include bridged or fused ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom may optionally be quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzolyl, benzothiadiazolyl, benzonaphtofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranolyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo [4,6 ] imidazo [1,2-a] pyridinyl, carbazolyl, cinolyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazapiryl, oxazolyl, oxiolyl, phenyazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinocyclidinyl, isoquinolinylthiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. Unless specifically stated otherwise in the specification, the term "heteroaryl" includes heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of: alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R15-OR14, -R15-OC (0) -R14, -R15 -N (R 4) 2, -R 15 -C (0) R 14, -R 5-C (0) OR 14, -R 15 -C (0) N (R 14) 2, -R 15 -N (R 14) C (0 ) OR16, -R 5 -N (R14) C (0) R16, -R15-N (R4) (S (0) tR16) (where t is 1 to 2), -R 5-S (O) OR16 (where t is 1 or 2), -R15-S (O) tR16 (where t is 0 to 2), and -R15-S (O), N (R14) 2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R15 is independently a straight or a straight or branched alkylene or alkenylene chain; and each R16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and wherein each of the above substituents is unsubstituted. "Heteroaryl of 1 to 12 carbon atoms", refers to a radical heteroaryl as defined above having one to twelve carbon atoms. The heteroaryl group of 1 to 12 carbon atoms may be optionally substituted as defined above for a heteroaryl group. "Heteroaryl of 5 to 12 carbon atoms" refers to a heteroaryl radical as defined above having five to twelve carbon atoms. The heteroaryl group of 5 to 12 carbon atoms can be optionally substituted as defined above for a heteroaryl group. "Heteroarylalkyl" refers to a radical of the formula -Ra-Rr where Ra is an alkyl radical as defined above. The heteroaryl part of the heteroarylalkyl radical can be optionally substituted as defined above by a heteroaryl group. The alkyl part of the radial heteroarylalkyl may be optionally substituted as defined above by an alkyl group. "Heteroarylalkyl of 3 to 12 carbon atoms" refers to a heteroarylalkyl radical as defined above having three to twelve carbon atoms. The heteroarylalkyl group of 3 to 12 carbon atoms may be optionally substituted as defined above for a heteroarylalkyl group. "Heteroarylcycloalkyl" refers to a radical of the formula -Rb-Rf where Rb is a cycloalkyl radical as defined above and Rf is a heteroaryl radical as defined above. The cycloalkyl part of The radical heteroarylcycloalkyl may be optionally substituted as defined above for a cycloalkyl group. The heteroaryl part of the heteroarylcycloalkyl radical can be optionally substituted as defined above for a heteroaryl group. "heteroarylalkenyl" refers to a radical of the formula -RbRf where Rb is an alkenyl radical as defined above and Rf is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkenyl radical can be optionally substituted as defined above by a heteroaryl group. The alkenyl part of the heteroarylalkenyl radical may be optionally substituted as defined above for an alkenyl group. "Hydroxyalkyl" refers to a radical of the formula -Ra-OH where Ra is an alkyl radical as defined above. The hydroxy group can be attached to the alkyl radical on any carbon in the alkyl radical. The alkyl part of the hydroxyalkyl group may be optionally substituted as defined above for an alkyl group. "Hydroxyalkyl of 2 to 12 carbon atoms" refers to a hydroxyalkyl radical as defined above containing two to twelve carbon atoms. The alkyl part of the hydroxyalkyl radical of 2 to 12 carbon atoms may be optionally substituted as defined above for an alkyl group. "Hydroxyalkyl of 3 to 12 carbon atoms" refers to a hydroxyalkyl radical as defined above containing three to twelve carbon atoms. The alkyl part of the hydroxyalkyl radical of 3 to 12 carbon atoms may be optionally substituted as defined above for an alkyl group. "Hydroxyalkyl of 7 to 12 carbon atoms" refers to a hydroxyalkyl radical as defined above containing seven to twelve carbon atoms. The alkyl part of the hydroxyalkyl radical of 7 to 12 carbon atoms may be optionally substituted as defined above for an alkyl group. "Hydroxyalkenyl" refers to a radical of the formula -Rc-OH where Rc is an alkenyl radical as defined above. The hydroxy group can be attached to the alkenyl radical on any carbon in the alkenyl radical. The alkenyl part of the hydroxyalkenyl group may be optionally substituted as defined above by an alkenyl group. "Hydroxyalkenyl of 2 to 12 carbon atoms", refers to a hydroxyalkenyl radical as defined above containing two to twelve carbon atoms. The alkenyl part of the hydroxyalkenyl radical of 2 to 12 carbon atoms may be optionally substituted as defined above for an alkenyl group. "Hydroxyalkenyl of 3 to 12 carbon atoms", refers to a hydroxyalkenyl radical as defined above containing three to twelve carbon atoms. The alkenyl part of the hydroxyalkenyl radical of 3 to 12 carbon atoms may be optionally substituted as defined previously for an alkenyl group. "Hydroxy-alkyl of 1 to 6 carbon atoms", refers to a radical of the formula -Rh-OH where Rh is an unbranched alkyl radical having one to six carbon atoms and the hydroxy radical is attached to the terminal carbon . "Trihaloalkyl" refers to an alkyl radical as defined above, which is substituted by three halo radicals, as defined above, for example, trifluoromethyl. The alkyl part of the trihaloalkyl radical can be optionally substituted as defined above for an alkyl group. "Trihaloalkyl of 1 to 3 carbon atoms" refers to a trihaloalkyl radical as defined above having one to six carbon atoms. The trihaloalkyl of 1 to 6 carbon atoms may be optionally substituted as defined above for a trihaloalkyl group. "Trihaloalkoxy" refers to a radical of the formula -ORg where Rg is a trihaloalkyl group as defined above. The trihaloalkyl part of the trihaloalkoxy group can be optionally substituted as defined above for a trihaloalkyl group. "Trihaloalkoxy of 1 to 6 carbon atoms" refers to a trihaloalkoxy radical as defined above having one to six carbon atoms. The trihaloalkoxy group of one to six carbon atoms can be optionally substituted as defined above for a trihaloalkoxy group. "A multi-ring structure" refers to a multicyclic ring system comprising two to four rings wherein the rings are independently selected from cycloalkyl, aryl, heterocyclyl, or heteroaryl as defined above. Each cycloalkyl may be optionally substituted as defined above for a cycloalkyl group. Each aryl may be optionally substituted as defined above by an aryl group. Each heterocyclyl can be optionally substituted as defined above for a heterocyclyl group. Each heterocyclyl can be optionally substituted as defined above for a heteroaryl group. The rings can be fixed to another through direct links or some or all of the rings can be fused together. Examples include, but are not limited to a cycloalkyl radical substituted by aryl group; a cycloalkyl group substituted by an aryl group, which, in turn, is replaced by another aryl group; and so on. "Prodrug" means a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted live to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to produce the precursor compound of the invention, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems." ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, Amsterdam Pharmaceutical Association and Program Press, 1987, both of which are incorporated herein by reference in their entirety.The term "prodrug" also includes any covalently linked carrier, which releases the active compound of the invention in vivo when said prodrug is administered to a mammalian subject Prodrugs of a compound of the invention can be prepared by modifying functional groups present in the compound of the invention in a manner that modifies them tions are fragmented, either in routine or in vivo manipulations, in the precursor compound of the invention. Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is linked to any group which, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or mercapto group free, respectively. Examples of prodrugs include, but they are not limited to acetate, formate and benzoate derived from alcohol or amino functional groups in the compounds of the invention and the like. "Stable compound" and "stable structure" indicate a compound that is sufficiently robust to survive isolation into a useful degree of purity from a reaction mixture, and formulation into an efficient therapeutic agent. "Mammal" includes domestic and human animals, such as cats, dogs, pigs, calves, sheep, goats, horses, rabbits, and the like. "Optional" or "optionally" means that the event of circumstances described subsequently may or may not occur, and that the description includes instances where said event or circumstances does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both aryl radicals and substituted aryl radicals that do not have substitution. "Pharmaceutically acceptable carriers, diluents or excipients" include without limitation any adjuvant, carrier, excipient, glidant, diluent, preservative, sweetening / coloring agent, flavor improver, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent , solvent or emulsifier, which have been approved by the United States Food and Drugs Administration as being acceptable for use in humans or pets.

"Pharmaceutically acceptable salt" includes both base addition salts and acid addition salts. "Pharmaceutically acceptable acid addition salt" refers to those salts that retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, and hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, acid aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulphonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethanoic acid, 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethane sulfonic acid, formic acid, fumaric acid, galactárico acid, acid gen consumptive, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyral acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid , malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-sulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, oratic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebasic acid, acid stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like. "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary amines, secondary, and tertiary, substituted amines including substituted amines as found naturally, cyclic amines and basic ion exchange resins, such as ammonia resins, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylethylaminoethanol , 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine and the similar ones. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. Often the crystallization produces a solvate of the compound of the invention. As used herein, the term "solvate" refers to a binder comprising one or more molecules of a compound of the invention with one or more solvent molecules. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compounds of the present invention can exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compound of the invention can be true solvates, while in other cases, the compound of the invention can merely retain adventitial water or be a mixture of water plus some adventitious solvent. A "pharmaceutical composition" refers to a formulation of a compound of the invention and a means generally accepted in the art for the release of the biologically active compound in mammals, e.g., humans. Such means include all carriers, diluents or excipients thereof pharmaceutically acceptable. "Therapeutically effective amount" refers to the amount of a compound of the invention which, when administered to a mammal preferably to a human, is sufficient to effect the treatment, as defined below, of a disease or condition mediated by SCD in the mammal, preferably a human. The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition, and the severity, and the age of the mammal to be treated, but can be routinely determined by an art expert who has respect for his own knowledge and description. "Treat" or "treatment" as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or disorder of interest, and includes: (i) preventing the disease or condition takes place in a mammal, in particular, when said mammal is predisposed to the condition but has not yet been diagnosed to have it; (ii) inhibit the disease or condition, that is, stop its development; or (ii) alleviate the disease or condition, that is, cause the regression of the disease or condition. As used herein, the terms "disease" and "condition" can be used interchangeably or they can be different in that the particular disease or condition can not have a known causative agent (so that the etiology has not yet been elaborated) and therefore is not yet recognized as a disease but only as an undesirable condition or syndrome, in which a more or less specific group of symptoms have been identified clinically. The compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms which can be defined, in terms of absolute stereochemistry, as (R) - or (S) - or, as (D) - or (L) - for amino acids. The present invention includes all possible isomers, as well as their racemic and optically pure forms. The (+) and (-), (R) -y (S) -, or (D) - and (L) -optically active isomers can be prepared using syntheses or chiral reagents, or can be solved using conventional techniques, such as HPLC using a chiral column. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is provided that the compounds include both geometric isomers E and Z. Similarly, it is also intended that they be included all tautomeric forms. A "stereoisomer" refers to a compound made up of identical atoms linked by identical bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and include "enantiomers", which refer to two stereoisomers whose molecules are mirror images not overlapping each other. A "tautomer" refers to a proton deviated from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of said compounds. The naming protocol and chemical structure diagrams used in the present employ and depend on the chemical naming characteristics as used by Chemdraw version 7.0.1. (available from Cambridgesoft Corp., Cambridge, MA). For the complex chemical names used herein, a substituent group is mentioned before the group to which it is attached. For example, cyclopropylethyl comprises an ethyl backbone with cyclopropyl substituent. In chemical structure diagrams, all the bonds are identified, except for some carbon atoms that are supposed to be linked to sufficient hydrogen atoms to complete the valence, For example, a compound of Formula (I) where x and y are both 1 : G is -C (H) = C (H) -; J and K are both N; L and M are both -N =, W is -N (H) C (O) -; R2 is 2-cyclopropylethyl and R3 is 5-trifluoromethylpyridin-2-yl, that is, a compound of the following formula: is referred to herein as 6- [4- (3-trifluoromethylpyridin-2-yl) piperazin-1-yl], pyridazin-3-carboxylic acid (2-cyclopropylethyl) amide. Certain radical groups of the compounds of the invention are disclosed herein as ligatures between two parts of the compounds of the invention. For example, in Formula (I) below: W, is described, for example, as being -N (R) C (O) -, - C (0) N (R1) -, or -N (R1) C (0) N (R1) -. This description means that it describes a group W fixed to the group R2 as follows: R2-N (R1) C (0) -, R2-C (0) N (R1) -, or R2-N (R1) C ( 0) N (R1) -. In other words, the description of the binding groups W means that they are read from left to right in view of the Formula (I) as set forth above.

Modes of the invention Of the compounds of Formula (I) described above in the Summary of the Invention, one embodiment is those compounds where J and K are both N, ie, compounds having the following Formula (s): of this modality, one modality are the compounds of Formula (la) where: X and y are each 1; G is -C (R4) = C (R4) -; L and M are both -N =; W is -N (R1) C (0) -, -C (0) N (R1) -; -OC (0) N (R1) -, -N (R) CO) N (R1) -, -N (R) S (O) p- (where p is 1 or 2), -S (0) pN (R1) - (where p is 1 or 2), -OS (O) 2N (R1) -, -C (0) 0- or -N (R1) C (0) O-; Each R1 is independently selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, and aralkyl of 7 to 19 carbon atoms; R2 is selected from the group consisting of alkyl of 7 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, hydroxyalkyl of 7 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 carbon atoms, alkoxyalkyl of 2 to 12 atoms carbon, cycloalkyl of 2 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 13 to 19 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 2 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms, and heteroarylalkyl of 3 to 12 carbon atoms; R3 is selected from the group consisting of aryl, heterocyclyl of 3 to 12 carbon atoms and heteroaryl of 1 to 12 carbon atoms; and each R 4 is independently selected from hydrogen, fluorine, chlorine, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, haloalkyl, cyano, nitro or -N (R 9) 2; R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms. carbon; provided that R2 is not pyrazinylalkyl of 5 to 10 carbon atoms, pyridinonyl, pyrrolidinonyl, methylimidazolyl or phenyl substituted with amino. Of these modalities, one modality is those compounds where R3 is aryl. Modalities specific to this modality include, but are not limited to, compounds selected from the group consisting of: 2- (4- (4-fluorophenyl) -piperazin-1-yl] pyridazin-3-cyclopropylethyl) amide carboxylic; and 6- (4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] pyridazine-3-carboxylic acid (2- cyclopropylethyl) amide. Of these embodiments, another embodiment is those compounds wherein R3 is heteroaryl of 1 to 12 carbon atoms. Specific modalities of this modality include, but are not limited to, compounds selected from the group consisting of: 2- (4-benzoxazol-2-yl-piperazin-1-yl) pyridazin-3-cyclopropylethyl-amide carboxylic; (2-cyclopropylethyl) amide 6- (4-benzothiazol-2-yl-piperazin-1-yl) -pyridazine-3-carboxylic acid; (2-cyclopropylethyl) amide 6- (4-quinazolin-4-yl-piperazin-1-yl) -pyridazine-3-carboxylic acid; (2-cyclopropylethyl) amide 6- [4- (3-trifluoromethylpyridin-2-yl-piperazin-1-yl) -pyridazine-3-carboxylic acid; (2-cyclopropylethyl) amide 6- (4-benzo [d] isothiazol-3-yl-piperazin-1-yl) -pyridazine-3-carboxylic acid; (2-cyclopropylethyl) amide 6- (4-pyridin-2-yl-piperazin-1-yl) -pyridazine-3-carboxylic acid; (2-cyclopropylethyl) amide 6- [4- (3-oxo-3H-isoindol-1-yl] -piperazin-1-yl] -pyridazine-3-carboxylic acid In another embodiment of the invention, the compounds of Formula (I) do not include the following "excluded" compounds, as designated by their Chemical Abstract Registry Nos. ("RN"), as defined by the Chemical Abstract Service of the American Chemical Society (Washington, DC): RN 331242-58 -1; RN 202135-24-8; RN 202135-25-9; RN 202135-26-0; RN 202135-27-1; RN 202135-28-2; RN 202135-36-2; RN 100241-46-; 1; RN 100241-62-1; RN 100224-53-1; RN 100224-54-2; RN 100224-67-7; RN 100241-07-4; RN 100241 -08-5; RN 100241-46-1; RN 100241 -52-9; RN 100241-53-0; 5 RN 100241-54-1: RN 100241 -55-2; RN 83773-90-4; and RN 75842-08-9. In yet another embodiment of the invention, a group of compounds of Formula (I) is directed to compounds where x and y are each 1; J and K are each independently N; G is -C (R4) = C (R4) -; L and M are both - N =; W is direct link; R2 is alkyl of 1 to 6 carbon atoms; R3 is substituted phenyl, with the proviso that R3 is substituted with substituents other than fluorine and substituted oxazolidine. In still another embodiment of the invention, a group of compounds of Formula (I) is directed to compounds where x is 1, 2 or 3 and y is 1; J is N or C (R10) and K is N; G is -C (R4) = C (R4) -; L and M are each independently -N = or -C (R4) =, provided that L and M can not be both -C (R) =; W is -N (R1) C (O) -, -C (0) N (R1) -, or -C (O) -; R3 is selected from alkyl of 1 to 20 12 carbon atoms, aryl, heteroaryl of 1 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings can be fused together; with the proviso that R 2 is different from alkyl of 1 to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms, and aryl-alkyl of 1 to 6 carbon atoms. In yet another embodiment of the invention, a group of compounds of Formula (I) is directed to compounds where G is -N (R4) - or -C (R) =, L is -N (R4) - and M is - N (R4) - or -C (R4) -. Specific embodiments of the embodiments described above of the invention are described herein in the Examples set forth below. In another embodiment of the invention, the methods of the invention are directed towards the treatment and / or mediated prevention of poesaroaroyl-CoA desaturase (SCD), especially human SCD (hSCD), preferably diseases related to dyslipidemia and disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like by administering an effective amount of a compound of the invention. The present invention also concerns the pharmaceutical composition containing the compounds of the invention. In one embodiment, the invention concerns a composition comprising compounds of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate the level of triglycerides or to treat diseases related to dyslipidemia and lipid metabolism disorders, when administered to an animal, preferably a mammal, a human patient is mostly preferred. In one embodiment of said composition, the patient has a high level of lipids, such as triglycerides or high cholesterol, before administration of said compound of the invention and the compound of the invention is present in an effective amount to reduce said level of lipids.

Utility and Tests of the Compounds of the Invention The present invention concerns compounds, pharmaceutical compositions and methods of using them compounds and pharmaceutical compositions for the treatment and / or prevention of diseases mediated by stearoyl-Co-A-desaturase (SCD), especially SCD human (hSCD), preferably diseases related to dyslipidemia and disorders of lipid metabolism, and especially a disease related to the elevated plasma level of lipids, especially cardiovascular disease, diabetes, obesity, metabolic syndrome and the like by administration to a patient in need of said treatment an effective amount of an SCD modulating agent, especially inhibitor. In general, the present invention provides a method for treating a patient for, or protecting a patient from developing, a disease related to dyslipidemia and / or a disorder of lipid metabolism, wherein the lipid levels in an animal, especially a human are outside the normal range (i.e. abnormal lipid level, such as elevated plasma lipid levels), especially higher than normal levels, preferably where said lipid is a fatty acid, such as a complex or free fatty acid, triglycerides , phospholipids, or cholesterol, such as where the LDL-cholesterol levels are high or HDL-cholesterol levels are reduced, or any combination thereof, where said lipid-related condition or disease is a disease or condition mediated by SCD, which comprises administering to an animal, such as a mammal, especially a human patient, a therapeutically effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention wherein the compound modulates the activity of SCD, preferably human SCD1. . The compounds of the invention modulate, preferably inhibit, the activity of human SCD enzymes, especially human SCD1. The general value of the compounds of the invention in modulating, especially inhibiting, SCD activity can be determined using the assay described later in Example 4. Alternatively, the general value of the compounds in treating disorders and diseases can be established in models industry standard animals to demonstrate the efficiency of the products in the treatment of obesity, diabetes or elevated cholesterol and triglyceride levels or to improve glucose tolerance. These models include obese fa / fa rats from Zucker (available from Hadan Sprague Dawley, Inc. (Indianapolis, Indiana)), or the Zucker diabetic fat rat (ZDF / GmiCrt-fa / fa) (available from Charles River Laboratories (Montreal, Quebec)). The compounds of the present invention are inhibitors of delta-9 desaturases and are useful for treating diseases and disorders in humans and other organisms, including all those human diseases and disorders which are the result of aberrant delta-9 desaturase biological activity or which they can be improved by modulating the biological activity of delta-9 desaturase. As defined herein, a disease or condition mediated by SCD includes but is not limited to a disease or condition, which is, or is related to cardiovascular disease, dyslipidemia ((which includes, but is not limited to, disorders of the serum levels of triglycerides, hypertriglyceridemia, VLDL, HDL, LDL, fatty acid desaturation index (eg, the ratio of fatty acids of 18: 1/18: 0, or other fatty acids, as defined elsewhere in present), cholesterol, and total cholesterol, hypercholesterolemia, as well as cholesterol disorders (including disorders characterized by defective reverse cholesterol transport), combined familial hyperlipidemia, coronary artery disease, arteriosclerosis, heart disease, cerebrovascular disease (including but not are limited to stroke, apoplexy with ischemia and transient ischemic attack (TIA), peripheral vascular disease, and ischemic retinopathy In a preferred embodiment, compounds of the invention will increase HDL levels and / or decreasing triglyceride and / or decreasing LDL levels or decreasing HDL or LDL cholesterol levels in a patient. A disease or condition mediated by SCD also includes metabolic syndrome (including but not limited to dyslipidemia, obesity and insulin resistance, hypertension, microalbuminemia, hyperuridicemia, and hypercoagulability, Syndrome X, diabetes, insulin resistance, decreasing glucose tolerance , non-insulin-dependent diabetes mellitus, type II diabetes, type I diabetes, diabetic complications, body weight disorders (including but not limited to obesity, overweight, cachexia and anorexia), weight loss, body mass index and Leptin-related diseases In a preferred embodiment, compounds of the invention will be used to treat diabetes mellitus and obesity As used herein, the term "metabolic syndrome" is a recognized clinical term used to describe a condition comprising combinations of type II diabetes, impaired glucose tolerance, insulin resistance, hypertension, obesity, increased abdominal perimeter, hypertriglyceridemia, low HDL, hyperuricemia, hypercoagulability and / or microalbuminemia. A disease or condition mediated by SCD also includes fatty liver, hepatic steatosis, hepatitis, non-alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis. Fatty liver acute, fatty liver of pregnancy, drug-induced hepatitis, erythropoietic protoporphyria, iron overload disorders, hereditary hemochromalosis, hepatic fibrosis, liver cirrhosis, hepatoma and conditions related to it. A disease or condition mediated by SCD also includes but is not limited to a disease or condition that is, or is related to, primary hypertriglyceridemia or secondary hypertriglyceridemia with another disorder or disease such as hyperlipoproteinemia, familial histiocytic cystic reticulosis, deficiency of lipoprotein lipase, deficiency of apolipoprotein (such as ApoCII deficiency or ApoE deficiency), and the like, or hypertriglyceridemia of unknown or unspecified etiology. A disease or condition mediated by SCD also includes a disorder of polyunsaturated fatty acids (PUFA), or a skin disorder, including but not limited to eczema, acne, psoriasis, formation or prevention of keloid scars, diseases related to the production or secretion of mucous membranes, such as monounsaturated fatty acids, wax esters, and the like. A disease or condition mediated by SCD also includes inflammation, sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, cystic fibrosis, and pre-menstrual syndrome. A disease or condition mediated by SCD also includes but is not limited to a disease or condition that is, or is related to cancer, neoplasia, malignant metastasis, tumors (benign or malignant), carcinogenic, hepatomas and Similar. A disease or condition mediated by SCD also includes a condition where lean body mass or lean muscle mass is desired, as is desirable in the improvement of results through muscle building. Myopathies and lipid myopathies such as carnitine palmitoyl transferase deficiency (CPT I or CPT II) are also included herein. Said treatments are useful in humans and in animal husbandry, including for administration to cattle, pigs or poultry or any other animal to reduce the production of triglycerides and / or to provide leaner meat products and / or healthier animals. A disease or condition mediated by SCD also includes a disease or condition that is, or is related to, neurological diseases, psychiatric disorders, multiple sclerosis, eye diseases, and immune disorders. A disease or condition mediated by SCD also includes a disease or condition that is, or is related to viral diseases or infections including but not limited to all positive-strand RNA viruses, coronaviruses, SARS viruses, coronaviruses associated with SARS, Togavirus, Picomavirus, Coxsackievirus, Yellow Fever Virus, Flaviviridae , ALPHAVIRUS (TOGAVIRIDAE) which includes Rubella virus, Equine encephalitis virus, Eastern, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Sindbis virus, Semliki, Chikungunya virus, O'nyong'nyong virus, Ross river virus, Mayara virus, Alphavirus; ASTROVIRIDAE including Astrovirus, Human Astrovirus; CALICIVIRIDAE including swine vesicular virus virus, Norwalk virus, Calcivirus, bovine calcivirus, porcine Calcivirus, Hepatitis E., CORONAVIRIDAE including Coronavirus, SARS virus, avian infectious bronchitis virus, bovine coronavirus, canine coronavirus, feline infectious peritonitis virus. Human coronavirus 299E, human coronavirus OC43, rodent hepatitis virus, porcine epidermal diarrhea virus, porcine haemagglutinating encephalomyelitis virus, porcine transmissible gastroenteritis virus, rat coronavirus. Turkey coronavirus, rabbit coronavirus, Berne virus, Breda virus, FLAVIVIRIDAE including hepatitis C virus, East Nile virus, Yellow fever virus, St. Louis encephalitis virus, Dengue group, virus of hepatitis G, Japanese B encephalitis virus, Murray Valley encephalitis virus, Central European tick encephalitis virus, Far East tick encephalitis virus, Kyasarur forest virus , Louping's disease virus, Powassan virus, Omsk hemorrhagic fever virus, Kumilinge virus, hypr virus. of Abselarov anzalova, lleus virus, Rocío encephalitis virus, Langat virus, Pestivirus, bovine viral diarrhea, swine cholera virus, Rio Bravo Group, Tyuleníy Group, Naya Group, Uganda S Group, Group of Modoc, PICORNAVIRIDAE which includes Coxsackie virus A., Rhinovirus, hepatitis A virus, encephalomyocarditis virus, Mengovirus, ME virus, human poliovirus 1, Coxsackie B; POTYVIRIDAE that includes Potivirus, Rymovirus, Bymovirus, Bymovirus. Additionally it can be a disease or infection caused by or linked to hepatitis viruses, hepatitis B virus, hepatitis C, human immunodeficiency virus (HIV) and the like. The treatable viral infections include those in which the virus employs an RNA intermediate as part of the replicative cycle (hepatitis or HIV); additionally it may be a disease or infection caused by or linked to negative strand virus in RNA such as influenza or parainfluenza virus. The compounds identified in the present specification inhibit the desaturation of several fatty acids (such as the desaturation of carbons 9 and 10 of stearoyl-CoA) which is achieved by delta-9 desaturases, such as stearoyl-CoA desaturase 1 (SCD1) . As such, these compounds inhibit the formation of various fatty acids and subsequent metabolites thereof. These can lead to an accumulation of stearoyl-CoA or palmitoyl-CoA and other previous precursors of various fatty acids; which may possibly result in a negative feedback loop that causes a total change in the metabolism of fatty acids. Any of these consequences may ultimately be responsible for the overall therapeutic benefit provided by these compounds. Typically, a successful SCD inhibitory therapeutic agent will satisfy any of the following criteria: The oral availability would be approximately 20%. The efficiency of the animal model is less than 2 mg / kg, 1 mg / kg or 0.5 mg / kg and the target human dose is between 50 and 250 mg / 70 kg, although doses in this range may be acceptable ("mg / kg ") means milligrams of compound per kilogram of body mass of the subject to whom it will be administered). The therapeutic index (or ratio of toxic dose to therapeutic dose) would be greater than 100. Potency (as expressed by the IC5o value) would be less than 10 μ ?, preferably less than 1 μ? and more preferably less than 50 nM. The IC5o ("Inhibitory Concentration - 50%) is a measure of the amount of compound required to achieve 50% inhibition of SCD activity, during a specific period of time, in a biological activity assay of SCD. Any process for measuring the activity of SCD enzymes, preferably human or mouse SCD enzymes, can be used to test the activity of the compounds useful in the methods of the invention by inhibiting said SCD activity. The compounds of the invention demonstrate an IC50 in a 15 minute microsomal assay of preferably less than 10 μ ?, less than 5 μ ?, less than 2.5 μ ?, less than 1 μ ?, less than 750 nM, less than 500 nM , less than 250 nM, less than 100 nM, less than 50 nM, and more preferably less than 20 nM. The compound of the invention can show reversible inhibition (ie, comparative inhibition) and preferably does not inhibit other iron-binding proteins. The required dosage would preferably be no more than about one to two times a day or at the time of meals.

The identification of compounds of the invention as SCD inhibitors was easily achieved using the SCD enzyme and the microsomal assay procedure described in Brownlie et al., Supra. When tested in this assay, compounds of the invention had less than 50% remaining SCD activity at a concentration of 10 μ? of the test compound, preferably less than 40% remaining SCD activity at 10 μ? of concentration of the test compound, more preferably less than 30% of remaining SCD activity at a concentration of 10 μ? of the test compound, and still more preferably less than 20% of the remaining SCD activity at a concentration of 10 μ? of the test compound, thus demonstrating that the compounds of the invention are potent inhibitors of SCD activity. These results provide the basis for the analysis of the structure-activity relationship (SAR) between the test compounds and SCD. Certain R groups tend to provide more potent inhibitory compounds. SAR analysis is one of the tools that those skilled in the art can currently employ to identify preferred embodiments of the compounds of the invention for use as therapeutic agents. Other methods of testing these compounds described herein are also readily available to those skilled in the art. Thus, in addition, said contacting can be achieved in vivo. In such a mode, said contacting in step (a) was achieved by administration of said chemical agent to an animal affected with a triglyceride-related disorder (TG) - or a very low density lipoprotein (VLDL) and subsequently detecting a change in the plasma level of triglycerides in said animal. Thus identifying a useful therapeutic agent in the treatment of a disorder related to a triglyceride (TG) - or a very low density lipoprotein (VLDL). In such an embodiment, the animal can be a human, such as a human patient afflicted with such a disorder and in need of treatment of said disorder. In specific embodiments of said in vivo process, said change in SCD1 activity in said animal is a decrease in activity, preferably wherein said SCD1 modulator does not substantially inhibit the biological activity of a delta-5 desaturase, delta-6. desaturase or fatty acid synthetase. Model systems useful for evaluation of the compound may include, but are not limited to the use of hepatic microsomes, such as mice that have been maintained on a high carbohydrate diet, or human donors, including people suffering from obesity, lines immortalized cells, such as HepG2 (from human liver), MCF-7 (from human breast cancer) and 3T3-L1 (from mouse adipocytes) can also be used. Primary cell lines, such as mouse primary hepatocytes, are also useful in testing the compounds of the invention. Where whole animals are used, mice were used as a source of primary hepatocyte cells can also be used where mice have been maintained on a high carbohydrate diet to increase SCD activity in microsomes and / or to elevate elevated plasma triglyceride levels (i.e., the ratio 18: 1/18: 0): alternatively mice with a normal diet or mice with normal triglyceride levels. Mouse models employing transgenic mice designed for hypertriglyceridemia are also available as is the mouse phenomena database. Rabbits and hamsters are also useful as animal models, especially those that express CETP (cholesteryl ester transfer protein). Another suitable method for determining the in vivo efficiency of the compounds of the invention is to indirectly measure their impact on the inhibition of the SCD enzyme by measuring the Index of Desaturation of a subject after administration of the compound. The "Desaturation Index" as used in this specification means the proportion of the product on the substrate for the SCD enzyme that was measured from a given tissue sample. This can be calculated using three different equations 18: 1 n-9/18: 0 (oleic acid on stearic acid); 16: 1 n-7/16: 0 (palmitoleic acid on palmitic acid); and / or 16: 1 n-7 + 18: 1 n-7/16: 0 (measurement of all desaturation reaction products of 16: 0 on 16: 0 substrate). The Desaturation Index is measured first in triglycerides in liver or plasma, but can also be measured in other lipid fractions selected from a variety of tissues. The Index of Desaturation, usually Talking is a tool for the plasma profile of lipids. Numerous human disorders and diseases are the result of aberrant SCD1 biological activity and can be improved by modulating the biological activity of SCD1 using the therapeutic agents of the invention. The inhibition of SCD expression may also affect the fatty acid composition of membrane phospholipids, as well as the production or levels of triglycerides and cholesterol esters. The fatty acid composition of phospholipids ultimately determines membrane fluidity, while the effects on the composition of triglycerides and cholesterol esters can affect lipoprotein metabolism and adiposity. In carrying out the methods of the present invention it is understood, of course, that reference to regulators, media, reagents, cells, particular culture conditions and the like are not intended as limiting, but are read as to include all related materials that an expert in the field will recognize as being of interest or value in the particular context in which the discussion was presented. For example, it is often possible to replace one regulatory system or culture medium for another and even similar achievement, if not identical results. Those skilled in the art will have sufficient knowledge of such systems and methodologies to be able, without undue experimentation, to make such substitutions that will optimally serve their purposes to the use the methods and procedures described herein.

Pharmaceutical Compositions of the Invention and Administration The present invention also concerns the pharmaceutical composition containing the compounds of the invention described herein. In one embodiment, the present invention concerns a composition comprising compounds of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate the level of triglycerides or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably to a mammal, more preferably to a human patient. In one embodiment of said composition, the patient has a high level of lipids, such as high cholesterol or triglycerides, before administration of said compound of the invention and the compound of the invention is present in an amount effective to reduce said level of lipids . The pharmaceutical compositions useful herein also contain a pharmaceutically acceptable carrier, which includes any suitable excipient or diluent, which includes any pharmaceutical agent that does not itself induce the production of antibodies detrimental to the individual receptor composition, and which may be administered without undue toxicity. Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol and ethanol, and the like. A thorough discussion of carriers, diluents, and other pharmaceutically acceptable excipients is presented in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N.J. current edition). Those skilled in the art will know how to determine suitable doses of the compounds for use in the treatment of the diseases and disorders contemplated herein. The therapeutic doses are generally identified through a variable dose study in humans based on preliminary evidence derived from animal studies. The doses should be sufficient to result in therapeutic benefit without causing undesirable side effects for the patient. The preferred dosage range for an animal is 0.001 mg / kg to 10,000 mg / kg including 0.5 mg / kg, 1.0 mg / kg and 2.0 mg / kg, through doses outside the range may be acceptable. The dosing schedule can be once or twice a day, although more often or less often can be satisfactory. Those skilled in the art are also familiar with the determination of methods of administration (oral, intravenous, by inhalation, subcutaneous, etc.) dosage forms, suitable pharmaceutical excipients and other matters relevant to the release of the compounds to a subject in need. of these. In an alternative use of the invention, the compounds of the invention can be used in in vivo or in vitro studies as agents exemplary for comparative purposes to find other compounds also useful in the treatment of, or protection from, the various diseases described herein.

Preparation of the Compounds of the Invention It will be understood that in the following description, combinations of substituents and / or variables of the formulas set forth are permissible only if said contributions result in stable compounds. Those skilled in the art will also appreciate that in the process described below the functional groups of intermediary compounds may need to be protected by suitable protecting groups. Said functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkysilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C (0) -R "(where R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or akyl esters. Protecting groups can be added or removed in accordance with standard techniques, which are well known to those skilled in the art and as described herein.

The use of protecting groups is described in detail in Green, T. W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3a. ed. Wiley The protecting groups can also be polymeric resins such as a Wang resin or a 2-chlorotryl chloride resin. Those skilled in the art will also appreciate, although such derivatives of protected compounds of this invention can not possess pharmacological activity as such, can be administered to a mammal and thereafter can be metabolized in the body to form compounds of the invention, which they are pharmacologically active. Said derivatives can therefore be described as "prodrugs". All prodrugs of compounds of this invention are included in the scope of the invention. The following Reaction Schemes illustrate methods for making compounds of the invention. Those skilled in the art will be able to make these compounds by means of similar methods or by methods known to those skilled in the art. In general, the initial components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridege, Matrix Scientific, TCI, and Fluorochem USA, etc., or synthesized according to sources known to experts in the art. art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed. (Wiley, December 2000)) or prepared as described in this invention. R1, R2, R3, R4, R5, R5a, R6, R6a, R7, R7a, R8, R8a are defined in the following Reaction Schemes as in Specification unless specifically defined otherwise. PG, represents a protective group such as BOC, benzyl group and the like. The compounds of the invention can also be prepared by one skilled in the art by methods similar to those described in the following publications: Patent Application Published by PCT, WO 03/076400 Patent Application Published by PCT, WO 03/066604; Patent Application Published by PCT, WO 01/019822; Patent Application Published by PCT, WO 99/02 834; Patent Application Published by PCT, WO 99/020606; Patent Application Published by PCT, WO 98/001446; Patent Application Published by PCT, WO 94/012495; European Published Patent Application, 0 300 526; European Published Patent Application, 0 156 433; European Published Patent Application, 0 055 583; European Published Patent Application, 0 009 655, U.S. Pat. No. 5,719,154; and U.S. Patent No. 5,494,908. In general, the compounds of Formula (I) of this invention can be synthesized following the general procedure as described below in Reaction Scheme 1, where L and M are both -N =, G is -C (R4) = C (R4) - and W is -N (R1) C (O) -. It will be understood that the compounds of Formula (I) where L, M, G and W are otherwise defined as set forth in the Summary of the previous Invention they can be prepared in a similar manner.

The starting materials for the above Reaction Scheme are commercially available or can be prepared according to methods known to the person skilled in the art or by the methods described herein. In general, the compounds of the invention are prepared in the above Reaction Scheme as follows: Methylpyridazine 101 can be oxidized to a carboxylic acid 102 using an oxidant such as, but not limited to, potassium dichromate in an acid such as, but not limited to, concentrated sulfuric acid. Amide 103 can be formed from carboxylic acid 102 by reaction with an appropriate amine in the presence of a base such as, but not limited to, diisopropylethylamine, 1-hydroxyl-1 H-benzotriazole and 1-ethyl-3- (3 -dimethylaminopropyl) carbodiimide in a solvent such as, but not limited to, dichloromethane. Alternatively, the amide 103 can be prepared by reaction of acyl chloride derived from 102 with an appropriate amine. The reaction may be carried out in the presence of a base such as, but not limited to, diisopropylethylamine in a solvent such as, but not limited to, dichloromethane. The reaction of the chloropyridazine compound 103 with piperazine 104 in a refluxing acetonitrile gives compound 105. The final product 106 can be achieved by reacting the piperazine compound 105 with a heteroaromatic halide in the presence of 1,8-diazabicyclo [5.4.0] undec-7. -nene and catalytic amount of tetra-n-butylammonium iodide in a solvent such as, but not limited to dioxane. Alternatively, compound 106 can be prepared by reaction of 105 with an appropriate aryl halide under Buchwald / Hartwig amination conditions (for example see Buchwald, S. L. et al J. Org Chem. 2000, 65, 1158). Alternatively, the piperazine compound 107 can be prepared from 104, by reacting 104 with a heteroaromatic halide or heteroaromatic amine under conditions known to one skilled in the art. The coupling of 107 with the chloropyridazine compound 103 in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene iodide and catalytic amount of tetra-o-butylammonium in a solvent such as, but not limiting to,?,? - dimethylformamide gives the final product 106 as well. Although anyone skilled in the art is capable of preparing the compounds of the invention according to the general techniques described above, more specific details on synthetic techniques for compounds of the invention are provided elsewhere in this specification for convenience. Again, all the reactants and reaction conditions employed in synthesis are known to the person skilled in the art and are available from ordinary commercial sources.

PREPARATION 1 Synthesis of 3-piperazin-1-ylbenzo [disothiazole] A mixture of anhydrous piperazine (2.75 g, 32 mmol) and 3-chloro-benzo [d] isothiazole (1.00 g, 5.8 mmol) were heated in a sealed tube in an oil bath at 120 ° C for 24 hours. The orange melt was then quenched with ice water and 50% NaOH was added in one portion. The mixture was extracted with dichloromethane to give the crude product which was purified by recrystallization to give the title compound as a pale yellow solid in 24% yield (0.369 g). MS (ES +) m / z 220 (M + 1).

PREPARATION 2 Synthesis of (2-cyclopropylethyl) amide 6-chloropyridazine-3-carboxylic acid A. To a mechanically stirred solution of 3-chloro-6-methylpyridazine (155.6 mmol) in 140 ml of concentrated sulfuric acid, finely powdered potassium dichromate (55.4 g) was added slowly, keeping the temperature below 50 ° C. When the addition was complete, stirring was continued for another 4 hours at 50 ° C. The dark green, viscous liquid was then cooled and crushed ice was cautiously added. The reaction mixture was extracted with ethyl acetate (6 x 400 mL). The ethyl acetate extracts were combined, dried over Na2SO4. anhydrous. The solvent was concentrated in vacuo to yield 6-chloropyridazine-3-carboxylic acid (106.6 mmol) slightly colored red. The material was used for the next reaction without further purification. Yield of 69%, P.F. = 145 ° C (dec.) 1 H NMR (300 MHz, DMSO-d 6) d 13.1, 8.20, 8.05. B. To a solution of 6-chloropyridazin-3-carboxylic acid (15.8 mmol), in dichloromethane (95 mL) were added diisopropylethylamine (46.7 mmol), 1-hydroxybenzotriazole monohydrate (23.7 mmol) and 1- (3 -dimethylaminopropyl) -3-ethylcarbodiimide (23.7 mmoles) under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 15 minutes and 2-cyclopropylethylamine (20.2 mmol) was added. After stirring for 36 hours at room temperature, the reaction mixture was diluted with dichloromethane (100 ml), then washed with water and dried over anhydrous Na 2 SO 4. The solvent was removed in vacuo. Purification via column chromatography (30% ethyl acetate in hexane) gave the title compound (8.70 mmol). 55% yield.

PREPARATION 3 Synthesis of (2-cyclopropylethyl) amide 6-piperazin-1-ylpyridazine-3-carboxylic acid A mixture of piperazine (1.48 g, 17.2 mmol) and (2-cyclopropylethyl) amide 6-chloropyridazine-3-carboxylic acid (1.29 g, 5.73 mmol) in Acetonitrile (60 ml) was heated to reflux for 16 hours. After the reaction mixture was cooled, the gummy material was diluted with dichloromethane (50 ml), washed with water (2 x 20 ml), dried over MgSO 4. After filtration, the filtrate was concentrated in vacuo. The crude material was purified by column chromatography eluting with dichloromethane (100%) then methanol: dichloromethane (1: 9) to obtain 1.18 g (75%) of the product as a solid. The syntheses of compounds of this invention are illustrated by, but not limited to, the following examples.

EXAMPLE 1 Synthesis of 6- (3- (4-Fluorophenyl) piperazin-1-l-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide] To a solution of (2-cyclopropylethyl) amide 6-chloropropylpyridazine-3-carboxylic acid (0.120 g, 0.532 mmol) in DMF (2.3 ml) was treated with 1- (4-fluorophenyl) piperazine (0.117 g, 0.638 mmol) in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.23 ml, 1.54 mmol) and tetra-n-butylammonium iodide (Bu4NI) (11 mg, 0.0298 mmol). The reaction mixture was heated at 75 ° C to 80 ° C for 15 hours, cooled to room temperature, diluted with ethyl acetate (100 ml). The organic layer was washed with water (3 x 10 mL), brine (3 x 10 mL), dried over Na 2 SO, and then concentrated in vacuo. The crude product was purified by column chromatography to give the title compound as a white powder in 74% yield (0.145 g). 1 H NMR (300 MHz, CDCl 3) d 8.05-7.99 (m, 2H), 7.02-6.89 (m, 5H), 3.90 (t, J = 5.2 Hz, 4H), 3.55 (m, 2H), 3.23 (t, J = 5.2 Hz, 4H), 1.55-1.47 (m, 2H), 0.79-0.72 (m, 1 H), 0.49-0.43 (m, 2H), 0.11-0.06 (m, 2H). MS (ES +) m / z 370.3 (M + 1).

EXAMPLE 1.1 Synthesis of 6- (4-benzo [d] isothiazol-3-ylpiperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide Following the procedure as described in Example 1, varying only as required when using 3-piperazin-1-ylbenzo [d] isothiazole to replace 1- (4-fluorophenyl) -piperazine to react with (2-cyclopropylethyl) amide 6-chloropyridazine-3-carboxylic acid, the title compound was obtained as a white powder in 25% yield (0.0307 g). 1 H NMR (300 MHz, CDCl 3) d 8.13 (d, J = 9.5 Hz, 1 H), 7.94 (m, 2 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.50 (t, J = 7.3 Hz , 1 H), 7.38 (t, J = 7.8 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 4.05 (m, 4 H), 3.73 (m, 4 H), 3.51 (m, 2 H) ), 1.50 (m, 2H), 0.73 (m, 1 H), 0.45 (m, 2H), 0.06 (m, 2H). MS (ES +) AT7 / Z 409 (M + 1).

EXAMPLE 1.2 Synthesis of 6- (4- (3-trifluoromethylpyridin-2-yl) piperazin-1-illpyridazine-3-carboxylic acid (2-cyclopropylethyl) amide] Following the procedure as described in Example 1, varying only as required to use 1- (3-trifluoromethylpyridin-2-yl) piperazine to replace 1- (4-fluorophenyl) -piperazine to react with (2-cyclopropylethylamide). -chloropyridazine-3-carboxylic acid, the title compound was obtained as a white powder with 43% yield (0.061 g). 1 H NMR (300 MHz CDCl 3) d 8.44 (m, 1 H), 8.01 (m, 2 H) -, 7.89 (m, 1 H), 7.02 (s, 2 H), 3.88 (m, 4 H), 3.54 (m, 2H), 3.41 (m, 4H) i 1.51 (m, 2H) i 0.78 (m, 1 H) i 0.45 (m, 2H), 0.07 (m, 2H). MS (ES +) m / z 421 (M + 1).

EXAMPLE 1.3 Synthesis of 6- (4-pyridin-2-ylpiperazin-1-yl) pyrazine-3-carboxylic acid (2-cyclopropylethyl) amide Following the procedure as described in Example 1, varying only as required to use 1-pyridin-2-ylpiperazine to replace 1- (4-fluorophenyl) piperazine to react with (2-cyclopropylethyl) amide 6-chloropyridazine-3 -carboxylic, the title compound was obtained as a white powder with 30% yield (0.036 g). 1 H NMR (300 MHz, CDCl 3) d 8.19 (m, 1 H), 8.01 (m, IH ^ 7.50 (m, 1 H) and 7.00 (d, J = 9.9 Hz, 1 H) 6.67 (m, 2H) i 3.89 (m, 4H) i 3.75 (m, 4H) n 3.54 (m, 2H)! 1 .50 (m, 2H), 0.74 (m, 1 H) i 0.45 (m, 2H)! 0.09 (m, 2H) .13C NMR (75 MHzi CDCI3) d 163.2, 160.2, 158.9, 147.9, 144.9, 137.8, 126.9, 1 3.8, 1 12.1, 107.2, 44.6, 39.6, 34.6, 8.67, 4.25 MS (ES +) m / z 353.6 (M + 1).

EXAMPLE 1.4 Synthesis of acid (2-cyclopropylethioamide 6-r4-f3-trifluoromethylphenyl) -pi perazi n-1 -i II pi ridazin-3-carboxyl ico Following the procedure as described in Example 1, varying only as required to use 1- (3-trifluoromethylphenyl) piperazine to replace 1- (4-fluorophenyl) -piperazine to react with (2-cyclopropylethyl) amide 6-chloropyridazine -3-carboxylic acid, the title compound was obtained as a white powder with 57% yield (0.210 g). 1 H NMR (300 MHz, CDCl 3) d 8.09 (d, J = 9.5 Hz, 1 H), 7.98 (t, J = 5.4 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 1 H), 7.12 ( m, 3H), 7.04 (d, J = 9.5 Hz, 1 H), 3.96 (m, 4H), 3.55 (m, J = 6.72 and 13.2 Hz, 2H), 3.40 (m, 4H), 1.51 ( dd, J = 6.7 and 13.8 Hz, 2H), 0.74 (m, 1 H), 0.45 (m, 2H), 0.08 (m, 2H). 13C NMR (75 MHz, CDCI3) d 162.9, 150.8, 145.2, 1 29.8, 127.2, 1 19.19, 1 16.75, 1 12.6, 48.5, 44.7, 39.7, 34.5, 8.7, 4.2.

EXAMPLE 2 Synthesis of 6- (4-benzooxazol-2-yl-piperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide To (2-cyclopropylethyl) amide 6-piperazin-1-yl-pyridazine-3-carboxylic acid (0.080 g, 0.290 mmol) in dioxane (7 mL) was added 2-chlorobenzooxazole (0.053 g, 0.34 mmol) followed by the addition of 1,8-diazabicyclo [5.4.0] undec-7-ene (0.132 ml, 0.87 mmol) and tetra-n-butylammonium iodide (3 mg). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate, then washed with citric acid, sodium bicarbonate and brine solution. The organic layer was separated and dried over anhydrous Na2SO4 and evaporated. The residue was purified by recrystallization from n-hexane to yield the title compound as a white powder with 44% yield (0.050 g). 1 H NMR (300 MHz, CDCl 3) d 8.07 (d, J = 9.5 Hz, 1 H), 7.99 (t, J = 5.3 Hz, 1 H), 7.39 (d, J = 7.4 Hz, 1 H), 7.28 ( d, J = 7.8 Hz, 1 H), 7.19 (m, 1 H), 7.05 (m, 2H), 3.92 (m, 8H), 3.55 (m, 2H), 1.48 (m, 2H), 0.79 (m , 1 H), 0.46 (m, 2H), 0.07 (m, 2H). MS (ES +) m / z 393 (M + 1).

EXAMPLE 2.1 Synthesis of 6- (4-benzothiazol-2-ylpiperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide Following the procedure as described in Example 2, varying only as required to use 2-chlorobenzothiazole to replace 2-chlorobenzooxazole to react with (2-cyclopropylethyl) amide 6-piperazin-1-yl-pyridazine-3-carboxylic acid , the title compound was obtained as a white powder with 27% yield (0.040 g). 1 H NMR (300 MHz, CDCl 3) d 8.07 (d, J = 9.5 Hz, 1 H), 7.99 (t, J = 5.4 Hz, 1 H), 7.59 (m, 2 H), 7.32 (t, J = 6.5 Hz , 1 H), 7.12 (t, J = 8.2 Hz, 1 H), 7.03 (d, J = 9.4 Hz, 1 H), 3.94 (m, 4 H), 3.81 (m, 4 H), 3.53 (m, 2 H) ), 1.50 (m 2 H), 0.75 (m, 1 H), 0.45 (m, 2H), 0.06 (m, 2H). MS (ES +) m / z 409.2 (M + 1).

EXAMPLE 2.2 Synthesis of 6- (4-quinazolin-4-ylpiperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide Following the procedure as described in Example 2, varying only as required to use 4-chloroquinazoline to replace 2-chlorobenzooxazole to react with (2-cyclopropylethyl) amide 6-piperazin-1-yl-pyridazine-3-carboxylic acid, the compound of title was obtained as a white powder with 27% yield (40 mg). 1 H NMR (300 MHz, CDCl 3) d 8.76 (s, 1 H), 8.06 (d, J = 9.4 Hz, 1 H), 7.95 (m, 3 H), 7.77 (t, J = 7.3 Hz, 1 H), 7.50 (t, J = 7.3 Hz, 1 H), 7.01 (d, J = 9.5 Hz, 1 H), 3.98 (m, 8H), 3.55 (m, 2H), 1.5 (m, 2H), 0.74 (m , 1 H), 0.43 (m, 2H), 0.08 (m, 2H). MS (ES +) m / z 403.67 (M + 1).

EXAMPLE 3 Synthesis of 6- (4- (3-oxo-3h-isoindol-1-yl) piperazin-1-yl] pyridazine-3-carboxyMethyl acid (2-cyclopropylethyl) amide 3-aminoisoindole-1-one (0.292 g, 2.00 mmol) and (2-cyclopropylethyl) amide 6-piperazin-1-yl-pyridazine-3-carboxylic acid (0.825 g, 3.00 mmol) in ethanol (20 ml) were boiled together. for 48 hours. The solution was concentrated in vacuo. This residue was purified by column chromatography. The title compound was obtained as a white solid with 40% yield (0.328 g). 1 H NMR (300 MHz, CDCl 3) d 8.07 (d, J = 9.5 Hz, 1 H), 7.97 (t, J = 5.8 Hz, 1 H), 7.76 (d, J = 7.0 Hz, 1 H), 7.64 (d. d, J = 7.3 Hz, 1 H), 7.52 (m, 1 H), 7.01 (d, J = 9.5 Hz, 1 H), 4.42-4.35 (m, 4H), 4.23-4.20 (m, 2H), 3.93-3.89 (m, 2H), 3.54 (dd, J = 6.7 and 13.2 Hz, 1 H), 1.49 (m, 1 H), 0.79-0.66 (m, 1 H), 0.47-0.41 (m, 2H) , 0.10-0.05 (m, 2H). 13 C NMR (75 MHz, CDCl 3) d 181, 5, 174.6, 162.9, 159.6, 145.6, 138.1, 134.9, 132.5, 131, 7, 127.3, 124.0 123.3, 112.2, 47. 2, 46.4 44.5, 43.2, 39.7, 34.5, 8.7, 4.2. MS (ES +) m / z 405.1 (M + 1).

EXAMPLE 4 Measurement of stearoyl-CoA desaturase inhibition activity of a test compound using mouse liver microsomes The identification of compounds of the invention as SCD inhibitors was easily achieved using the SCD enzymes and the microsomal assay procedure described in Brownlie et al., Patent application published by PCT, WO 01/62954.

Preparation of Mouse Liver Microsomes Male ICR mice, with a low-fat, high-carbohydrate diet, under light halothane anesthesia (15% in mineral oil) were sacrificed by exsanguination during periods of high enzyme activity. The livers are immediately rinsed with 0.9% cold NaCl solution, weighed and shredded with scissors. All procedures were performed at 4 ° C unless otherwise specified. The livers were homogenized in a solution (1: 3 weight / volume) containing 0.25M sucrose, 62 mM potassium phosphate buffer (pH 7.0), 0.15 M KCI, 1.5 mM N-acetylcysteine, 5 mM MgCl2. and 0.1 mM EDTA using 4 strokes of a Potter-Elvehjern tissue homogenizer. The homogenate is centrifuged at 10,400 g for 20 minutes to eliminate the mitochondria and cell debris. The supernatant was filtered through three layers of cheese blanket and centrifuged at 105,000 g for 60 min. The microsomal compaction is gently suspended in the same homogenization solution with a small Teflon / glass homogenizer and stored at -70 ° C. The absence of mitochondrial contamination was enzymatically evaluated. The protein concentration was measured using bovine serum albumin as the standard.

Incubation of Mouse Liver Microsomes with Test Compounds Reactions were initiated by adding 2 mg of microsomal protein to pre-incubated tubes containing 0.20 pCi of the fatty acid substrate (1-14C palmitic acid) to a final concentration of 33.3 μ? in 1.5 ml of homogenization solution, containing 42 mM of NaF, 0.33 mM of niacinamide, 1.6 mM of ATP, 1.0 mM of NADH, 0.1 mM of coenzyme A and a concentration of 10 μ? of test compound. The tubes are vigorously vortexed and after 15 minutes of incubation in a shaking water bath (37 ° C), the reactions are stopped and the fatty acids are analyzed. The fatty acids were analyzed as follows: The reaction mixture was saponified with 10% KOH to obtain free fatty acids which are further methylated using BF3 in methanol. The esters Methyls of fatty acids were analyzed by high performance liquid chromatography (HPLC) using a Hewlett Packard 1090, Series II chromatograph equipped with a diode array detector set at 205 nM, a radioisotope detector (Model 171, Beckman, CA) with a solid scintillation cartridge (efficiency of 97% efficiency for 14C detection) and a Beckman reverse phase ODS (C-18) column (250 mm x 4.6 mm diameter); 5 pm particle size) attached to a guard column with a Beckman pBondapak C-18 insert. The methyl esters of fatty acids were separated with acetonitrile / water (95: 5 by volume) at an expense of 1 mL / min and identified by comparison with authentic standards. Alternatively, methyl esters of fatty acids can be analyzed by capillary column gas chromatography (GC, Gas Chromatography) or Thin Layer Chromatography (TLC). Those skilled in the art are aware of a variety of modifications to this assay that may be useful for measuring the inhibition of stearoyl-CoA desaturase activity in microsomes by test compounds. Representative compounds of the invention showed activity as SCD inhibitors when tested in this assay. The activity was defined in terms of% SCD enzymatic activity remaining at the desired concentration of the test compound. All publications of U.S. patent applications, patents U.S., U.S. patent applications, foreign patents, foreign patent applications and different patent publications mentioned in this specification and / or listed in the Application Data Sheet are hereby incorporated by reference in their entirety. From the foregoing it will be appreciated that, although specific embodiments of the invention have been described for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except by the appended claims.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a compound of Formula (I): wherein x and y are each independently 0, 1, 2 or 3; G is -N (R4) -, -O-, -S (0) t- (where t is 0, 1 or 2), -C (R4) = or -C (R4) = C (R4); J and K are each independently N or C (R10); L and M are each independently -N =, -N (R4) -, or -C (R) =, provided that when G is -C (R4) = or -C (R4) = C (R4) -, L and M can not be both -C (R4) =; W is a direct bond, -N (R1) C (0), -C (0) N (R1) -, -OC (0) N (R1) -, -N (R1) C (O) N (R1) ) -, -O-, -N (R1) -, -S (O) t- (where t is 0, 1, or 2), -N (R) S (0) p- (where p is 1 or 2), -S (O) pN (R1) - (where p is 1 or 2), -C (O) -, -OS (0) 2N (R1) -, -OC (O) -, -C ( 0) 0- or N (R1) C (0) 0-, each R1 is independently selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon and aralkyl atoms of 7 to 19 carbon atoms; R 2 is selected from the group consisting of alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 atoms carbon, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 19 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms, and heteroarylalkyl of 2 to 12 carbon atoms; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings can be fused together; R3 is selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 19 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms carbon, heteroaryl of 1 to 12 carbon atoms and heteroarylalkyl of 3 to 12 carbon atoms; or R3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings can be fused together; each R4 is independently selected from hydrogen, fluorine, chlorine, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, haloalkyl, cyano, nitro or -N (R9) 2; or two adjacent R4 groups, together with the carbon to which they are fixed, can form a ring system aryl, heteroaryl or heterocyclyl; R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R5 and R5a together, R6 and R6a together, or R7 and R7a together, or R8 and R8a together are an oxo group; or one of R5, R5a, R6 and R6a together with one of R7, R7a, R8 and R8a form a direct bond or an alkylene bridge, while the remaining R5, R5a, R6, R6a, R7, R7a, R8, and R8a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; each R9 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R10 is independently selected from hydrogen, fluorine, chlorine, alkyl of 1 to 12 carbon atoms or alkoxy of 1 to 12 carbon atoms, in the manufacture of a medicament useful for treating a disease or condition mediated by stearoyl-CoA desaturase ( SCD) in a mammal. 2. A compound of formula (I): wherein x and y are each independently 0, 1, 2 or 3; G is -N (R4) -, -O-, -S (0) t- (where t is 0, 1 or 2), -C (R4) = or -C (R) = C (R4); J and K are each independently N or C (R10); L and M are each independently -N =, -N (R4) =, or -C (R) =; provided that when G is -C (R) = or -

C (R4) = C (R4) -, L and M can not be both -C (R4) =; W is a direct bond, -N (R) C (0) -C (0) N (R1) -, -OC (0) N (R1) -, -N (R1) C (O) N (R1) ) -, -O-, -N (R1) -, -S (O) r (where t is 0, 1, or 2), -N (R1) S (O) p- (where p is 1 or 2) ). -S (0) pN (R1) - (where p is 1 or 2), -C (O) -, -OS (0) 2N (R1) -, -OC (O) -, -C (0) 0 - oN (R1) C (O) 0-, each R1 is independently selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms and aralkyl of 7 to 19 carbon atoms; R 2 is selected from the group consisting of alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 carbon atoms, alkoxyalkyo of 2 to 12 atoms carbon, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 19 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms, and heteroarylalkyl of 3 to 12 carbon atoms; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings can be fused together; R3 is selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 19 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms and heteroarylalkyl of 3 to 12 carbon atoms; or R3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings can be fused together; each R4 is independently selected from hydrogen, fluorine, chlorine, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, haloalkyl, cyano, nitro or -N (R9) 2; or two adjacent R4 groups, together with the carbon to which they are attached, can form an aryl, heteroaryl or heterocyclyl ring system; R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R5 and R5a together, R6 and R6a together, or R7 and R7a together, or R8 and R8a together are an oxo group; or one of R5, R5a, R6 and R6a together with one of R7, R7a, R8 and R8a form a direct bond or an alkylene bridge, while the remaining R5, R5a, R6, R6a, R7, R7a, R8, and R8a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; each R9 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R10 is independently selected from hydrogen, fluorine, chlorine, alkyl of 1 to 12 carbon atoms or alkoxy of 1 to 12 carbon atoms.

3. The compound according to claim 2, further characterized in that J and K are both N, ie a compound that has Formula (la):

4. - The compound according to claim 3, further characterized in that: X and y are each 1; G is -C (R4) = C (R4) -; L and M are both -N =; W is -N (R1) C (O) -, -C (0) N (R1) -; -OC (0) N (R1) -, -N (R) CO) N (R1) -, -N (R1) S (O) p- (where p is 1 or 2), -S (O) pN (R1) - (where p is 1 or 2), -OS (O) 2N (R1) -, -C (0) 0- or -N (R1) C (0) 0-; each R1 is independently selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, and aralkyl of 7 to 19 carbon atoms; R2 is selected from the group consisting of alkyl of 7 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, hydroxyalkyl of 7 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 carbon atoms, alkoxyalkyl of 2 to 12 atoms carbon, cycloalkyl of 2 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 13 to 19 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 2 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms, and heteroarylalkyl of 3 to 12 carbon atoms; R3 is selected from the group consisting of aryl, heterocyclyl of 3 to 12 carbon atoms and heteroaryl of 1 to 12 carbon atoms; and each R4 is independently selected from hydrogen, fluorine, chlorine, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, haloalkyl, cyano, nitro or -N (R9) 2; R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; provided that R2 is not pyrazinylalkyl of 5 to 10 carbon atoms, pyridinonyl, pyrrolidinonyl, methylimidazolyl or phenyl substituted with amino.

5. The compound according to claim 4, further characterized in that R3 is aryl.

6. The compound according to claim 5, further characterized in that it is selected from the group consisting of the following: 6- (4- (4-fluorophenyl) -piperazin-1-yl] pyridazine acid (2- cyclopropylethyl) amide -3-carboxylic acid; and 6- (4- (3-trifluoromethylphenyl) -piperazin-1-yl] pyridazine-3-carboxylic acid (2- cyclopropylethyl) amide.

7. The compound according to claim 4, further characterized in that R3 is heteroaryl of 1 to 12 carbon atoms.

8. The compound according to claim 7, further characterized in that it is selected from the group consisting of the following: 2- (4-benzooxazol-2-yl-piperazin-1-yl) pyridazine acid (2- cyclopropylethyl) amide - 3-carboxylic; (2-cyclopropylethyl) amide 6- (4-benzothiazol-2-yl-piperazin-1-yl) -pyridazine-3-carboxylic acid; (2-cyclopropylethyl) amide 6- (4-quinazolin-4-yl-piperazin-1-yl) -pyridazine-3-carboxylic acid; (2-cyclopropylethyl) amide 6- [4- (3-trifluoromethylpyridin-2-yl-piperazin-1-yl) -pyridazine-3-carboxylic acid; (2-cyclopropylethyl) amide 6- (4-benzo [d] isothiazol-3-yl-piperazin-1-yl) -pyridazine-3-carboxylic acid; (2-cyclopropylethyl) amide 6- (4-pyridin-2-yl-piperazin-1-yl) -pyridazine-3-carboxylic acid; (2-cyclopropylethyl) amide 6- [4- (3-oxo-3H-isoindol-1-yl] -piperazin-1-yl] -pyridazine-3-carboxylic acid 9.- A pharmaceutical composition comprising an excipient or pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (I): wherein x and y are each independently O, 1, 2 or 3; G is -N (R4) -, - O-, -S (O) r (where t is O, 1 or 2), -C (R4) = or -C (R4) = C (R4); J and K are each independently N or C (R10); L and M are each independently -N =, -N (R4) =, or -C (R4) = provided that when G is -C (R) = or -C (R4) = C (R4) - , L and M can not be both -C (R4) =; W is a direct bond, -N (R1) C (O) -, -C (0) N (R1) -, - OC (0) N (R1) -, -N (R1) C (0) N ( R1) -, -O-, -N (R1) -, -S (O) t- (where t is O, 1, or 2), -N (R1) S (0) p- (where p is 1 or 2). -S (O) pN (R1) - (where p is 1 or 2), -C (O) -, -OS (O) 2N (R1) -, -0C (0) -, -C (0) O - oN (R1) C (0) 0-, each R1 is independently selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms and aralkyl of 7 to 19 carbon atoms; R2 is selected from the group consisting of alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms , cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 19 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms, and heteroarylalkyl from 2 to 12 carbon atoms; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings can be fused together; R3 is selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, hydroxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 19 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms carbon, heteroaryl of 1 to 12 carbon atoms and heteroarylalkyl of 3 to 12 carbon atoms; or R3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings can be fused together; each R4 is independently selected from hydrogen, fluorine, chlorine, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, haloalkyl, cyano, nitro or -N (R9) 2; or two adjacent R4 groups, together with the carbon to which they are attached, can form an aryl, heteroaryl or heterocyclyl ring system; R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R5 and R5a together, R6 and R6a together, or R7 and R7a together, or R8 and R8a together are an oxo group; or one of R5, R5a, R6 and R6a together with one of R7, R7a, R8 and R8a form a direct bond or an alkylene bridge, while the remaining R5, R5a, R6, R6a, R7, R7a, R8, and R8a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; each R9 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R10 is independently selected from hydrogen, fluorine, chlorine, alkyl of 1 to 12 carbon atoms or alkoxy of 1 to 12 carbon atoms.