MXPA06001205A - Pyridazine derivatives and their use as therapeutic agents - Google Patents

Abstract

Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I), where x, y, W, V, R2, R3, R4, R5, R6, R6a, R7, R7a, R8, R8a, R9 and R9a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.

Description

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

BACKGROUND OF THE INVENTION Acyl desaturase enzymes catalyze the formation of double bonds in fatty acids derived from either dietary sources or novel syntheses 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 at the C9-C10 position of saturated fatty acids. The preferred substrates are palmitoyl-CoA (16: 0) and stearyl-CoA (18: 0), which are converted to palmitoloyl-CoA (16: 1) and oleoyl-CoA (18: 1), respectively. The resulting monosaturated fatty acids are substrates for incorporation into phospholipids, triglycerides, and cholesteryl esters. A number of mammalian SCD genes have been cloned. For example, two genes have been cloned from rats (SCD1, SCD2) and four SCD genes have been isolated from mice (SCD 1, 2, 3, and 4). Since the basic biochemical role of SCD has been known since the 1970's (Jeffcoat, R. et al., Elsevier Science (1984), Vol. 4, pp. 85-112; de Antueno, RJ, Lipids (1993), Vol. 28 , No. 4, pp. 285-290), has only recently been directly implicated in human disease processes. A single SCD gene, SCD1 has been characterized in humans. SCD1 is disclosed in Brownie et al., PCT published patent application, WO 01/62954, the disclosure of which is incorporated herein by reference in its entirety. Recently, a second human SCD isoform has been identified, and because it has a small sequence homology for alternating mouse and rat sophomores, it has been named SCD5 or human hSCD5 (PCT published patent application, WO 02/26944, incorporated herein). by reference in its entirety). To date, the small molecule drug type compounds are known to specifically inhibit or modulate SCD activity. Certain long-chain hydrocarbons have historically been used to study the activity of SCD. Known examples include fatty acids, cyclopropenoid fatty acids, and certain conjugated linoleic acid isomers. Specifically, conjugated linoleic acid cis-12, trans-10 is believed to inhibit the activity of the SCD enzyme and reduce the abundance of SCD1 mRNA while conjugated linoleic acid cis-9, trans-11 does not. The cyclopropenoid fatty acids such as those found in sterile and cotton seeds are also known to inhibit SCD activity. For example, (8- (2-octylcyclopropenyl) octanoic acid) stearyl acid and (7- (2-octylcyclopropenyl) heptanoic acid) mavicic acid are C18 and C16 derivatives of esterculoyl and malvaloyl fatty acids, respectively, having rings of cyclopropene in its C9-C10 positions. These agents are believed to inhibit SCD enzymatic activity through direct interaction with the enzyme, thus inhibiting delta-9 desaturation. Other agents that can inhibit SCD activity include thia-fatty acids, such as thiaestearic 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 desaturases delta-9, since they also inhibit other desaturases and enzymes. Thia-fatty acids, conjugated linoleic acids and cyclopropene fatty acids (malvial acid and sterocholine acid) are also not useful at reasonable physiological doses, nor with specific inhibitors of the biological activity of SCD1, rather they demonstrate the cross-inhibition of other desaturases , in particular the desaturases delta-5 and delta-6 through fatty acids of cyclopropene. The absence of small molecule inhibitors of SCD enzyme activity is a major scientific and medical disillusionment because the evidence now is to compel SCD activity to be directly involved in disease processes in ordinary humans: See , for example, Attie, AD et al., "Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia", J. Lipid Res. (2002), Vol. 43, No. 11, pp. 1899-907; Cohen, P. et al., "Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss", Science (2002), Vol. 297, No. 5579, pp. 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, pp. 11482-6. 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 lipid metabolism disorders, especially diseases related to high lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like.

Related Literature The Patent of E.U.A. No. 6,677,452 discloses novel pyridinecarboxamide or sulfonamide derivatives. PCT Published Patent Application, WO 03/075929, WO 03/076400 and WO 03/076401, disclose compounds having histone deacetylase that inhibit enzymatic activity.

COMPENDIUM OF THE INVENTION The present invention provides pyridazine derivatives that modulate the activity of stearyl-CoA desaturase. Methods for the use of 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 the formula (I): wherein: x and y are each independently 1, 2 or 3; W is -C (0) N (R1) -; -C (0) N [C (0) R1a] -, -N (R1) C (0) N (R1) - or -N (R1) C (0) -; V is -C (O) -, -C (S) -, or -C (R10) H; each R1 is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxyl; R1a is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl; 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, alkoxy of 1 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 12 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 from 2 to 4 rings, wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and wherein some or all of the rings may be fused together with the other; R3 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, alkoxy of 1 to 12 carbon 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 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl from 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 from 2 to 4 rings, wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and wherein some or all of the rings may be fused together with the other; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N (R12) 2; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together are an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not form an oxo group, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a each is independently selected from hydrogen, or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, Rda, R7, R7a, R8, R8a, R9, and R9a each it is independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; R10 is hydrogen or alkyl of 1 to 3 carbon atoms; each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable composition thereof or a prodrug thereof.

In another aspect, the invention provides compounds of the formula (II): wherein: x and y are each independently 1, 2 or 3; W is selected from -C (0) N (R1) - and -N (R1) C (0) -; each R1 is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxy; R2 is selected from the group consisting of alkyl of 7 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 7 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 atoms carbon, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aralkyl of 13 to 19 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, and heteroarylalkyl of 3 to 12 carbon atoms; or R2 is a multi-ring structure having from 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein some or all of the rings may be fused with one another; R3 is selected from the group consisting of alkyl of 3 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 3 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 carbon atoms, alkoxy of 3 to 12 carbon atoms, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 12 carbon atoms , heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, heteroaryl of 5 to 12 carbon atoms and heteroarylalkyl of 3 to 12 carbon atoms; or R3 is a multi-ring structure having from 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and wherein some or all of the rings may be fused with each other; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together are an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not forming an oxo group, while the rest of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; including a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition or a prodrug thereof. In another aspect, the invention provides compounds of the formula (III): wherein: x and y are each independently 1, 2 or 3; A is oxygen or sulfur; W is selected from -C (0) N (R1) - and -N (R1) C (0) -; each R1 is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxy; 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, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 12 carbon atoms carbon, 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 from 2 to 4 rings, wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein some or all of the rings may be fused with one another; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R11) 2, -OC (0) R11, -C (0) OR11, -S (0) 2N (R11) 2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl, provided that R3 is not phenyl substituted with optionally substituted thien; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together is an oxo group, provided that when V is -C (O) -, R7 and R7a together o and R8 and R8a together do not form an oxo group, while the remainder of R6, R6a, R7, R7a, R8, R6a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6 R6a, R7, R7a, R8, R8a, Rs, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; and each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition or a prodrug thereof. In another aspect, the invention provides compounds of the formula (IV): wherein: x and y are each independently 1, 2 or 3; each R1 is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxy; 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, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, aryl, aralkyl of 7 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 from 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and wherein some or all of the rings may be fused to one another; R3 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, alkoxy of 1 to 12 carbon 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 12 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 from 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and wherein some or all of the rings may be fused with each other; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together are an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not form an oxo group, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition or a prodrug thereof.

In another aspect, the invention provides compounds of the formula (Goes): wherein: x and y are each independently 1, 2 or 3; W is -C (0) N (R1) -; -N (R1) C (0) N (R1) - or -N (R) C (0) -; each Rβ is independently selected from the group consisting of hydrogen; alkyl of t to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxy; 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, alkoxy of 1 to 12 atoms of carbon, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aralkyl of 13 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; R3 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, alkoxy of 1 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 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl from 3 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms and heteroarylalkyl of 3 to 12 carbon atoms; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N (R12) 2; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together are an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not they form an oxo group, while the rest of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each one independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; R10 is hydrogen or alkyl of 1 to 3 carbon atoms; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; provided, however, that R2 can not be pyrazinyl, pyridinonyl, pyrrolidinone or imidazolyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition or a prodrug thereof. In another aspect, the invention provides compounds of the formula (Vb): wherein: x and y are each independently 1,2 or 3; W is -C (0) N (R1) -; -N (R1) C (0) N (R ') - or -N (R1) C (0) -; each R1 is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxy; 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, alkoxy of 1 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 12 carbon atoms carbon, heterocyclyl 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; R3 is selected from the group consisting of alkyl of 7 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, alkoxy of 1 to 12 carbon atoms or alkoxyalkyl of 1 to 12 carbon atoms; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N (R12) 2; R £ R 6a R 7, R 7a Rf R 8a Re R 9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together are an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not they form an oxo group, while the rest of R6, R6a, R7, R7a, R8, R3a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, R6a R7, R7a, R8, R8a, R9a and R9a is independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; R10 is hydrogen or alkyl of 1 to 3 carbon atoms; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; as a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition or a prodrug thereof. In another aspect, the invention provides methods for 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 It was established earlier. 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 the metabolic syndrome (including dyslipidemia, insulin resistance and obesity). In another aspect, the invention provides methods for preventing or treating a disease or condition related to elevated lipid levels, such as plasma lipid levels, especially high triglyceride or cholesterol levels, in a patient afflicted with such elevated levels, which comprises administering to said patient a therapeutically or prophylactically effective amount of a composition as described herein. The present invention also relates to novel compounds that have the therapeutic ability to reduce lipid levels in an animal, especially triglyceride and cholesterol levels. In another aspect, the invention provides pharmaceutical compositions comprising the compounds of the invention as set forth above, and pharmaceutically acceptable excipients. In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate the level of triglyceride, or to treat diseases related to dyslipidemia and disorders of lipid metabolism , when administered to an animal, preferably a mammal, preferably a human patient. In one embodiment of said composition, the patient has a high lipid level, such as elevated triglycerides or cholesterol in the plasma, before the administration of said compound and said compound is present in an amount effective to reduce said lipid level. In another aspect, the invention provides methods for treating a patient of, or protecting a patient from development, a disease or condition mediated by stearoyl-CoA desaturase (SCD), which method comprises administering to a patient afflicted with said disease or condition, or risk of developing said disease or condition, a therapeutically effective amount of a compound that inhibits the activity of SCD in a patient when administered thereto. In another aspect, the invention provides methods for treating a variety of diseases involving lipid metabolism using compounds identified by the methods described herein. Accordingly, a variety of compounds having said activity are described herein, based on a classification assay to identify, from a collection of test compounds, a therapeutic agent that modulates the biological activity of said SCD and is useful in the treatment of a human disorder or condition related to serum lipid levels, such as triglycerides, VLDL, HDL, LDL, and / or total cholesterol.

DETAILED DESCRIPTION OF THE INVENTION Definitions Certain chemical groups mentioned here are preceded by an abbreviated notation that indicates the total number of carbon atoms that will be found in the chemical group indicated. For example; C7-C12 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 above, having a total of 4 to 12 carbon atoms. The total number of carbons in the abbreviated notation does not include carbons that may exist in substituents of the described group. Accordingly, as used in the specification and the appended claims, unless otherwise specified, the following terms have the indicated meaning: "Metoxy" refers to a radical -OCH3. "Ciano" refers to the radical -CN. "Nitro" refers to the radical -N02. "Trifluoromethyl" refers to the radical -CF3. "Oxo" refers to the substituent = 0. "Tioxo" refers to the substituent = S. "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, not containing unsaturation, having one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon atoms, and which is linked to the rest of the molecule through a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like. Unless specifically stated otherwise in the specification, an alkyl group may be optionally substituted by one of the following groups: alkyl, alkenyl, halogen, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, -OR14, - 0C (0) -RU, -N (R1) 2, -C (0) 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 (0), OR16 (where t is 1 to 2) ), -S (0) tR16 (where t is from 0 to 2), and -S (0) tN (R14) 2 (where t is from 1 to 2) wherein each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkyalkyl, aryl (optionally substituted with one or more halogen groups), aralkyl, heterocyclic, 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. "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 by an alkyl group. "Alkyl of 1 to 6 carbon atoms" refers to an alkyl radical as defined above containing from one to six carbon atoms. The alkyl of 1 to 6 carbon atoms may be optionally substituted as defined by an alkyl group. "Alkyl of 1 to 12 carbon atoms" refers to an alkyl radical as defined above containing from one to twelve carbon atoms. The alkyl radical of 1 to 12 carbon atoms may be optionally substituted as defined by an alkyl group. "Alkyl of 2 to 6 carbon atoms" refers to an alkyl radical as defined above containing from two to six carbon atoms. The alkyl radical of 2 to 6 carbon atoms may be optionally substituted as defined by an alkyl group. "Alkyl of 3 to 6 carbon atoms" refers to an alkyl radical as defined above containing from three to six carbon atoms. The alkyl radical of 3 to 6 carbon atoms may be optionally substituted as defined by an alkyl group. "Alkylate of 3 to 12 carbon atoms" refers to to an alkyl radical as defined above containing from three to twelve carbon atoms. The alkyl radical of 3 to 12 carbon atoms may be optionally substituted as defined by an alkyl group. "Alkyl of 6 to 12 carbon atoms" refers to an alkyl radical as defined above containing from six to twelve carbon atoms. The alkyl radical of 6 to 12 carbon atoms may be optionally substituted as defined by an alkyl group. "Alkyl of 7 to 12 carbon atoms" refers to an alkyl radical as defined above containing from seven to twelve carbon atoms. The alkyl radical of 7 to 12 carbon atoms may be optionally substituted as defined by an alkyl group. "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, which contains at least one double bond, having from two to twelve carbon atoms, preferably from one to eight carbon atoms and which is linked to the rest of the molecule through a single bond, for example, ethenyl, prop -1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless specifically stated otherwise in the specification, an alkenyl group may be optionally substituted by one of the following groups: alkyl, halogenalkenyl, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl heteroaryl , heteroarylalkyl, -OR14, -OC (0) -R14, -N (R14) 2, -C (0) R14 -C (0) OR14, -C (0) N (R14) 2, -N (R14) C (0) OR16, -N (R14) C (0) R16 -N (R1) (S (0) tR16) (where t is 1 to 2), -S (0) tOR16 (where t is 1 to 2), -S (0) tR16 (where t is from 0 to 2), and -S (0) tN (R14) 2 (wherein t is from 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 from three to twelve carbon atoms. The alkenyl radical of 3 to 12 carbon atoms may be optionally substituted as defined for an alkenyl group. "C 2 -C 12 alkenyl" refers to an alkenyl radical as defined above containing from 2 to 12 carbon atoms. The alkenyl radical of 2 to 12 carbon atoms may be optionally substituted as defined above by an alkenyl group. "Alkylene" and "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, which binds the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, not containing unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons, for example, methylene, ethylene, propylene, n-butlene, and the like. The alkylene chain can be linked to the rest of the molecule and to the radical group through a carbon within the chain or through any of two carbons within the chain. "Alkenylene" and "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain that links the remainder of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and which has from two to twelve carbon atoms, for example, ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is linked to the rest of the molecule through a single bond and to the radical group through a double bond or an individual bond. The binding points of the alkenylene chain to the rest of the molecule and to the radical group can be through a carbon or any of two carbons within the chain. "Alkylene bridge" refers to a straight or branched divalent hydrocarbon bridge, which links two different carbons of the same ring structure, consisting solely of carbon and hydrogen, not containing unsaturation and having from one to twelve carbon atoms , preferably having from one to eight carbons, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene bridge can link any two carbons within the ring structure. "Alkoxy" refers to a radical of the formula -ORa wherein Ra is an alkyl radical as defined above. The alkyl part of the alkoxy radical may be optionally substituted as defined above by an alkyl radical. "Alkyl of 1 to 6 carbon atoms" refers to an alkoxy radical as defined above containing from one to six carbon atoms. The alkyl part of the alkyl radical of 1 to 6 carbon atoms may be optionally substituted as defined above by an alkyl group. "Alkoxy of 1 to 12 carbon atoms" refers to an alkoxy radical as defined above containing from 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 by an alkyl group. "Alkoxy of 3 to 12 carbon atoms" refers to an alkoxy radical as defined above containing from three to twelve carbon atoms. The alkyl part of the alkoxy radical of 3 to 12 carbon atoms it may be optionally substituted as defined above by an alkyl group. "Alkoxyalkyl" refers to a radical of the formula -Ra-0-Ra wherein each Ra is independently an alkyl radical as defined above. The oxygen atom can be bonded to any carbon in any alkyl radical. Each alkyl part of the alkoxyalkyl radical may be optionally substituted as defined above by an alkyl group. "Alkoxyalkyl of 2 to 12 carbon atoms" refers to an alkoxyalkyl radical as defined above containing from two to twelve carbon atoms. Each alkyl part of the alkoxyalkyl radical of 2 to 12 carbon atoms may be optionally substituted as defined above by an alkyl group. "C 3 -alkoxyalkyl" 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 by an alkyl group. "Alkoxyalkyl of 3 to 12 carbon atoms" refers to an alkoxyalkyl radical as defined above containing from three to twelve carbon atoms. Each alkyl part of the alkoxy of 3 to 12 atoms of the carbonylalkyl radical may be optionally substituted as defined above by an alkyl group. "Alkylsulfonyl" refers to a radical of the formula -S (0) 2Ra wherein Ra is an alkyl group as defined above. The alkyl part of the alkylsulfonyl radical may be optionally substituted as defined above by an alkyl group. "C 1 -C 6 -alkylsulfonyl" refers to an alkylsulfonyl radical as defined above having from one to six carbon atoms. The alkylsulfonyl group of 1 to 6 carbon atoms may be optionally substituted as defined above by an alkylsulfonyl group. "Aryl" refers to an 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, wherein the ring system may be partially or completely saturated. Aryl groups include, but are not limited to, groups such as fluorenyl, phenyl, and naphthyl. Unless specifically stated otherwise in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl) is intended to include optionally substituted aryl radicals through one or more substituents selected from the group consisting of alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R15-OR14, -R15-OC (0) -R14, -R 5-N (R1) 2, -R15-C (0) R14, -R15-C (0) OR14, -R 5-C (0) N (R14) 2, -R15-N (R14) C (0) OR16, -R 5 -N (R14) C (0) R16, -R15-N (R14) (S (0) tR16) (where t is 1 to 2), -R15-S (Q) tOR16 (where t is from 1 to 2), -R15-s (0) tR16 (where t is from 0 to 2), and -R15-S (0) tN (R14) 2 (where t is from 1 to 2) wherein each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R15 is independently a straight or a straight or branched alkenylene alkylene 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 wherein 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 alkyl part of the alkyl radical may be optionally substituted as described above for an aryl group.

"Aralkyl of 7 to 12 carbon atoms" refers to an aralkyl group as defined above containing from seven to twelve carbon atoms. The aryl portion of the aralkyl radical of 7 to 12 carbon atoms may be optionally substituted as described above by an aryl group. The alkyl part of the aralkyl radical of 7 to 12 carbon atoms may be optionally substituted as defined above by an alkyl group. "Aralkyl of 3 to 19 carbon atoms" refers to an aralkyl group as defined above containing from thirteen to nineteen carbon atoms. The aryl portion of the aralkyl radical of 3 to 19 carbon atoms may be optionally substituted as described above by an aryl group. The alkyl part of the aralkyl radical of 3 to 19 carbon atoms may be optionally substituted as defined above by an alkyl group. "Aralkenyl" refers to a radical of the formula -RcRb wherein Rc is an alkenyl radical as defined above and Rb is one or more aryl radicals as defined above, w may be optionally substituted as described above. The aryl portion of the aralkenyl radical may be optionally substituted as described above by an aryl group. The alkenyl part of the aralkenyl radical may be optionally substituted as defined above by an alkenyl group.

"Aryloxy" refers to a radical of the formula -OR wherein Rb is an aryl group as defined above. The aryl portion of the aryloxy radical may be optionally substituted as defined above. "Aryl-alkyl of 1 to 6 carbon atoms" refers to a radical of the formula -Rh-Rj; wherein Rh is an unbranched alkyl radical having from one to six carbons and R i is an aryl group linked to the terminal carbon of the alkyl radical. "Cycloalkyl" refers to a 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 w is saturated or unsaturated and is bound to the rest of the molecule through a single bond, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl and the like. Unless otherwise specifically stated in the specification, the term "cycloalkyl" is intended to include cycloalkyl radicals w are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R15-0R14, -R15-OC (0) -R14, -R15-N (R14) 2) -R15-C (0) R14, - R15-C (0) OR14, -R15-C (0) N (R14) 2, -R 5 -N (R14) C (0) OR16, -R15-N (R14) C (0) R16, -R 5-N (R14) (S (0) tR16) (where t is 1 to 2), -R15-S (0) t0R16 (where t is 1 to 2), -R15-S (0) tR16 (where t is from O to 2), and -R15-S (0) tN (R14) 2 (where t is from 1 to 2) wherein each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl , aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; 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. "Cycloalkyl of 3 to 6 atoms "carbon" refers to a cycloalkyl radical as defined above having from three to six carbon atoms The cycloalkyl radical of 3 to 6 carbon atoms may be optionally substituted as defined above for a cycloalkyl group. 3 to 12 carbon atoms "refers to a cycloalkyl radical as defined above having from three to twelve carbon atoms.The cycloalkyl radical of 3 to 12 carbon atoms may be optionally substituted as defined above by a cycloalkyl group." "Cycloalkylalkyl" refers to a radical of the formula -RaRd wherein Ra is an alkyl radical as defined above and R is a cycloalkyl radical as defined above The cycloalkyl part of the cycloalkyl radical may be optionally substituted as defined above by a cycloalkyl radical The alkyl part of the cycloalkyl radical may optionally be subst as defined above by an alkyl radical. "Cycloalkylalkyl of 4 to 12 carbon atoms" refers to a cycloalkyl radical as defined above having from 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. "Halogen" refers to bromine, chlorine, fluorine or iodine. "Haloalkyl" refers to an alkyl radical, as defined above, which is substituted by one or more halogen radicals, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl -2-f luoroethyl, 3-b romo-2-f luoro pro pyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl part of the halogen radical may be optionally substituted as defined above by an alkyl group. "Haloalkenyl" refers to an alkenyl radical, as defined above, which is substituted by one or more halogen radicals, as defined above, for example, 2-bromoethenyl, 3-bromoprop-1-enyl, and the like. The alkenyl part of the haloalkenyl radical may be optionally substituted as defined above by an alkyl group. "Heterocyclyl" refers to a non-aromatic ring radical of 3 to 18 members consisting of carbon atoms and one to five heterogeneous atoms 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 fused or bridged ring systems; and the nitrogen, carbon and sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl radical may be partially or completely saturated. Examples of heterocyclyl radicals include, but are not limited to, dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, -piperidonyl, pyrrolidinyl, idolyl pyrazole, thiazolidinyl, tetrahydrofuryl, trityanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless specifically stated otherwise in the specification, the term "heterocyclyl" is intended to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R15-OR14, -R15-OC (0) -R14, -R15-N (R14) 2, -R15 -C (0) R14, -R15-C (0) OR14, -R15-C (O) N (R14) 2, -R15-N (R14) C (0) OR16, -R15-fM (R14) C (O) R16, -R 5- N (R14) (S (0) tR16) (where t is 1 to 2), -R15-S (0) tOR16 (where t is 1 to 2), -R15-S (0) tR16 (where t is from 0 to 2), and -R > 115 S (0) tN (R14) 2 (wherein t is from 1 to 2) wherein each R14 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; 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 from three to twelve carbons. The heterocyclyl radical 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 wherein 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 linked to the alkyl radical on the nitrogen atom. The alkyl portion of the heterocyclylalkyl radical may be optionally substituted as defined above by an alkyl group. The heterocyclyl part of the heterocyclylalkyl radical may be optionally substituted as defined above by a heterocyclyl group. "Heterocyclylalkyl of 3 to 12 carbon atoms" refers to a heterocyclylalkyl radical as defined above having from three to twelve carbons. The heterocyclylalkyl radical of 3 to 12 carbon atoms may be optionally substituted as defined above by a heterocyclylalkyl group. "Heteroaryl" refers to an aromatic ring radical of 5 to 18 members consisting of carbon atoms and one to five heterogeneous atoms 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 fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may optionally be quaternized. ples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzolotolyl, benzothiadiazolyl, benzonaphtofuranyl, benzoxazolyl, benzodioxolyl, benzodloxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo [4,6 ] imidazo [1,2-ajpyridinyl, carbazolyl, cinolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isolndolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, phenazinyl , phenothiazinyl, phenoxazinyl, phthalazinyl, pteriinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. Unless specifically stated otherwise in the specification, the term "heteroaryl" is intended to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R15-OR14, -R15-OC (0) -R14, -R15-N (R14) 2, -R 5-C (0) R 14, -R 15 -C (0) OR 14, -R 15 -C (0) N (R 14) 2, -R 5 -N (R 14) C (0) OR 16, -R 15 -N (R 14) ) C (0) R16, -R15-N (R14) (S (0) tR16) (where t is from 1 to 2), -R15-S (0) tOR16 (where t is from 1 to 2) , -R15-S (0) tR16 (where t is from 0 to 2), and -R15-S (0) tN (R14) 2 (where t is from 1 to 2) where each R14 is independently hydrogen , alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; 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 heteroaryl radical as defined above having from one to twelve carbon atoms. The heteroaryl group of 1 to 12 carbon atoms may be optionally substituted as defined above by a heteroaryl group. "Heteroaryl of 5 to 12 carbon atoms" refers to a radical heteroaryl radical as defined above having from five to twelve carbon atoms. The heteroaryl group of 5 to 12 carbon atoms may be optionally substituted as defined above by a heteroaryl group. "Heteroarylalkyl" refers to a radical of the formula -RaRf wherein Ra is an alkyl radical as defined above and Rf is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above by a heteroaryl group. The alkyl portion of the heteroarylalkyl radical 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 from three to twelve carbon atoms. The heteroarylalkyl group of 3 to 12 carbon atoms may be optionally substituted as defined above by a heteroarylalkyl group. "Heteroarylcycloalkyl" refers to a radical of the formula-RdRf wherein Rd is a cycloalkyl radical as defined above and Rf is a heteroaryl radical as defined above. The cycloalkyl portion of the heteroarylcycloalkyl radical may be optionally substituted as defined above by a cycloalkyl group. The heteroaryl portion of the heteroarylcycloalkyl radical may be optionally substituted as defined above by a heteroaryl group. "Heteroarylalkenyl" refers to a radical of the formula -RbRf wherein Rb is an alkenyl radical as defined above and Rf is a heteroaryl radical as defined above. The heteroaryl portion of the heteroarylalkenyl radical may be optionally substituted as defined above by a heteroaryl group. The alkenyl part of the heteroarylalkenyl radical may be optionally substituted as defined above by an alkenyl group. "Hydroxyalkyl" refers to a radical of the formula -Ra-OH wherein Ra is an alkyl radical as defined above. The hydroxy group may be linked to the alkyl radical at any carbon within the alkyl radical. The alkyl part of the hydroxyalkyl group may be optionally substituted as defined above by an alkyl group. "Hydroxyalkyl of 2 to 12 carbon atoms" refers to a hydroxyalkyl radical as defined above containing from 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 by an alkyl group. "Hydroxyalkyl of 3 to 12 carbon atoms" refers to a hydroxyalkyl radical as defined above containing from 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 by an alkyl group. "Hydroxyalkyl of 7 to 12 carbon atoms" refers to a hydroxyalkyl radical as defined above containing from 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 by an alkyl group. "Hydroxyalkenyl" refers to a radical of the formula -Rc-OH wherein Rc is an alkenyl radical as defined above. The hydroxy group can be linked to the alkenyl radical at any carbon within the alkenyl radical. The part of the alkenyl 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 from 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 by an alkenyl group. "Hydroxyalkenyl of 3 to 12 carbon atoms" refers to a hydroxyalkenyl radical as defined above containing from three to twelve carbon atoms. The alkenyl part of the hydroxyalkenyl radical of 3 to 12 carbon atoms may be optionally substituted as defined above by an alkenyl group. "Hydroxy-alkyl of 1 to 6 carbon atoms" refers to a radical of the formula -Rh-OH wherein Rh is an unbranched alkyl radical having from one to six carbons and the hydroxy radical is linked to the terminal carbon. "Trihaloalkyl" refers to an alkyl radical, as defined above, which is substituted by three halogen radicals, as defined above, for example, trifluoromethyl. The alkyl part of the trihaloalkyl radical may be optionally substituted as defined above by an alkyl group. "Trihaloalkyl of 1 to 6 carbon atoms" refers to a trihaloalkyl radical as defined above having from one to six carbon atoms. The trihaloalkyl of 1 to 6 carbon atoms may be optionally substituted as defined above by a trihaloalkyl group. "Trihaloalkoxy" refers to a radical of the formula -ORg wherein Rg is a trihaloalkyl group as defined above. The trihaloalkyl portion of the trihaloalkoxy group may be optionally substituted as defined above by 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 1 to 6 carbon atoms group may be optionally substituted as defined above by A trihaloalkoxy group "A multi-ring structure" refers to a multicyclic ring system comprising two to four rings in the rings are independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl as defined above Each cycloalkyl may optionally be substituted as defined above by a cycloalkyl group Each aryl may be optionally substituted as defined above by an aryl group Each heterocyclyl may be optionally substituted as defined above by a heterocyclyl group Each heteroaryl may be optionally substituted as defined above by a group het eroaryl The rings may be linked to each other through direct bonds or some or all of the rings may be fused together. Examples include, but are not limited to a cycloalkyl radical substituted by an aryl group; a cycloalkyl group substituted by an aryl group, which, in turn, is replaced by another aryl group; and so on. "Prodrugs" are intended to indicate a compound that can be converted under physiological conditions through 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 in vivo into an active compound of the invention. Prodrugs are typically easily transformed in vivo to produce the parent compound of the invention, for example, through hydrolysis in the blood. The prodrug compound generally 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, Drug Design, ed. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The term "prodrug" is also intended to include any covalently linked carriers that release the active compound of the invention in vivo when said prodrug is administered to a mammalian subject. The prodrugs of a compound of the invention can be prepared through the modification of the functional groups present in the compound of the invention in such a way that the modifications are divided, either in routine manipulation or in vivo, in the parent 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 is divided to form a free hydroxy, free amino or mercapto group free, respectively. Examples of prodrugs include, but are not limited to, acetate derivatives, alcohol formeate and benzoate or amine functional groups in the compounds of the invention and the like. "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive the isolation to a useful degree of purity of a reaction mixture, and the formulation into an effective therapeutic agent. "Mammal" includes humans and domestic animals, such as cats, dogs, pigs, cattle, sheep, goats, horses, rabbits and the like. "Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and the instances in which it does not occur. For example, "optionally substituted" means that the aryl radical may or may not be substituted and that the description includes both the substituted aryl radicals and the aryl radicals that do not have substitution. "Carrier, diluent, pharmaceutically acceptable excipient" includes without limitation any auxiliary, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / dye, flavor improver, surface active agent, wetting agent, dispersing agent, dispersing agent, suspension, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans and pets. "Pharmaceutically acceptable salt" includes both acid addition salts and base salts. "Pharmaceutically acceptable acid addition salts" refers to those salts that retain the effectiveness of the biological activity and the properties of the free bases, which are biologically or otherwise undesirable, and which are formed with inorganic acids such as , but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid , ascorbic 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, acid dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethane sulfonic acid, formic acid, fumaric acid co, galactactic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, acid lauric, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, napphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid , orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like. "Pharmaceutically acceptable base addition salts" refers to those salts that retain the effectiveness and biological 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, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. The preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia resins, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexlamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. In general, crystallizations produce a solvate of the compound of the invention. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the invention with one or more molecules of the solvent. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent may be an organic solvent. In this way, 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 solvate forms. The compound of the invention can be a true solvent, while in other cases, the compound of the invention can merely retain spontaneous water or be a mixture of water plus some spontaneous solvent. A "pharmaceutical composition" refers to a formulation of a compound of the invention and a means generally accepted in the art for the distribution of the biologically active compound to mammals, e.g., humans. Said medium includes all pharmaceutically acceptable carriers, diluents or excipients thereof. "Therapeutically effective amount" refers to that amount of compound of the invention which, when administered to a mammal, preferably a human being, is sufficient to effect the treatment, as defined below, of a disease or condition mediated by SCD in the mammal, preferably a human being. The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition, and its severity, and the age of the mammal to be treated, but can be determined routinely by one skilled in the art. in the technique you have with respect to your own knowledge and this description. "Treating" or "treatment" as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human being, that has the disease or disorder, and includes: (i) preventing the occurrence of the disease or condition in a mammal, in particular, when said mammal is predisposed to the condition but has not yet been diagnosed as having it; (ii) inhibit the disease or condition, that is, stop its development; or (iii) alleviating the disease or condition, that is, causing the regression of the disease or condition. As used herein, the terms "disease" and "condition" may be used interchangeably or may be different in that the condition or condition may not have a known causative agent (so the etiology has not yet worked) and therefore It is not yet recognized as a disease, but only as an undesirable condition or syndrome, where a more or less specific group of symptoms has been identified by physicians. The compounds of the invention, or their pharmaceutically acceptable salts, may contain asymmetric centers and may be in the form of giving rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined, in terms of absolute stereochemistry, as (R) - or (S) - or, as (D) - or (L) - for amino acids. The present invention is intended to include all such isomers, as well as their racemic and optically pure forms. The optically active isomers (+) and (-), (R) - and (S) -, or (D) -y (L) - can be prepared using chiral synthons, or chiral reagents, or resolved 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, the compounds are intended to include both geometric isomers E and Z. Likewise, it is intended to include all tautomeric forms. A "stereoisomer" refers to a compound made from the same atoms linked through the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates several stereoisomers and mixtures thereof and includes "enantiomers", which refer to two stereoisomers whose molecules are mirror images not superimposed on one another. A "tautomer" refers to a proton exchange from one atom of one molecule to another atom of the same molecule. The present invention includes tautomers of any of said compounds. The protocol for the chemical naming and structure diagrams used here employ and are based on the chemical naming characteristics as used by the Chemdraw version 7.0.1 (available from Cambridgesoft Corp., Cambridge, MA). For the complex chemical names used herein, a substituent group is called before the group to which it is linked. For example, cyclopropylethyl comprises an ethyl determination with the cyclopropyl substituent. In chemical structure diagrams, all bonds are identified, except for some carbon atoms that are assumed to be bound with enough hydrogen atoms to complete the valence. For example, a compound of the formula (III), as set forth above in the Compendium of the invention, wherein x e and both are 1; A is oxygen; W is -N (R1) C (0) -; R1, R4, R5, R6, R6a, R7, R7a, R8, R8a, R9, and R9a each is hydrogen; R2 is 2-cyclopropi leti lo and R3 is 2,5-dichlorophenyl, that is, a compound of the following formula: is referred to herein as 6- [4- (2,5-dichlorobenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide. Certain radical groups of the compounds of the invention are described herein as bonds between two parts of the compounds of the invention. For example, in the following formula (I): W is described, for example, as being -N (R1) C (0) -, -C (O) N (R1) -, or -N (R1) C (0) N (R1) -; and V is described as -C (O) -, -C (S) - or -C (R10) -. This description is intended to describe a group W linked to the group R2 as follows: R2-N (R1) C (0) -, R2-C (0) N (R1) -, or R2-N (R1) C (0) N (R1) -; and is intended to describe a group V linked to the group R3 as follows: -C (0) -R3, -C (R10) -R3, or -C (S) -R3. In other words, the description of the linking groups W and V is intended to be read from left to right in view of the formula (I), as described above.

Modes of the invention In one embodiment of the invention as set forth above in the Compendium of the invention, a group of compounds of the formula (II) is directed to compounds wherein x and each is 1; W is selected from -C (0) N (R1) - and -N (R1) C (0) -; each R1 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; R2 is selected from the group consisting of alkyl of 7 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 7 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 atoms carbon, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aralkyl of 13 to 19 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, and heteroarylalkyl of 3 to 12 carbon atoms; each R2 is optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) OR11, Tihaloalkyl of 1 to 6 carbon atoms, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; R3 is selected from the group consisting of alkyl of 3 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 3 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 carbon atoms, alkoxy of 3 to 12 atoms of carbon, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aralkyl of 7 to 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, heteroaryl of 5 to 12 carbon atoms and heteroarylalkyl of 3 to 12 carbon atoms; each R3 is optionally substituted by one or more substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms carbon, alkylsulfonyl of 1 to 6 carbon atoms, halogen, cyano, nitro, hydroxy, -N (R12) 2, -C (0) OR11, -S (0) 2N (R12) 2, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl and heteroarylcycloalkyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; each "R11" is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl or aralkyl, and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.From this group of compounds of the formula (II) ), a subgroup of compounds is directed to compounds wherein W is -N (R1) C (0) -, R1 is hydrogen, R2 is cycloalkylalkyl of 4 to 12 carbon atoms, R3 is alkyl of 3 to 12 carbon atoms or alkenyl of 3 to 12 carbon atoms, each optionally substituted with one or more halogen groups, R4 and R5 are each hydrogen, and R6, R6a, R7, R7a, Ra, R8a, R9, and R9a are each hydrogen Another subgroup of this group of compounds of the formula (11) is directed to compounds wherein W is -N (R1) C (0) -; R1 is hydrogen; R2 is cycloalkylalkyl of 4 to 12 carbon atoms; R3 is cycloalkyl of 3 to 12 carbon atoms optionally substituted with one or more substituents selected from hydroxy, thihaloalkyl of 1 to 6 carbon atoms or aralkyl of 1 to 6 carbon atoms; R4 and R5 are each hydrogen; and R6, R6a, R7 R7a, R8, R8a, R9, and R9a are each hydrogen. Another subgroup of this group of compounds of the formula (II) is directed to compounds wherein W is -N (R1) C (0) -; R2 is Cycloalkylalkyl of 4 to 12 carbon atoms and R3 is Hydroxyalkyl of 3 to 12 carbon atoms optionally substituted with one or more halogen groups; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen. Another subgroup of this group of compounds of the formula (II) is directed to compounds wherein W is -N (R1) C (0) -; R1 is hydrogen; R2 is cycloalkylalkyl of 4 to 12 carbon atoms; R3 is alkoxy of 3 to 12 carbon atoms; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen. Another subgroup of this group of compounds of the formula (II) is directed to compounds wherein W is -N (R) C (0) -; R1 is hydrogen; R2 is cycloalkylalkyl of 4 to 12 carbon atoms; R3 is aralkyl of 7 to 12 carbon atoms optionally substituted with one or more substituents independently selected from halogen or trihaloalkyl of 1 to 6 carbon atoms; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen. Another subgroup of this group of compounds of the formula (II) is directed to compounds wherein W is -N (R1) C (0) -; R1 is hydrogen; R2 is cycloalkylalkyl of 4 to 12 carbon atoms; R3 is Heterocyclyl of 3 to 12 carbon atoms or Heteroaryl of 5 to 12 carbon atoms, each optionally substituted with one or more substituents independently selected from halogen, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms or aralkyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen. In another embodiment of the invention as set forth above in the Compendium of the invention, a group of compounds of the formula (III) is directed to compounds wherein x and y are each 1; A is oxygen or sulfur; W is selected from -C (0) N (R1) - and -N (R1) C (0) -; each R1 is independently selected from hydrogen or alkyl of 1 to 6 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, alkyl of 1 to 6 atoms carbon, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 12 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; each R2 is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR11, -C (O) R11, -OC (0) R11, -C (0) OR 11, -C (0) N (R 12) 2, -N (R 12) 2, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R11, -C (0) OR11, -S (0) 2N (R12) 2, cycloalkyl, heterocyclyl and heteroarylcycloalkyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together or R9 and R9a together are an oxo group, while the remainder of R6, Rda, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms. carbon; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. Of this group of compounds of the formula (III), a subgroup of compounds is directed to compounds wherein x and y are each 1; A is oxygen or sulfur; W is -N (R1) C (0)? R1 is hydrogen, methyl or ethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms. Of this group of compounds of the formula (III), a group of compounds is directed to compounds wherein R2 is cycloalkylalkyl of 4 to 12 carbon atoms optionally substituted by one or more substituents selected from the group consisting of -OR11, 1 to 3 carbon atoms or aryl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R11, -C (0) OR11, -S (0) 2N (R 2) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. Another group of this subgroup of compounds of the formula (III) is directed to compounds wherein A is oxygen; R 2 is alkyl of 1 to 12 carbon atoms or alkenyl of 2 to 12 carbon atoms, each optionally substituted by one or more substituents selected from the group consisting of halogen, aryloxy, -C (0) R 11, -OC (0) ) R11o -C (0) OR11; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms to Iq uilsu Ifoní lo of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R11, -C (0) OR11, -S (0) 2N (R12) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. Another group of this subgroup of compounds of the formula (III) is directed to compounds wherein A is oxygen; R 2 is hydroxy alkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 carbon atoms, each optionally substituted by one or more halogen groups; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R11, -C (0) OR11, -S (0) 2N (R12) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

Another group of this subgroup of compounds of the formula (III) is directed to compounds wherein A is oxygen; R2 is aralkyl of 7 to 12 carbon atoms, wherein the aryl portion of the aralkyl of 7 to 12 carbon atoms group is optionally substituted by one or more substituents independently selected from halogen, alkyl of 1 to 3 carbon atoms, - OR 11, -C (0) OR 11, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl and aryl, and the alkyl part of the aralkyl group of 7 to 12 carbon atoms is optionally substituted by one or more substituents independently selected from hydroxy, halogen, -OR11 and -OC (O) R11; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R11, -C (0) OR11, -S (0) 2N (R12) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. Another group of this subgroup of compounds of the formula (III) is directed to compounds wherein A is oxygen; R 2 is alkoxy of 1 to 6 carbon atoms or alkoxyalkyl of 3 to 12 carbon atoms, each optionally substituted with one or more substituents independently selected from halogen or cycloalkyl of 3 to 6 carbon atoms; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R1? (0) OR11, -S (0) 2N (R12) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. Another group of this subgroup of compounds of the formula (III) is directed to compounds wherein A is oxygen; R2 is aryl optionally substituted with one or more substituents independently selected from halogen, cyano, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) R11, -OC (0) R11, -C (0) OR11, -C (O) N (R12) 2, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; R3 is phenyl optionally substituted by trihaloalkyl of 1 to 6 carbon atoms or Trihaloalkoxy of 1 to 6 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. Another group of this subgroup of compounds of the formula (III) is directed to compounds wherein A is oxygen; R2 is heteroaryl of 1 to 12 carbon atoms optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) R11, -OC (0) R11, -C (0) OR11, -C (0) N (R12) 2 and trihaloalkyl of 1 to 6 carbon atoms; R3 is phenyl optionally substituted by trihaloalkyl of 1 to 6 carbon atoms or trihaloalkoxy of 1 to 6 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. Of this group of compounds of the formula (III), a subgroup of compounds is directed to compounds wherein heteroaryl of 1 to 12 carbon atoms is selected from the group consisting of pyridinyl, purinyl, pyrazinyl, indolyl, indazolyl, benzoimidazolyl, midazolyl, tetrazolyl, triazolyl, isoxazolyl, pyrazolyl, pyrimidinyl , thiadiazolyl, thiazolyl and pyridazinyl. Another group of this subgroup of compounds of the formula (III) is directed to compounds wherein A is oxygen; R2 is heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms or heteroarylalkyl of 3 to 12 carbon atoms, each optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo , alkyl of 1 to 3 carbon atoms, -OR11, -C (0) R11, - OC (0) R11, -C (0) OR11, -C (0) N (R12) 2 and trihaloalkyl of 1 to 6 carbon atoms; R3 is phenyl optionally substituted by halogen, trihaloalkyl of 1 to 6 carbon atoms or trihaloalkoxy of 1 to 6 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. Of the group of compounds of the formula (III) as stated above, another subgroup of compounds of the formula (III) is directed to compounds wherein x and y are each 1; A is oxygen; W is -C (0) N (R1) -; R1 is hydrogen, methyl or ethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms. From this subgroup of compounds, a group of compounds of the formula (III) is directed to compounds wherein R2 is cycloalkyl of 3 to 12 carbon atoms or cycloalkylalkyl of 4 to 12 carbon atoms, each optionally substituted by one or more substituents selected from the group consisting of -OR11, alkyl of 1 to 3 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms or aryl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms and trihaloalkoxy of 1 to 6 carbon atoms; and each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl. Another group of this subgroup of compounds of the formula (III) is directed to compounds wherein R2 is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkyl of 1 to 6 carbon atoms or alkoxyalkyl of 3 to 12 carbon atoms, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) R11, -OC (0) R11, -C (0) OR11, -C (0) N (R12) 2, -N (R12) 2, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl and aryl; R3 is phenyl optionally substituted by halogen, trihaloalkyl of 1 to 6 carbon atoms or trihaloalkoxy of 1 to 6 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. Another group of this subgroup of compounds of formula (III) is directed to compounds wherein R2 is aralkyl of 7 to 12 carbon atoms optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR 11, -C (0) R 11, -OC (0) R 11, -C (0) OR 1 0 -C (0) N (R 1) 2, -N (R 12) 2 , trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl and aryl; R3 is phenyl optionally substituted by halogen, trihaloalkyl of 1 to 6 carbon atoms or trihaloalkoxy of 1 to 6 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. In another embodiment of the invention as set forth above in the Compendium of the invention, another group of compounds of the formula (III) is directed to compounds wherein x and y are each 1; A is oxygen; W is -N (R1) C (0) -; R1 is hydrogen, methyl or ethyl; R2 is cyclopropylethyl or cyclopropylmethyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen. In another embodiment of the invention as set forth above in the Compendium of the invention, another group of compounds of the formula (III) is directed to compounds wherein x and y are each 1; A is oxygen; W is -N (R1) C (0) -; R1 is hydrogen, methyl or ethyl; R2 is alkyl of 1 to 6 carbon atoms optionally substituted by -C (0) OR11; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; R4 and R5 are each hydrogen; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen; and R11 is hydrogen, methyl, ethyl or 1, 1-d and methylethi. In another embodiment of the invention as set forth above in the Compendium of the invention, another group of compounds of the formula (III) is directed to compounds wherein x and y are each 1; A is oxygen; W is -N (R1) C (0) -; R1 is hydrogen, methyl or ethyl; R2 is 2-f-enyl or 3-phenylpropyl wherein the phenyl group is optionally substituted by one or more substituents independently selected from chloro, fluoro or -OR11; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; R4 and R5 are each hydrogen; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen; and R11 is hydrogen, methyl, ethyl or 1,1-dimethylethyl. In another embodiment of the invention as set forth above in the Compendium of the invention, another group of compounds of the formula (III) is directed to compounds wherein x and y are each 1; A is oxygen; W is -C (0) N (R1) -; R1 is hydrogen, methyl or ethyl; R2 is cyclopropylethyl, cyclopropylmethyl or ciciopenti leti lo; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen. In another embodiment of the invention as set forth above in the Compendium of the invention, another group of compounds of the formula (III) is directed to compounds wherein x and y are each 1; A is oxygen; W is -C (0) N (R1) -; R1 is hydrogen, methyl or ethyl; R2 is alkyl of 1 to 6 carbon atoms; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen. In another embodiment of the invention as set forth above in the Compendium of the invention, another group of compounds of the formula (III) is directed to compounds wherein x and y are each 1; A is oxygen; W is -C (0) N (R1) -; R1 is hydrogen, methyl or ethyl; R2 is 3-phenylpropyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen.

In another embodiment of the invention as set out above in the Compendium of the invention, the group of compounds of the formula (IV) is directed to compounds wherein x and y are each 1; each R1 is hydrogen or alkyl of 1 to 6 carbon atoms; R2 is selected from the group consisting of alkyl of 3 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 3 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 carbon atoms, alkyl of 3 to 12 atoms carbon, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkyl of 4 to 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, aryl, aralkyl of 7 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms, and heteroarylalkyl of 3 to 12 carbon atoms; each R2 is optionally substituted by one or more substituents selected from the group consisting of halogen, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR11, -C (O) OR11, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; R3 is selected from the group consisting of alkyl of 3 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 3 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 carbon atoms, alkoxy of 3 to 12 atoms carbon, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 12 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; wherein each of the above R3 groups is optionally substituted by one or more substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms, alkyl from 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, halogen, cyano, nitro, hydroxy, -N (R12) 2, -C (0) OR11, -S (0) 2N (R 2) 2 , cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl); R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together or R7 and R7a together are an oxo group while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, R7a, together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each one independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; each R1 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkyl of 3 to 6 carbon atoms, aryl or aralkyl; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. Of this group of compounds of the formula (IV), a subgroup of compounds is directed to compounds wherein R 2 is cycloalkyl of 3 to 12 carbon atoms or cycloalkylalkyl of 4 to 12 carbon atoms, each optionally substituted by one or more substituents selected from the group consisting of -OR11, alkyl of 1 to 3 carbon atoms or aryl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms and trihaloalkoxy of 1 to 6 carbon atoms; and each R1 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl. Another subgroup of this group of compounds of formula (IV) is directed to compounds wherein R2 is aralkyl of 7 to 12 carbon atoms optionally substituted by one or more substituents selected from the group consisting of halogen, -OR11 or alkyl of 1 to 3 carbon atoms; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms and trihaloalkoxy of 1 to 6 carbon atoms; and each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl.

Another subgroup of this group of compounds of formula (IV) is directed to compounds wherein R2 is aryl optionally substituted by one or more substituents selected from the group consisting of halogen, -OR11- or alkyl of 1 to 3 carbon atoms; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms and trihaloalkoxy of 1 to 6 carbon atoms; and each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl. Another subgroup of this group of compounds of the formula (IV) is directed to compounds wherein R 2 is alkyl of 3 to 12 carbon atoms, hydroxyalkyl of 3 to 12 carbon atoms or alkoxyalkyl of 3 to 12 carbon atoms, each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR11 or -C (0) OR11; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms and trihaloalkoxy of 1 to 6 carbon atoms; and each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl. In another embodiment of the invention as set forth above in the Compendium of the invention, another group of compounds of the formula (IV) is directed to compounds wherein x and y are each 1; each R1 is hydrogen, methyl or ethyl; R2 is benzyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen. In another embodiment of the invention as set forth above in the Compendium of the invention, another group of compounds of the formula (IV) is directed to compounds wherein x and y are each 1; each R1 is hydrogen, methyl or ethyl; R2 is pentyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each. one hydrogen In another embodiment of the invention as set out above in the Compendium of the invention, a group of compounds of the formula (Va) is directed to compounds wherein x and y are each independently 1; W is -N (R1) C (0) -; each R1 is hydrogen or alkyl of 1 to 6 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, alkoxy of 1 to 12 atoms of carbon, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aralkyl of 3 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; each R2 is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) R11, -OC (0) R11, -C (0) OR 11, -C (0) N (R 12) 2, -N (R 12) 2, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; R3 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, alkoxy of 1 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 12 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; each R3 is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms alkylsulfonyl of 1 to 6 carbon atoms, -N (R) 2, ~ OC (0) R -C (0) ORA -S (0) 2N (R1) 2, cycloalkyl, heterocyclyl and heteroarylcycloalkyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N (R12) 2; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; R10 is hydrogen or alkyl of 1 to 3 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl; and each R 11 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. Of this group of compounds of the formula (Va), the subgroup of compounds is directed to compounds wherein R 2 is cycloalkyl of 3 to 12 carbon atoms or cycloalkylalkyl of 4 to 12 carbon atoms, each optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms, -OR11, alkyl of 1 to 3 carbon atoms or aryl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R11, -C (0) OR11, -S (0) 2N (R12) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms. The specific embodiments of the groups, subgroups and groups of compounds described above of the formula (II), (III), (IV) and (Va) are described in the Examples set out below. In one embodiment, the methods of the invention are directed towards the treatment and / or prevention of diseases mediated by stearoyl-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 through the administration of an effective amount of a compound of the invention. The present invention also relates to the pharmaceutical composition containing the compounds of the invention. In one embodiment, the invention relates to 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 a mammal, preferably a patient human being. In one embodiment of said composition, the patient has a high lipid level, such as elevated triglycerides or cholesterol, prior to the administration of said compound of the invention and the compound of the invention is present in an effective amount to reduce said level of lipid Utility and Testing of the Compounds of the Invention The present invention relates to compounds, pharmaceutical compositions and methods for using the compounds and pharmaceutical compositions for the treatment and / or prevention of diseases mediated by stearoyl-CoA (SCD) desaturase, especially human SCD (hSCD), preferably diseases related to dyslipidemia and disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, especially cardiovascular disease, diabetes, obesity, metabolic syndrome and the like, by administration to a patient in need of such treatment an effective amount of an agent for modulation, especially inhibition of SCD. In general, the present invention provides a method for treating a patient for, or protecting a patient from the development of, a disease related to dyslipidemia and / or a disorder of lipid metabolism, wherein the levels of lipid in an animal, especially a human being, they are outside the normal range (i.e., abnormal lipid level, such as elevated plasma lipid levels), especially higher than normal levels, preferably wherein said lipid is a fatty acid, such as a free or complex fatty acid, triglycerides, phospholipids, or cholesterol, such as where the LDL-cholesterol levels are elevated or the HDL-cholesterol levels are reduced, or any combination of these, wherein said condition or lipid-related disease is a disease or condition mediated by SCD, which comprises administering to an animal, such as a mammal, especially a patient human being, a The 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 the modulation, especially inhibition, the SCD activity can be determined using the assay described later in the Example 33. Alternatively, the general value of the compounds in the treatment of disorders and diseases can be established in industry-standard animal models to demonstrate the efficacy of the compounds in the treatment of obesity, diabetes or elevated levels of triglycerides or cholesterol. or to improve the . glucose tolerance. Such models include obese fa / fa rats from Zucker (available from Harlan Sprague Dawley, Inc. (Indianapolis, Indiana)), or Zucker diabetic adipose rats (ZDF / GmiCrl-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 that are the result of the biological activity of aberrant delta-9 desaturase or which can be decreased 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 that is, or is related to, cardiovascular disease, dyslipidemia (including but not limited to disorders of serum triglyceride levels, hypertriglyceridemia, VLDL, HDL, LDL, Fatty acid desaturation index (for example the ratio of 18: 1/18: 0 of fatty acids, or other fatty acids, as defined elsewhere in the present), cholesterol, and cholesterol total, hypercholesterolemia, as well as cholesterol disorders (including disorders characterized by defective reverse cholesterol transport), familial combined hyperlipidemia, coronary artery disease, atherosclerosis, heart disease, cerebrovascular disease (including but not limited to shock, ischemic shock) and temporal ischemic attack (TIA), peripheral vascular disease and ischemic retinopathy. Referring, the compounds of the invention, in a patient, will increase HDL levels and / or lower triglyceride levels and / or lower levels of LDL or non-HDL cholesterol. A disease or condition mediated by SCD also includes metabolic syndrome (including but not limited to dyslipidemia, obesity and insulin resistance, hypertension, microalbuminemia, hyperuricaemia, and hypercoagulability), Syndrome X, diabetes, insulin resistance, impaired glucose tolerance, diabetes mellitus. non-insulin dependent, Type II diabetes, Type I diabetes, diabetic complications, weight disorders of the body (including, but not limited to, obesity, overweight, cachexia, and anorexia), weight loss, and index-related diseases of body mass, and leptin. In a preferred embodiment, the 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 to describe a condition comprising combinations of Type II diabetes, impaired glucose tolerance, insulin resistance, hypertension, obesity, increased abdominal circumference, hypertriglyceridemia, low HDL. , hyperuricaemia, hypercoagulability and / or microalbuminemia. A disease or condition mediated by SCD also includes fatty liver, hepatic steatosis, hepatitis, non-alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, protoporphyria erythrohepatic, iron-overload disorders, hereditary hemochromatosis, hepatic fibrosis, liver cirrhosis, hepatoma and related conditions. 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 hyperlipoproteinemias, familial histiocytic reticulosis, deficient lipase lipoprotein, apolipoprotein deficiency (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 polyunsaturated fatty acid disorder (PUFA), or a skin disorder, including but not limited to eczema, acne, psoariasis, formation or prevention of keloid scar, diseases related to the production or secretions of mucous membranes, such as monounsaturated fatty acid, wax esters and the like. A disease or condition mediated by SCD also includes inflammation, sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, cystic fibrosis, and premenstrual 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, malignancy, metastasis, tumors (benign or malignant), carcinogenesis, hepatomas and the like. A disease or condition mediated by SCD also includes a condition wherein the increase of the thin body mass, or thin muscle mass, is desired, as is desirable in improving functioning through the construction of muscles. Myopathies and lipid myopathies such as carnitine palmitoyltransferase deficiency (CPT I or CPT II) are also included here. Said treatments are useful in the conservation of humans and animals, including administration to a bovine, porcine or avian domestic animal, or any other animal to reduce the production of triglycerides and / or provide thinner meat products and / or animals more healthy 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 RNA viruses of positive chain structure, coronaviruses, SARS virus, coronavirus associated with SARS, Togaviruses, Picornaviruses, Coxsaquievirus, Yellow Fever virus, Flavíviridae, ALPHAVIRUS (TÓGAVIRIDAE) including rubella virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Sindbis virus , Semliki forest virus, virus Chikungunya, O'nyong'nyong virus, Ross river virus, Mayaro virus, Alphaviruses; ASTROVIRIDAE including Astrovirus, Human Astroviruses; CALICIVIRIDAE including Vesicular exanthema of swine virus, Norwalk virus, Callcivirus, Bovine calcivirus, Pork calcivirus, Hepatitis E; CORONAVIRIDAE including Coronavirus, SARS virus, Avian infectious bronchitis virus, Bovine coronavirus, Canine coronavirus, Feline infectious peritonitis virus, Human 299E coronavirus, OC43 human coronavirus, murine hepatitis virus, Porcine epidemic diarrhea virus, Porcine Encephalomyelitis Haemagglutination Virus, Porcine Transmissible Gastroenteritis Virus, Rat Coronavirus, Turkey Coronavirus, Rabbit Coronavirus, Berne Virus, Breda Virus; FLAVIVIRIDAE including Hepatitis C virus, West Nile virus, Yellow fever virus, St. Louis encephalitis virus, Dengue group, Hepatitis G virus, Japanese B encephalitis virus, Murray Valley encephalitis virus, Central European tick-borne encephalitis, Far East tick-borne encephalitis virus, Kyasanur forest virus, Louping's disease virus, Powassan virus, Omsk haemorrhagic fever virus, Kumilinge virus, Absetarov hypr anzalova virus, liheus virus, Rocio encephalitis virus, Langat virus, Pestivirus viral diarrhea virus, Bovine viral diarrhea, Hog cholera virus, Rio Bravo Group, Tyuleniy Group, Ntaya Group, Uganda S Group, Modoc Group; PICORNAVIRIDAE including Coxsackie A virus, Rhinovirus, Hepatitis A virus, Encephalomyocarditis virus, Mengovirus, ME virus, Human poliovirus 1, Coxsackie B; POTYVIRIDAE including Potyvirus, Rymovirus, Bimovirus. Additionally there may be a disease or infection caused by or linked to Hepatitis virus, Hepatitis B virus, Hepatitis C virus, Human immunodeficiency virus (HIV) and the like. Treatable viral infections include those in which the virus employs an RNA intermediate as part of the replication cycle (hepatitis or HIV); additionally there may be a disease or infection caused by or linked to RNA negative chain structure viruses such as influenza virus and parainfluenza. The compounds identified in the present specification inhibit the desaturation of several fatty acids (such as the C9-C10 desaturation of stearoyl-CoA) which is achieved through desaturases delta-9, such as stearoyl-CoA1 desaturase (SCD1 ). As such, these compounds inhibit the formation of various fatty acids and metabolites in stream below them. This can lead to an accumulation of stearoyl-CoA or palmitoyl-CoA and other upstream precursors of various fatty acids; which possibly will result in a negative feedback loop causing a global change in the fatty acid metabolism. Any of these consequences may ultimately be responsible for the overall therapeutic benefits provided by these compounds.

Typically, a successful SCD inhibitory therapeutic agent will meet some or all of the following criteria. Oral availability should be above 20%. The efficacy 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 outside this range may be acceptable. ("mg / Kg" means milligrams of the compound per kilogram of the body mass of the subject to whom it is being administered). The therapeutic index (or ratio of toxic dose to therapeutic dose) should be greater than 100. The potency (as expressed by the IC50 value) should be less than 10 μM, preferably below 1 μM and more preferably below 50 nM. . IC50 ("Inhibitor Concentration - 50%") is a measure of the amount of the compound required to achieve 50% inhibition of SCD activity, for a specific period of time, in a SCD biological activity assay. Any process for measuring the activity of SCD enzymes, preferably mouse or human SCD enzymes, can be used to test the activity of compounds useful in the methods of the invention in inhibiting said SCD activity. The compounds of the invention demonstrate an IC50 in a 15 minute microsomal assay of preferably less than 10 μM, less than 5 μM, less than 2.5 μM, less than 1 μM, 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 a reversible inhibition (i.e., competitive inhibition) and preferably does not inhibit other iron binding proteins. The required dose should preferably not be more than once or twice a day or at meals. The identification of the compounds of the invention as SCD inhibitors was easily achieved using the SCD enzyme and the microsomal assay procedure described in Brownie et al., Supra. When tested in this assay, compounds of the invention had less than 50% remaining SCD activity at a concentration of 10 μM of the test compound, preferably less than 40% of the remaining SCD activity of the test compound, more preferably 30% of the remaining SCD activity at a concentration of 10 μM of the test compound, and still more preferably 20% of the remaining SCD activity at a concentration of 10 μM of the test compound, thereby demonstrating that the The compounds of the invention are potent inhibitors of SCD activity. These results provide the basis for an analysis of the relationship between structure-activity (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 now use to identify preferred embodiments of the compounds of the invention for use as therapeutic agents. Other methods for testing the compounds described herein are also readily available to those skilled in the art. In this way, in addition, such contact can be achieved in vivo. In one such modality, said contact in step (a) is achieved through the administration of said chemical agent to an animal afflicted with a disorder related to triglyceride (TG) or very low density lipoprotein (VLDL) and subsequently detecting a change in the level of triglyceride in the plasma in said animal, therefore a therapeutic agent useful for treating a disorder related to triglyceride (TG) or very low density lipoprotein (VLDL) is identified. In such an embodiment, the animal may be a human being, such as a patient human being afflicted with said disorder and in need of such treatment of said disorder. In specific embodiments of said in vivo processes, 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 delta-5 desaturase, delta-6 desaturase. or fatty acid synthetase. Model systems useful for the evaluation of the compound may include, but are not limited to, the use of liver microsomes, such as from mice that have been maintained on a high carbohydrate diet, or from human donors, including persons suffering from of obesity. Immortalized cell lines, 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 primary mouse hepatocytes, are also useful in testing the compounds of the invention. When whole animals are used, mice used as a source of primary hepatocyte cells can also be used where the mice have been maintained on a high carbohydrate diet to increase the SCD activity in microsomes and / or to raise the levels of triglycerides in the plasma (ie, a ratio of 18: 1/18: 0); Alternatively mice with a normal diet, or mice with abnormal triglyceride levels can be used. Mouse models employing transgenic mice designed for hypertriglyceridemia are also available as in the mouse phenome database. Rabbits and hamsters are also useful as animal models, especially those expressing CETP (cholesteryl ester transfer protein). Another suitable method for determining the in vivo efficacy of the compounds of the invention is indirectly to measure their impact on the inhibition of the SCD enzyme through the measurement of the subject's Desaturation index after the administration of the compound. The "Desaturation index" employed in this specification means the proportion of the product on the substrate for the SCD enzyme as measured from a given tissue sample. This can be calculated using three different equations 18: 1n-9/18: 0 (oleic acid on stearic acid); 16: 1n-7/16: 0 (palmitoleic acid on palmitic acid); and / or 16: 1n-7 + 18: 1n-7/16: 0 (measuring all 16: 0 reaction products of desaturation over 16: 0 of substrate). The desaturation index was mainly measured in triglycerides in the liver or plasma, but it can also be measured in other lipid fractions selected from a variety of tissues. The index of desaturation, generally speaking, is a tool for the perfusion of lipid in plasma. A number of human diseases and disorders are the result of the aberrant biological activity of SCD1 and can be ameliorated by modulating the biological activity of SCD1 using therapeutic agents of the invention. The inhibition of SCD expression can 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 the fluidity of the membrane, while the effects on the composition of triglycerides and cholesterol esters can affect the metabolism and adiposity of lipoprotein. In carrying out the methods of the present invention will of course be understood that the particular reference to buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all materials related ones that one skilled in the art would recognize as being of interest or value in the particular context in which this discussion is presented. For example, it is possible to replace one pH regulating system or culture medium with another and still achieve similar results, if not identical. Those skilled in the art will have sufficient knowledge of such systems and methodologies to be able, without improper experimentation, to make such substitutions that optimally serve their purposes in using the methods and procedures described herein.

Pharmaceutical Compositions of the Invention and Administration The present invention also relates to a pharmaceutical composition containing the compounds of the invention described herein. In one embodiment, the present invention relates to 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 administers to an animal, preferably a mammal, preferably a patient human being. In one embodiment of said composition, the patient has a high lipid level, such as elevated triglycerides or cholesterol, prior to the administration of said compound of the invention and the compound of the invention is present in an effective amount to reduce said lipid level. Pharmaceutical compositions useful herein also contain a pharmaceutically acceptable carrier, including any suitable diluent or excipient, which includes any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without a undue toxicity. Pharmaceutically acceptable carriers include, but are not limited to, liquids, such as water, saline, glycerol and ethanol, and the like. A detailed discussion of the pharmaceutically acceptable carriers, diluents, and other excipients is presented in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N.J. current edition). Those skilled in the art know how to determine suitable doses of the compounds for use in the treatment of the diseases and disorders contemplated herein. Therapeutic doses are usually identified through a dose scale study in humans based on preliminary evidence derived from animal studies. Doses should be sufficient to result in a desired therapeutic benefit without causing unwanted side effects to the patient. The preferred dose scale 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, although doses outside this range may be acceptable. The scheduling of the dosage can be once or twice a day, although more often or less often it can be satisfactory. Those with skill in the art are also familiar with the methods of administration (oral, intravenous, inhalation, subcutaneous, etc.), dosage forms, pharmaceutically suitable excipients and other relevant subjects in the distribution of the compounds to a subject in need. thereof. In an alternative use of the invention, the compounds of the invention can be used in in vitro or in vivo studies as illustrative agents 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 is understood that in the following description, the combinations of the substituents and / or variables of the formula described are permissible only if said contributions result in stable compounds. It will also be appreciated by those skilled in the art that in the process described below the functional groups of intermediary compounds may need to be protected through suitable protecting groups. Said functional groups include hydroxy, amino, mercapto and carboxylic acid. Said 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, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C (0) -R11 (wherein R11 is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like.

Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protective groups can be added or removed according to standard techniques, which are well known to those skilled in the art and are described herein. The use of protective 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 group can also be a polymer resin such as a Wang resin or a 2-chlorotryl chloride resin. It will also be appreciated by those skilled in the art that while said protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and then metabolized in the body to form the compounds of the invention. which are pharmacologically active. Said derivatives can therefore be described as "prodrugs". All prodrugs of the compounds of this invention are included within the scope of the invention. The following Reaction Schemes illustrate methods for making the compounds of this invention. It is understood that one skilled in the art will be able to make these compounds through similar methods known to one skilled in the art. In general, the starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to the sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described in this invention. In general, the compounds of the formula (1) of this invention wherein W is -N (R 1) C (0) - can be synthesized following the general procedure as described in Reaction Scheme 1.

REACTION SCHEME 1 Formula (I) Starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or through the methods described herein. In general, the compounds of the invention were prepared in the above reaction scheme as follows: Compound 101. A carboxylic acid of the formula (100) can be easily converted to an ester of the formula (101) following a standard procedure in the literature known to one with experience in the art. Compound 102. A mixture of a compound of the formula (101) obtained above and phosphorus oxychloride was carefully heated to reflux for 2-8 hours. The reaction mixture was then cooled and the excess phosphorus oxychloride was removed. The residue was then poured into ice water. The obtained precipitate was collected by filtration, washed with saturated NaHCO 3 and water, and then dried to yield the compound of the formula (102). Compound 104. A mixture of the compound of the formula (102) (1 equivalent) and the compound of the formula (103) (3 equivalents) in a solvent such as N, N-dimethylformamide or acetonitrile but not limited thereto was brought to reflux for 1-4 hours. The solvent was then removed in vacuo. The residue was dissolved in a solvent such as dichloromethane or ethyl acetate but not limited thereto. The resulting solution was washed with water, brine, and then dried. The organic phase was concentrated in vacuo to give the compound of the formula (104). Compound 106. To a stirred solution of the compound of the formula (104) (1 equivalent) in a solvent such as dichloromethane, toluene or THF but not limited thereto was added the solution of a chlorine or bromine of the formula (105) ( 1 equivalent) in the presence of a base such as triethylamine or Hunigs base but not limited thereto at 0 ° C. The resulting mixture was stirred at room temperature for 6-18 hours and then quenched with water. The organic phase was washed with water, brine, dried and then concentrated in vacuo to give the product of the formula (106) which was then purified by chromatography or crystallization. Compound 107. A solution of a compound of the formula (106) obtained above was dissolved in a suitable solvent and the ester was converted to a carboxylic acid under a standard condition known to one skilled in the art to obtain the carboxylic acid of the formula (107). Compound of the formula (I). To a solution of a compound of the formula (107) (1 equivalent) in a solvent such as dichloromethane, toluene or THF but not limited thereto was added a base such as triethylamine or Hunigs base but not limited thereto (2.5 equivalents) , followed by the addition of a coupling agent such as N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (1.1 equivalents). The resulting mixture was stirred for 15 minutes at one hour and an amine of the formula (108) (1.1 equivalents) was added. The mixture was stirred for 8-24 hours, then washed with water, dried and concentrated in vacuo. Purification through column chromatography or crystallization from a suitable solvent gave the compound of the formula (I). Alternatively, the compounds of the formula (I) of this invention wherein W is -N (R 1) C (0) - can be synthesized following the general procedure as described in Reaction Scheme 2.

REACTION SCHEME 2 (113) Formula (I) The starting materials of the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or through methods described herein. In general, the compounds of the invention were prepared in the above reaction scheme as follows: Compound 111. To a solution of 6-chloropyridazinyl-3-carboxylic acid of the formula (109) (1 equivalent) in a solvent such as dichloromethane , toluene or THF but not limited thereto, was added to a base such as triethylamine or Hunigs base but not limited thereto (2.5 equivalents), followed by the addition of a coupling agent such as N- (3-dimethylaminopropyl) - N'-ethylcarbodiimide (1.1 equivalents). The resulting mixture was stirred for 15 minutes at one hour and an amine of the formula (110) (1.1 equivalents) was added. The mixture was stirred for 8-24 hours, then wd with water, dried and concentrated in vacuo. Purification through column chromatography or crystallization from a suitable solvent gave the compound of the formula (111).

Compound 113. A mixture of the compound of the formula (111) (1 equivalent) and the compound of the formula (112) (3 equivalents) in a solvent such as N, N-dimethylformamide or acetonitrile but not limited thereto was brought to reflux for 1-4 hours. The solvent was then removed in vacuo. The residue was dissolved in a solvent such as dichloromethane or ethyl acetate but not limited thereto. The resulting solution was wd with water, brine, and then dried. The organic phase was concentrated in vacuo to give the compound of the formula (113). Compound of the formula (I). To a stirred solution of the compound of the formula (113) (1 equivalent) in a solvent such as dichloromethane, toluene or THF but not limited thereto was added the solution of a chlorine or bromine of the formula (114) (1 equivalent) in the presence of a base such as triethylamine or Hunigs base but not limited thereto at 0 ° C. The resulting mixture was stirred at room temperature for 6-18 hours and then quenched with water. The organic phase was wd with water, brine, dried and then concentrated in vacuo to give the compound of the formula (I) which was then purified by chromatography or crystallization. Alternatively, the compounds of the formula (I) of this invention wherein W is -C (0) N (R1) - can be synthesized following the general procedure as described in Reaction Scheme 3.

REACTION SCHEME 3 (115) (116) (117) (120) The starting materials of the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or through methods described herein. In general, the compounds of the invention were prepared in the above reaction scheme as follows: Compound 117. To a stirred solution of the amine of the formula (115) (1 equivalent) in a solvent such as dichloromethane or toluene but not limited to these was added to the solution a chlorine or bromine of the formula (116) (1 equivalent) in a solvent such as dichloromethane or toluene, but not limited thereto, in the presence of a base such as triethylamine or Hunigs base but not limited to these. The resulting mixture was stirred at room temperature for a suitable period of time and then quenched with water. The organic phase was wd with water, brine, dried and then concentrated in vacuo to give the product of formula (117). Compound 118. A solution of the compound of the formula (117) obtained above was dissolved in a suitable solvent and the protecting group R1 was removed under standard deprotection conditions, such as hydrolysis or hydrogenation to obtain the amine of the formula (118). Compound 120. A mixture of chloropyridazines of the formula (119) (1 equivalent) and the amine of the formula (118) obtained above (1.5 equivalents) in a suitable solvent was heated to reflux for 4-24 hours. A basic solution was added to the reaction mixture, such as NaOH solution. The aqueous layer was extracted through an organic solvent such as dichloromethane or ethyl acetate. The combined organic phase was dried, then evaporated to dryness. The crude compound was purified by column chromatography or crystallization to give the compound of the formula (120). Compound of the formula (I). Method A. To a stirred solution of the compound of the formula (120) (1 equivalent) in a solvent such as dichloromethane, acetonitrile or toluene was added the solution of a compound of the formula (121) (1 equivalent) in the presence of a base such as triethylamine or Hunigs base (1 equivalent) at 0 ° C. The resulting mixture was stirred at room temperature for 8-24 hours and then quenched with water. The organic phase was washed with water, brine, dried and then concentrated in vacuo. Further purification through column chromatography or crystallization from a suitable solvent gave the compound of formula (I). Method B. To a solution of carboxylic acid of the formula (122) (1 equivalent) in a solvent such as dichloromethane, toluene or THF was added to a base such as triethylamine or Hunigs base (2.5 equivalents), followed by the addition of a coupling agent such as (3-dimethylaminopropyl) and carbodiimide (1.1 equivalents). The resulting mixture was stirred for 15 minutes to one hour and an amine of the formula (120) (1.1 equivalents) was added. The mixture was stirred at room temperature for 8-24 hours, then washed with water, dried and concentrated in vacuo. Purification through column chromatography or crystallization, from a suitable solvent gave the compound of the formula (I). Alternatively, the compounds of the formula (IV) of this invention can be synthesized following the general procedure as described in Reaction Scheme 4.

REACTION SCHEME 4 Formula (IV) The starting materials of the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or through methods described herein. In general, the compounds of the invention were prepared in the above reaction scheme as follows: Compound of the formula (IV): Method C. To an agitated solution of the compound of the formula (120) (1 equivalent) in an anhydrous solvent such as DMF but not limited thereto, an isocyanate of the formula (123) was added. ) (3 equivalents), and the mixture was then heated to 60-80 ° C for 4-24 hours. The mixture was concentrated in vacuo. Purification of the crude product through column chromatography or crystallization from a suitable solvent gave the compound of the formula (IV). Method D. A compound of the formula (120) (1 equivalent) was slowly added to an iced solution of 1,1 '-carbonyldiimidazole (1.5 to 2.5 equivalents) in an anhydrous solvent such as dichloromethane. The temperature was then raised to room temperature and the reaction mixture was stirred for a further 2-8 hours. Then an amine of the formula (124) (1 equivalent) was added to the reaction mixture, which was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was then washed with saturated sodium bicarbonate and brine solution, concentrated and purified by flash column chromatography to give the compound of the formula (IV). Although anyone skilled in the art is capable of preparing the compounds of the invention in accordance with the general techniques described above, more specific details on the synthetic techniques for the compounds of the invention are provided elsewhere in this specification for convenience. Again, all the reactants and reaction conditions employed in the synthesis are known to those of ordinary skill in the art and are available from normal commercial sources.

PREPARATION 1 SYNTHESIS OF 2-CICLOPROPILETILAMINE .66 ml of concentrated sulfuric acid were added dropwise to 764.4 mmoles of a vigorously stirred suspension of lithium-aluminum hydride in 800 ml of anhydrous ethyl ether (40 ml) at 0 ° C for at least a period of 2 hours. The reaction mixture was warmed to room temperature and stirred for 1 hour, and a solution of anhydrous ethyl ether was added dropwise. The resulting mixture was heated to reflux for 2 hours, then cooled to 0 ° C, quenched carefully with crushed ice. A solution of 38 g of NaOH in 350 ml of water was added, and the organic layer was decanted from the resulting aluminum hydroxide precipitate. The precipitate was vigorously washed with three 600 ml portions of ethyl ether. All the ether extracts were combined, dried over anhydrous Na 2 SO 4 and the solvent was distilled to give 172.5 mmoles of 2-cyclopropylethylamine as a colorless liquid (bp 100-108 ° C). Yield 70%.

PREPARATION 2 SYNTHESIS OF 6-CLQR0PIRIDAZIN-3-CARB0XYLIC ACID To a mechanically stirred solution of 3-chloro-6-methylpyridazine (155.6 mmoles) in 140 ml concentrated sulfuric acid, 55.40 g of finely reduced potassium dichromate was slowly added to powder, the temperature kept below 50 ° C. When the addition was complete, stirring was continued for a further 4 hours at 50 ° C. The dark green, viscous liquid was then cooled and crushed ice was added carefully. The reaction mixture was extracted with 6 portions of 400 ml of ethyl acetate. The ethyl acetate extracts were combined, dried over anhydrous Na2SO4. The solvent was concentrated in vacuo to yield slightly red 6-CHLOROPYRIDAZINE-3-carboxylic acid (106.6 mmol). This material was used in the next reaction without further purification. Performance 69%. p.f. 145 ° C (dec). 1 H NMR (300 MHz, DMSO-d 6) d 13.1, 8.20, 8.05.

PREPARATION 3 SYNTHESIS OF (2- CYCLOPROPYLTHYL) AMID OF ACID 6- CHLOROPYRIDAZINE-3-CARBOXYLIC To a solution of 15.8 mmoles of 6-chloropyridazine-3-carboxylic acid in 95 ml of dichloromethane was added diisopropylethylamine (46.7 mmoles), 23.7 mmoles of 1-hydroxybenzotriazole monohydrate and 23.7 mmoles of 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide under a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 15 minutes and 20.2 mmoles of 2-cyclopropylethylamine were added. After stirring for 36 hours at room temperature, the reaction mixture was diluted with 100 ml of dichloromethane, then washed with water and dried over anhydrous Na 2 SO 4. The solvent was removed in vacuo. Purification through column chromatography (30% ethyl acetate in hexanes) gave the title compound (8.70 mmol). Performance 55%.

PREPARATION 4 SYNTHESIS OF (3-METHYLBUTIDAMIDE OF ACID 6- CHLOROPYRIDAZINE-3-CARBOXYLICQ The mixture of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid monohydrate (3.16 g, 20.0 mmol), 0.5 ml of dimethylformamide and 5-7 ml of thionyl chloride in 70 ml of chloroform was maintained at 50-60 ° C during the night. The reaction mixture was evaporated in vacuo to dryness. The solid residue was dissolved in 70 ml of dichloromethane and added dropwise to the mixture of 3-methylbutylamine (30 mmol, 2.7 ml) and 5 ml of triethylamine in 150 ml of dichloromethane at room temperature. The mixture was stirred for 30 minutes, washed sequentially with 10% HCl solution, saturated NaHCO 3 and water, and then dried over MgSO 4. The final compound was isolated through recrystallization from etherphexanes (5: 1) (19.76 mmoles). Yield: 98%.

PREPARATION 5 SYNTHESIS OF r4- (6-AMIN0PIRIDAZIN-3-IL) PIPERAZIN-1 -ILU2- TRIFLUOROMETHYL-FENIDMETANONE A. To a stirred solution of 1-Boc-piperazine (1.96 g, 10.5 mmol) in 50 mL of dichloromethane was added 2-trifluoromethylbenzoyl chloride (2.09 g, 10.0 mmol) as a solution of dichloromethane in the presence of 3 mL of triethylamine at 0 ° C. The resulting mixture was stirred at room temperature for 18 hours and then quenched with 25 ml of water. The organic phase was washed with water, saturated NaCl, dried over MgSO4 and then concentrated in vacuo to give the desired product as a pale yellow solid used in the reaction of the next step without further purification. B. A solution of 10 mmol of the compound obtained above in 50 ml of a 1: 4 mixture of trifluoroacetic acid and dichloromethane was stirred at room temperature for 5 hours. After concentration in vacuo, the residue was dissolved in 100 ml of dichloromethane and washed sequentially with 10 ml of 1N NaOH, water, saturated NaCl, and then dried over MgSO 4, filtered and concentrated in vacuo to yield piperazine. -1-yl- (2-trifluoromethylpheni) methanone as a light yellow oil. This oil was converted to the HCl salt by the addition of 10 ml of 2N of HCl in ether and 100 ml of anhydrous ether to the solution of the compound in 10 ml of dichloromethane. The white solid formed was filtered and dried to produce the HCl salt. C. A mixture of 3-amino-6-chloropyridazine (0.648 g, 5.00 mmol) and the previously obtained HCl salt (7.5 mmol) was heated at 150 ° C for 24 hours. To the reaction mixture was added 10 ml of 1N NaOH and 100 ml of dichloromethane, and the aqueous layer was extracted twice with 100 ml of dichloromethane. The combined organic phase was dried over Na 2 SO 4, evaporated to dryness. The crude compound was purified via flash chromatography to give the title compound as a yellow solid.

PREPARATION 6 SYNTHESIS OF (5-FLUQR0-2-TRIFLU0R0METILFENIL) PlPERAZIN-1 - ILMETANONE A. To a solution of 1-benzylpiperazine (4.65 g, 4.58 mL, 26. 4 mmol) in 200 mL of dichloromethane was added diisopropylethylamine (4.65 g, 6.2 mL, 36.0 mmol) followed by 5-fluoro-2- ( trifluoromethyl) benzoyl (5.43 g, 3.63 ml, 23.9 mmol) at 0 ° C. The reaction solution was stirred at room temperature for 16 hours then diluted with 100 ml of dichloromethane and washed with three 100 ml portions of water. After removing the solvent in vacuo, the product (9.81 g, Quantitative yield) was obtained as a viscous oil which was used in the reaction of the next step without further purification. B. The viscous oil was diluted in 100 ml of methanol and 981 mg of Pd / C was added. The mixture was stirred under H2 for 16 hours. After filtration, the filtrate was concentrated in vacuo to yield 6.98 g (94%) of the product.

PREPARATION 7 SYNTHESIS OF (2- CYLOPOPEPLIACLETIPAMIDE OF ACID 6- PIPERAZIN-1-IL-PYRIDAZINE-3-CARBOXYLIC A mixture of piperazinA (1.48 g, 17. 2 mmol) and 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide (1.29 g, 5.73 mmol) in 60 mL of acetonitrile was refluxed for 16 hours. After the reaction mixture was cooled, the gummy material was diluted with 50 ml of dichloromethane, washed with two 20 ml portions of water, dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The crude material was purified by column chromatography eluting with dichloromethane (100%) then with methano-dichloromethane (1: 9) to obtain 1.18 g (75%) of the product as a solid.

PREPARATION 8 SYNTHESIS OF 2-AMI Q-1 -CICLOPROPILETANOL A. To a stirred mixture of cyclopropanecarboxaldehyde (1.00 g, 14.3 mmole) and nitromethane (0.765 g, 14. 3 mmole) in MeOH a 0 ° C a solution of NaOH (0.57 g) in water was added dropwise. The reaction mixture was allowed to stir for 1 hour and a white solid precipitated. Then glacial acetic acid (0.807 ml) was added to this mixture dropwise. The organic layer was extracted with 3 portions of 7 ml of ether and dried over MgSO4 to yield 2-nitro-1-cyclopropyl ethanol which was used in the reaction of the next step without further purification. B. The nitro compound obtained above was dissolved in 4 ml of dry ether and then added dropwise to a stirred slurry of lithium-aluminum hydride (0.997 g, 26.3 mmol) in 30 ml of dry ether under reflux for 1 hour . The reflux was maintained for a further 2 hours and then-9 ml of 2-propanol was added and continued through the addition of 3 ml of saturated NaCl solution. The mixture was stirred for another 20 minutes and then extracted with a mixture of 2-propanol: ether (1: 3). 2-Amino-1-cyclopropyl ethanol was obtained after removal of the solvents and was used in the next step reaction without further purification.

PREPARATION 9 SYNTHESIS OF (2-CYCLOPROP1L-2-HYDROXYET1DAM1DA OF 6-CL0R0PIRIDAZIN-3-CARB0XYLIC ACID To a solution of 6-chloropyridazine-3-carboxylic acid (375 mg, 2. 37 mmol) in 5 ml of dioxane was added thionyl chloride (420 mg, 3.56 mmol). The mixture was refluxed 4 hours and the solvent was removed in vacuo. 2-Amino-1-cyclopropyl ethanol (479 mg, 4.73 mmol) in 5 ml of dioxane was added to the residue and followed through the addition of 0.2 ml of triethylamine. The mixture was stirred at room temperature overnight. Water was added to the mixture and then extracted with ethyl acetate. The organic extract was separated, washed with water and brine; dried over Na2SO4. The residue was purified after removal of the solvent via column chromatography, eluted with ethyl acetate: hexane (70:30) to yield 58 mg of the desired white product.

PREPARATION 10 SYNTHESIS OF PIPERAZIN-1 -IL- (2-TRIFLUQROMETILFENIL) METANONE A. 2-Trifluoromethylbenzoyl chloride was added dropwise to a stirred (0 ° C) stirred solution of 0.100 moles of 1-Boc-piperazine and 0.12 moles of triethylamine in 250 ml of dichloromethane for 15 minutes. The resulting mixture was stirred at room temperature for 6 hours. Then 100 ml of water was added to the mixture and the aqueous phase was extracted with two 100 ml portions of dichloromethane. The combined organic phase was washed with water and brine; dried over Na2SO4 and then concentrated in vacuo to give the product in quantitative yield.

B. A solution of the 4- (2-trifluoromethylbenzoyl) piperazine-1-carboxylic acid tert-butyl ester obtained above (10 mmol) in a mixture of trifluoroacetic acid and dichloromethane (1: 4, 50 mL) was stirred at room temperature for 5 hours. After concentration in vacuo, the residue was dissolved in 100 ml of dichloromethane and washed sequentially with saturated sodium bicarbonate, water, and brine; dried over anhydrous Na2SO4 and concentrated to give piperazin-1-yl- (2-trifluoromethylphenyl) -methanone in 97% yield.

PREPARATION 11 SYNTHESIS OF (3-METHYLBUTYL) ACID AMID 6-PIPERAZI N-1 ILPIRIDAZIN-3-CARBOXYLIC A solution of 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide (2.52 g, 11.0 mmol) and piperazine (2.83 g, 32.8 mmol) in 30 mL of acetonitrile was refluxed for 2 hours. The solvent was removed by evaporation, the residue was dissolved in 50 ml of water and extracted with three 100 ml portions of dichloromethane. The organic extract was dried over anhydrous Na2SO4 and then evaporated. The residue was passed through a pad of silica gel and concentrated to give 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide (2.68 g, 88% Yield). MS (ES +) m / z 278 (M + 1).

PREPARATION 12 SYNTHESIS OF (2- C1CLOPROPILETIL) ACID AMID 6- PIPERAZIN-1-ILPIRIDAZIN-3-CARBOXYLIC A solution of the 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide (7.8 g, 34 mmol) and piperazine (8.93 g, 103 mmol) in 100 mL of acetonitrile was refluxed for 2 hours. The solvent was removed by evaporation and the residue was dissolved in 100 ml of water. The aqueous solution was extracted with 5 100 ml portions of dichloromethane and the organic extract was dried over anhydrous Na 2 SO 4, filtered through a pad of silica gel and concentrated to give 6-piperazine (2-cyclopropylethyl) amide -1-ilpyridazine-3-carboxylic acid (8.2 g, 88%). 1 H NMR (300 MHz, CDCl 3) d 7.90-7.87, 6.89, 3.78-3.50, 3.12-2.90, 1.77-1.49, 0.83-0.60, 0.51-0.36, 0.15-0.01.

PREPARATION 13 SYNTHESIS OF r2- (3-FLUOROFENIL) ETHYLAMIDE OF ACID 6- CHLOROPYRIDAZI-3-CARBOXYLIC To a solution 6-chloropyridazine-3-carboxylic acid (0.31 g, 1. 94 mmol) in 15.5 ml of dichloromethane was added diisopropylethylamine (0.73 ml, 4.19 mmole), followed by 1-hydroxybenzotriazole monohydrate (0.28 g, 2.1 mmole) and 1- (3-dimethylamino) propyl-3-ethylcarbodiimide (0.37 ml, 2.1 mmoles). The resulting mixture was stirred for 15 minutes, followed by the addition of 3-fluorophenethylamine (0.28 ml, 2.1 mmol). After stirring for 27 hours at room temperature, the reaction mixture was diluted with 200 ml of dichloromethane, washed with 4 portions of 25 ml of water, dried over Na 2 SO 4 and concentrated in vacuo. Purification through column chromatography eluted with dichloromethane: ethyl acetate (2: 1) gave the product as a white powder (0.205 g). 1 H NMR (400 MHz, CDCl 3) d 8.26, 8.12, 7.67, 7.28-7.23, 6.95-6.89, 3.80-3.75, 2.95.

PREPARATION 14 SYNTHESIS OF ACID (E) -2-TRIFLUOROMETHYLLOCYCLOPROPAN CARBOXYLIC A. To a stirred solution of trimethylsulfoxonium iodide (4.85 g, 22.0 mmol) in 20 ml of DMSO under nitrogen at 25-30 ° C was added a dispersion of sodium hydride in mineral oil (0.88 g, 22 mmol) in portions . After completion of the evolution of hydrogen (30 minutes), a solution of ethyl 4,4,4-trifluorocrotonate (3.36 g, 3 ml, 20 mmol) in 10 ml of DMSO was added dropwise so that the temperature did not exceed 35 ° C. The resulting mixture was stirred at 25-30 ° C for 30 minutes and then at 55-60 ° C for 1 hour. The mixture was poured into 150 ml of an aqueous solution of ammonium chloride (4 g). The solution was extracted with ether and the ether extract was dried over Na2SO4 and concentrated to give a crude product. B. To a solution of the crude product obtained above was added 75 ml of tetrahydrofuran, 38 ml of water and lithium hydroxide (3.36 g, 80 mmol). The mixture was stirred and heated at 80 ° C for 5.5 hours and then evaporated to remove the tetrahydrofuran. The aqueous layer was extracted with 2 30 ml portions of hexanes, acidified with concentrated HCl and then extracted with 3 100 ml portions of dichloromethane. The organic layer was dried over Na2SO4. Removal of the solvent gave 2-trifluoromethylcyclopropane-carboxylic acid (1.53 g).

PREPARATION 15 SYNTHESIS OF PENTILAMIDE OF 6-CHLOROPIRIDAZIN-3-CARBOXYLIC ACID To a flask containing 6-chloropyridazine-3-carboxylic acid (375 mg, 2.37 mmoles) in 5 ml of dioxane (5 ml) was added thionyl chloride (420 mg, 0.26 ml, 3.56 mmoles). The brown mixture was refluxed for 6 hours under nitrogen with stirring. After cooling to room temperature, the solvent was removed through a rotary evaporator. The gummy black material was diluted with 5 ml of dioxane and the resulting solution was cooled in an ice water bath. Amyl amine (410 mg, 0.55 ml, 4.74 mmol) was added to the cooled solution. The resulting black reaction solution was stirred at room temperature for 16 hours under nitrogen. The solvent was removed in vacuo and the residue was dissolved in 25 ml of dichloromethane. The solution was washed with 2 portions of 10 ml of water and the organic layer was dried over MgSO 4, the solid was filtered and concentrated to give a gummy material which was purified by column chromatography eluted with dichloromethane to yield 310 mg (57% ) of the product as a colorless solid, mp 98-101 ° C. 1 H NMR (300 MHz, CDCl 3) d 8.28, 8.05, 7.68, 3.51, 1.69-1.63, 0.90. MS (ES +) m / z 228 (M + 1).

PREPARATION 16 SYNTHESIS OF 3-CYCLOPROPYLPROPILAMINE A. P-Toluenesulfonyl chloride (7.20 g, 37.8 mmol) was added to a cooled (0 ° C) solution of 2-cyclopropyl ether (4.00 g, 46.4 mmol) in 10 ml of pyridine and 60 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, then diluted with 200 ml of ether and washed sequentially with water, 10% HCl, water and brine and then dried over anhydrous Na 2 SO 4. 2-Cyclopropylethyl ester of toluene-4-sulfonic acid (8.1 g, 89%) was obtained after removal of the solvent and was used in the next step reaction without further purification. B. A mixture of 2-cyclopropylethyl ester of toluene-4-sulfonic acid (8.1 g, 33.7 mmol), sodium cyanide (5.0 g, 102 mmol) and tetrabutylammonium iodide (0.5 g) in 30 ml of DMF was heated at 90 ° C overnight. The reaction mixture was then cooled to room temperature, diluted with 200 ml of ether, washed with water and brine, and dried over anhydrous Na 2 SO 4. 3-Cyclopropylpropionitrile (3.2 g, 99%) was obtained after removal of the solvent. C. 2.73 ml of concentrated sulfuric acid was added dropwise to a vigorously stirred ethereal solution of lithium-aluminum hydride (3.792 g, 99.43 mmol) in 40 ml of ether at 0 ° C. The reaction mixture was then warmed to room temperature and stirred for 1 hour. A solution of 3-cyclopropylpropionitrile (3085 g, 32.47 mmol) in 10 ml of ether was added dropwise. The resulting mixture was heated to reflux for 2 hours, then cooled to 0 ° C, and subsequently quenched slowly with water. A solution of the NaOH (2 g in 18 ml of H20) was added and the organic phase was decanted from the resulting precipitate of aluminum hydroxide, which was washed with 3 portions of 20 ml of ether.

All the etheric portions were combined, and the solvent was distilled off and 3-cyclopropylpropylamine was obtained as a light yellow liquid (2.01 g, 62.5%).

PREPARATION 17 SYNTHESIS OF (2-CICLOPRQPILETIL) OF AMID ACID 6- (3,5- DIMETHYL-PIPERAZIN-1-IL) PIRIDAZIN-3-CARBQXYLIC To a solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) (0.57 g, 2.52 mmole) and Bu4NBr (0.16 g, 0. 50 mmoles) in 20 ml of dioxane was added 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.75 ml, 0.77 g, 5.04 mmoles).

The brown reaction mixture was heated to reflux for 16 hours, then cooled to room temperature. The solvent was removed in vacuo. The crude material was diluted with 50 ml of ethyl acetate. The solution was washed 3 portions of 20 ml of water, dried over MgSO4. After filtration, the filtrate solvent was removed in vacuo. The product was isolated as a brown gummy material (0.72 g, 74%) that was used directly in the next step without further purification.

PREPARATION 18 SYNTHESIS OF (2-CYCLOPROPOLETLL) ACID AMID 6-M.41 DIAZEPAN-1-IL-PIRIDAZIN-3-CARBOXYLIC A. A mixture of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide (0.15) g, 0.665 mmoles), [1,4] diazepane-1-carboxylic acid tert-butyl ester (0.133 g, 0.665 mmol) and triethylamine (0.093 ml, 0.665 mmol) was heated to reflux in toluene for 18 hours. The solvent was removed in vacuo, and the residue was purified by flash column chromatography to produce the product (0.226 g, 87%) which was used in the reaction of the next step without further purification. B. The product obtained above was dissolved in a 2: 1 mixture of dichloromethane / trifluoroacetic acid, and the mixture was stirred for 15 minutes. The solvent was then removed in vacuo. The residue was diluted with dichloromethane, and the resulting solution was washed with 10% aqueous sodium hydroxide solution, dried and concentrated to yield 6- (1,4) diazepane-1- (cyclopropylethyl) amide. il-pyridazin-3-carboxylic acid PREPARATION 19 SYNTHESIS OF (2-CYCLEBUTILETIDAMIDE OF ACID 6- CHLOROPYRIDAZI-3-CARBOXYLIC A. To a solution of cilclobutanmethanol (4.00 g, 46.4 mmoles) in 60 ml of dichloromethane were added 10 ml of pyridine, followed by the addition of p-toluenesulfonyl chloride (7.20 g, 37.8 mmoles) at 0 ° C. The reaction mixture was stirred for 23 hours at room temperature, and then diluted with 350 ml of diethyl ether, washed sequentially with water, 1% aqueous solution of HCl, water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give the product (9.00 g, 80.7%). B. To a solution of toluene-4-sulfonic acid cyclobutylmethyl ester (9.00 g, 37.5 mmol) in 34 ml of DMF was added sodium cyanide (5.62 g, 114.6 mmol) and tetra-n-butylammonium iodide (0.56 g). 1.41 mmoles). The reaction mixture was stirred at 90 to 95 ° C for 6.5 hours. After cooling to room temperature, the reaction mixture was diluted with 450 ml of diethyl ether, washed with water and brine. The organic layer was dried over Na 2 SO 4 and concentrated at atmospheric pressure to give a product (3.50 g). C. Concentrated sulfuric acid (1.71 mL, 32.6 mmol) was added dropwise to a vigorously stirred solution of lithium-aluminum hydride (2.47 g, 65.1 mmol) in 65 mL of ether at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 1 hour, and a solution of the cyclobutylacetonitrile (2 g, 21.03 mmol) in 9 ml of ether was added dropwise. The resulting mixture was heated to reflux for 3.5 hours and then stirred at room temperature for 21 hours. The reaction mixture was cooled to 0 ° C, and slowly quenched with 16 ml of water. A solution of 7.85 g of sodium hydroxide in 69 ml of water was added, and the organic phase was decanted from the resulting precipitate of aluminum hydroxide, which was rinsed with three 50 ml portions of ether. All the etheric portions were combined, and the solvent was distilled to leave 2- cyclobutylethylamine as a colorless liquid (1.9 g, 91%). D. To a 100 ml round bottom flask, 6-oxo-1,6-dihydropyridazine-3-carboxylic acid monohydrate (0.64 g, 3.6 mmol), 14 ml of chloroform, 0.1 ml of dimethylformamide and 1.2 ml were added. of thionyl chloride. The reaction mixture was stirred at 60 ° C for 16 hours. The reaction mixture was evaporated in vacuo to dryness. The solid residue was dissolved in 13 ml of dichloromethane and added dropwise to the mixture of cyclobutylethylamine (0.47 g, 4.74 mmol) and 0.8 ml of triethylamine in 25 ml of dichloromethane at room temperature. After stirring for 1 hour, the reaction mixture was diluted with 100 ml of dichloromethane and washed sequentially with 10% aqueous solution of HCl, saturated NaHCO 3 and water. The organic layer was dried over Na2SO4 and evaporated in vacuo. Purification through column chromatography (silica gel, hexane / EtOAc (2: 1)) gave the product as a white powder (0.572 g, 59%). 1 H NMR (300 MHz, CDCl 3) d 8.25, 7.97, 7.65, 3.42, 2.36, 2.08, 1.91-1.59.

PREPARATION 20 SYNTHESIS OF 3-CICLOBUTILPROPILAMINE A. A solution of trimethylphosphine in toluene (1 M, 60 ml, 60 mmol) at 0 ° C under nitrogen was diluted with 30 ml toluene and 30 ml tetrahydrofuran. Then iodoacetonitrile (4.2 ml, 9.69 g, 58 mmol) was added dropwise with vigorous stirring, while a colorless solid was precipitated. When the addition was complete, the ice bath was removed and stirring continued at room temperature for 51 hours. The mixture was filtered, and the solid was washed with toluene and dried under reduced pressure. Recrystallization from 37.5 ml of acetonitrile gave the compound as colorless crystals (9.89 g, Yield: 70%). B. To a mixture of cyclobutan-methanol (0.861 g, 10 mmol) and (cyanomethyl) -trimethylphosphonium iodide (6.20 g, 25.5 mmol) was added 20 mL of propionitrile) and diisopropylethylamine (5.5 mL, 32 mmol), and the mixture was stirred at 97 ° C for 48 hours. Water (1 mL, 55.5 mmol) was added, and stirring at 97 ° C continued for another 18 hours. 125 ml of water and concentrated hydrochloric acid (5 ml, 60 mmol) were added, and the mixture was extracted with 3 100 ml portions of dichloromethane. The combined extracts were washed once with brine, dried with magnesium sulfate, and concentrated at atmospheric pressure to give the product (1.09 g). C. Concentrated sulfuric acid (3.15 mL, 60.05 mmol) was added dropwise to a vigorously stirred solution of lithium-aluminum hydride (4.35 g, 113.8 mmol) in 114 mL of ethyl ether at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 1 hour, and a solution of the cyclobutylpropionitrile (1.09 g, 10 mmol) in 15 mL of ether was dropwise added dropwise. The resulting mixture was heated to reflux for 2 hours and then stirred at room temperature for 48 hours. The reaction mixture was cooled to 0 ° C, and quenched slowly with 12 ml water. A solution of 5.89 g of sodium hydroxide in 52 ml of water was added, and the organic phase was decanted from the resulting precipitate of aluminum hydroxide, which was rinsed with three 50 ml portions of ether. All the etheric portions were combined, and the solvent was distilled to leave 0.36 g (32%) of 2-cyclobutylpropylamine as a colorless liquid.

PREPARATION 21 SYNTHESIS OF (2-CYCLEBUTILETIDAMIDE OF 6-PIPERAZIN-1-ILPIRIDAZI-3-CARBOXYLIC ACID To a solution of 6-chloroplridazine-3-carboxylic acid (2-cyclobutylethyl) -amide (1.2 g, 5.00 mmol) in 40 ml of acetonitrile was added piperazine (1.29 g, 15.00 mmol). The reaction mixture was heated to reflux overnight. The mixture was evaporated and the solid residue was taken up in 100 ml of ethyl acetate and 100 ml of water. The organic layer was separated and the aqueous layer was extracted with 2 100 ml portions of ethyl acetate. The combined ethyl acetate was dried over Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (1.14 g, 78.4% Yield).

PREPARATION 22 SYNTHESIS OF 2.2- (DIMETHYL CYCLOPROPIL) METHYLAMINE Lithium aluminum hydride (7.77 g, 0.194 mmol) was added to a solution of 2,2-dimethylcylclopepcarboxamide (10.0 g, 88.3 mmol) in 200 mL of THF at 0 ° C. The reaction mixture was refluxed for 5 hours, then cooled to 0 ° C, quenched with water, and extracted with diethyl ether. The combined ether layer was dried over anhydrous Na2SO4, and distilled to yield the title compound with 36% Yield (3.2 g). b.p. 94-96 ° C. 1H NMR (300 MHz, CDI3) d 2.68-2.53, 1.13, 1.03, 1.00, 0.70-0.61, 0.38-0.34, -0.02--0.05.

PREPARATION 23 SYNTHESIS OF ACID 6-r4- (2-TRIFLUOROMETILBENZOIL) PIPERAZIN-1-IL1 PIRIDAZIN-3-CARBOXYLIC A. To a methanol solution of 6-OXO-1,6-dihydropyridazine-3-carboxylic acid monohydrate (5.00 g, 31.6 mmol) was added thionyl chloride (0.36 mL, 0.59 g, 4.94 mmol). The reaction mixture was heated to reflux at 80 ° C for 16 hours. The product crystallized after the reaction mixture was cooled to room temperature ambient. The crystals were collected and washed with methanol and the mother liquor was concentrated and recrystallized. The total amount of the isolated product was 4,954 g (100% yield). B. A mixture of 6-hydroxypyridazine-3-carboxylic acid methyl ester obtained above and phosphorus oxychloride was carefully heated to reflux temperature and kept there for 2.5 hours. The reaction mixture was then cooled and evaporated in vacuo to remove excess phosphoryl chloride, and the residue was then poured into ice water. The precipitate was collected through filtration, washed with saturated NaHCO 3 and water, and dried under vacuum to yield the product as a yellow solid (4,359 g, 79% Yield). C. A solution of 6-chloropyridazine-3-carboxylic acid methyl ester obtained above (4.359 g, 25.3 mmol) in 145 ml of dioxane was treated with hydrochloric acid salt of 1- (2-trifluoromethyl-benzoyl) piperazine (7.80 g, 26.5 mmol) in the presence of K2C03 (10.14 g, 73.4 mmol) and tetra-n-butylammonium iodide (0.071 g, 0. 192 mol). The reaction mixture was heated to reflux for 24 hours and evaporated to remove the dioxane. The residue was purified by column chromatography to give the desired product (8.666 g, 87% Yield). D. To a solution of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid methyl ester (4.436 g, 11.25 mmol) in 50 ml of tetrahydrofuran and 25 ml of water was added. lithium hydroxide monohydrate (2.30 g, 54.81 mmol). The reaction mixture was stirred at room temperature for 23 hours and the pH of the solution was adjusted to 3 with 5.3 ml of concentrated hydrochloric acid at 0 ° C. The mixture was concentrated. 100 ml of ethyl acetate was added to the residue and the product was precipitated. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to give the title compound (3.60 g). The aqueous layer was extracted with ethyl acetate, dried over Na 2 SO 4 and concentrated to give the second portion of the title compound (0.463 g). The total amount of the product was 4,063 g (95% yield).

PREPARATION 24 SYNTHESIS OF PENT-4-ENILAMIDE OF ACID 6-PIPERAZIN-1 - ILPIRIDAZIN-3-CARBOXYLIC A. To a solution of 4-penten-1-ol (4.8 ml, 4.00 g, 46.4 mmol) in 60 ml of dichloromethane was added 10 ml of pyridine, followed by the addition of p-toluenesulfonyl chloride (7.2 g). , 37.8 mmol) at 0 ° C. The reaction mixture was stirred for 21 hours at room temperature. The reaction mixture was then diluted with 350 ml of diethyl ether, washed sequentially with water, 1% HCl, water and brine. The organic layer was dried over Na 2 SO and concentrated to give the product with 93% Yield (8.48 g) which was used in the reaction of the next step without further purification. B. To a solution of pent-4-enyl ester of toluene-4-sulfonic acid obtained above (3.42 g, 14.3 mmol) in 55 ml of THF was added ammonium hydroxide (content of ammonia 28.0-30.0%) (100 ml , 1532.6 mmoles). The reaction mixture was stirred at room temperature for 5 days. The reaction mixture was extracted with diethyl ether. The combined ether solution was dried over Na2SO4 and distilled under an atmosphere at 50 ° C to produce a THF solution of pent-4-enylamine, which was used in the next step reaction without further purification. C. 6-Oxo-1,6-dihydropyridazine-3-carboxylic acid monohydrate (1.60 g, 10.1 mmol), 36 ml of chloroform, 0.25 ml of dimethylformamide and 3.05 ml of thionyl chloride were added in a round-bottomed flask of 100 ml. The reaction mixture was stirred at 69 ° C for 43 hours and then evaporated to dryness. The solid residue was dissolved in dichloromethane and the solution was added dropwise to the mixture of pent-4-enylamine in THF prepared above and triethylamine at room temperature. After stirring for 1 hour, the reaction mixture was diluted with dichloromethane and washed with 10% HCl, saturated NaHCO 3 and water. The organic layer was dried over Na2SO4 and evaporated in vacuo. Purification through column chromatography gave the product as a white powder (1.08 g, 61.6% Yield). D. To a solution of 6-chloropyridazine-3-carboxylic acid pent-4-enylamide synthesized above (1.08 g, 4.79 mmol) in 39 mL of acetonitrile was added piperazine (1.25 g, 14.5 mmol). The reaction mixture was heated to reflux overnight (TLC indicated that the reaction was complete). The mixture was evaporated and the solid residue was dissolved in a mixture of 100 ml of ethyl acetate and 100 ml of water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layer was dried over Na 2 SO 4 and concentrated to yield the title compound as a yellow solid (1169 g, 88.6% Yield). The synthesis of the compounds of this invention is illustrated by, but is not limited to the following examples.

EXAMPLE 1 SYNTHESIS OF. { 6-r4- (2-TRIFLU0R0METILBENZ0IL) -PIPERAZlN-1 -l Ll PYRIDAZIN-3-IDAMIDE OF 4-METHYL PENTANEOIC ACID To a stirred solution of [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl-phenyl) methanone (0.226 g, 0.645 mmol) in 10.0 ml of tetrahydrofuran 4-methylpentanoic acid (0.500 g, 4.30 mmol) was added followed by 1.0 ml of (3-dimethylaminopropyl) ethyl carbodiimide. The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried with Na 2 SO 4, concentrated, and the residue was dissolved again in a small amount of ethyl acetate. The solid, which was precipitated through the dropwise addition of hexane was filtered and dried under vacuum to give 0.070 g of the title product as a white solid in 24% yield. 1 H NMR (300 MHz, CDCl 3) d 9.15, 8.36, 7.74, 7.63, 7.56, 7.36, 7.05, 4.03-3.98, 3.93-3.89, 3.69-3.62, 3.55-3.53, 3.33-3.31, 2.51, 1.63-1.61, 0.91 .

EXAMPLE 1.1 4-PHENYL-N-f6-r4- (2-TRIFLUQR0METILBENZ0IL) PlPERAZIN-1-IL1 PIRIDAZ1N-3-IL} BUTIRAMIDE Following the procedure of Example 1, making only the required variations to use 4-phenylbutyric acid in place of 4-methylpentanoic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethylphenol) ) methanone, the title compound was obtained as a white powder (9% Yield). 1 H NMR (300 MHz, CDCl 3) d 9.13, 8.36, 7.74, 7.62, 7.56, 7.36, 7.28-7.25, 7.19-7.16, 7.05, 4.03-3.98, 3.93-3.88, 3.69-3.60, 3.54-3.52, 3.33-3.1 , 2.70, 2.52, 2.06.

EXAMPLE 1.2 4- (4-METOXYPENYL) -N- 6-r4- (2-TRIFLUOROMETILBENZOYL) PIPERAZIN-1-1L1PIRIDAZIN-3-IL1BUTIRAMIDE Following the procedure of Example 1, making only the required variations to use 4- (4-methoxyphenyl) butyric acid in place of 4-methylpentanoic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl ] (2-trifluoromethylphenyl) -methanone, the title compound was obtained as a white powder (20% Yield). 1 H NMR (300 MHz, CDCl 3) d 9.14, 8.29, 7.67, 7.55, 7.49, 7.30, 7.01, 6.98, 6.73, 3.95-3.91, 3.86-3.81, 3.70, 3.61-3.55, 3.48-3.45, 3.26-3.24, 2.57 , 2.45, 1.96.

EXAMPLE 2 SYNTHESIS OF 2-BENCILOXI-N-. { 6-r4- (2-TRIFLUOROMETILBENZ01L) PI PERAZI N-1-IL1-PIR1DAZIN-3-IDACETAMI DA To a stirred solution of [4- (6-aminopyridazin-3-yl) piperazin-1 -yl] - (2-trifluoromethylpheni) methanone (1.30 g, 3.7 mmol) in 60 ml of dichloromethane was added 1.5 g of diisopropylethylamine. , followed by 1.1 g of 1-hydroxybenzotriazole monohydrate and 2 ml of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide. The resulting mixture was stirred for 15 minutes and then 1.2 ml of benzyloxyacetic acid was added. After stirring for 2 hours, the reaction mixture was washed with 10% HCl, 1N NaOH and water, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give the final amide as a dark yellow oil. The oil was purified through column chromatography (dichloromethane: MeOH = 98: 2) yielding 1.64 g of pure final compound as a white solid in 89% yield. 1 H NMR (300 MHz, CDCl 3) d 9.12, 8.29, 7.72, 7.63-7.49, 7.35-7.33, 6.99, 4.65, 4.10, 4.05-3.83, 3.66-3.54, 3.33-3.29. MS (ES +) m / z 500.2 (M + 1).

EXAMPLE 2.1 4-CICLOHEXI L-N. { 6-r4- (2-TRIFLUOROMETILBENZOIL) PI PERAZI N-1 - IL1PIRIDAZIN-3-IDBUTIRAMIDE Following the procedure of Example 2, making only the variations required to use 4-cylcohexylbutyric acid in place of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethylphenyl) methanone , the title compound was obtained as a white powder (18% NMR Yield (300 MHz, CDl3) d 9.04, 8.32, 7.68, 7.56, 7.49, 7.30, 7.04-7.00, 3.99-3.23, 2.40, 1.89-1.83, 1.69-0.84.

EXAMPLE 2.2 2-ETOXI-N. { 6-r4- (2-TRIFLUOROMETILBENZOIL) PIPERAZIN-1 -ILI P1RIDAZIN-3-IL1-ACETAMIDE Following the procedure of Example 2, making only the variations required to use ethoxyacetic acid in place of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethylphenyl) methanone, obtained the title compound as a yellow solid (67% Yield). 1 H NMR (300 MHz, CDCl 3) d 9.18, 8.35, 7.75, 7.63, 7.56, 7.37, 7.04, 4.08, 4.04-3.88, 3.70-3.64, 3.60-3.58, 3.35-3.33, 1.31. MS (ES +) m / z 438.4 (M + 1).

EXAMPLE 2.3 2-CICLOPROPYLMETOXY-N-f6-r4- (2-TRIFLUOROMETILBENZOlL) PIPERAZIN-1-IL1-P1RIDAZIN-3-IL1ACETAMIDE Following the procedure of Example 2, making only the variations required to utilize cylcopropylmethoxy acid in place of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trif luoromethylphenyl) methanone , the title compound was obtained as a white powder (41% Yield). H NMR (300 MHz, CDCI3) d 9.17, 8.32, 7.72, 7.61, 7.54, 7.35, 4.10, 4.01-3.88, 3.69-3.61, 3.57-3.55, 3.43, 3.33-3.30, 1.14-1.08, 0.61-0.57, 0.27 -0.24. MS (ES +) m / z 464.5 (M + 1).

EXAMPLE 2.4 2- (2-METOXlETOXI) -N-. { 6-r4- (2-TRIFLU PROMETÍ LBENZOIL) PIPERAZIN-1-1L1-PIRIPAZ1N-3-IL1ACETAMIDE Following the procedure of Example 2, making only the required variations to use (2-methoxyethoxy) acetic acid instead of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2- trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (72% Yield). 1 H NMR (300 MHz, CDCl 3) d 9.53, 8.34, 7.74, 7.63, 7.56, 7.34, 7.02, 4.16, 4.04-3.89, 3.80-3.77, 3.69-3.65, 3.63-3.61, 3.59-3.56, 3.46, 3.34-3.32 . MS (ES +) m / z 468.3 (M + 1).

EXAMPLE 2.5 • f6-r4- (2-TRIFLUOROMETILBENZOIL) PIPERAZIN-1 -IL1 PIRIDAZIN-3- ACID ILLUMINATION 2.2.3.3-TETRAMETILCICLOPROPAN-CARBOXÍLICO Following the procedure of Example 2, making only the variations required to use 2,2,3,3-tetramethylcyclopropane carboxylic acid instead of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl ] (2-trifluoromethylphenyl) -methanone, the title compound was obtained as a white powder (48% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.77, 8.28, 7.72, 7.60, 7.53, 7.34, 6.99, 4.01-3.85, 3.63-3.60, 3.52-3.45, 3.31-3.27, 1.78-1.74, 1.28, 1.20. MS (ES +) m / z 476.3 (M + 1).

EXAMPLE 2.6 (6-f4- (2-TRI FLUORO METHYL BENZOIL) PI PERAZI N -1-1 L1PIRID AZI N-3- IDAMIDE OF CYLOPROPAN-CARBOXYLIC ACID Following the procedure of Example 2, making only the required variations to utilize cyclopropane carboxylic acid in place of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-tri-fluoro methyl) nil) methanone, the title compound was obtained as a white powder (32% Yield). 1 H NMR (300 MHz, CDCl 3) d 10.07, 8.40, 7.72, 7.61, 7.53, 7.34, 7.03, 4.02-3.82, 3.67-3.55, 3.49-3.46, 3.30-3.27, 2.09- 2.01, 1.09-1.04, 0.88-0.82 . MS (ES +) m / z 420.2 (M + 1).

EXAMPLE 2.7. { 6-r4- (2-TRIFLUOROMETHYLBENZOYL) PIPERAZIN-1-IL1PIRIDAZIN-3- 1-TRIFLUOROMETHYLLOCYLOPROPAN-CARBOXYLIC ACID IL1AM1PA Following the procedure of Example 2, making only the variations required to use 1-trifluoromethylcyclopropane carboxylic acid instead of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethylphenyl) -metanone, the title compound was obtained as a white powder (16% yield). 1 H NMR (300 MHz, CDCl 3) d 8.62, 8.18, 7.74, 7.63, 7.56, 7.34, 7.01, 4.03-3.89, 3.71-3.62, 3.60-3.58, 3.34-3.32, 1.54-1.52, 1.39-1.36. MS (ES +) m / z 487.9 (M + 1).

EXAMPLE 2.8 N-. { 6- { 4- (2-TRlFLUOROMETILBENZOIL) PIPERAZlN-1-IL} PIRIDAZIN- 3-IL} -2- (3,3,3-TRIFLUOROPROPOXI) ACETAMIDE Following the procedure of Example 2, making only the required variations to use (3,3,3-trifluoropropoxy) acetic acid instead of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl ] (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (50% Yield). 1 H NMR (300 MHz, CDCl 3) d 9.03, 8.32, 7.75, 7.63, 7.56, 7.37, 7.03, 4.13, 4.03-3.98, 3.94-3.89, 3.84, 3.71-3.63, 3.60-3.58, 3.35-3.32, 2.56-2.48 . MS (ES +) m / z 506. 5 (M + 1).

EXAMPLE 2.9 3-METOXY-N-. { 6-r4- (2-TRIFLUOROMETILBENZOIL) PIPERAZIN-1- I Ll PIRIDAZIN-3-IDPROPlON AMIDA Following the procedure of Example 2, making only the required variations to use 3-methoxypropionic acid in place of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-tri-fluoro-methyl) nylon) methanone, the title compound was obtained as a white powder (11% Yield). 1 H NMR (300 MHz, CDCl 3) d 9.44, 8.31, 7.74, 7.63, 7.55, 7.36, 7.02, 4.02-3.98, 3.94-3.89, 3.73, 3.70-3.61, 3.57-3.54, 3.43, 3.33-3.31, 2.73. MS (ES +) m / z 438.1 (M + 1).

EXAMPLE 2.10 3-FENOXI-N-. { 6-4- (2-TRIFLUOROMETILBENZOIL) PIPERAZIN-1-IL1 PL RID AZI N-3-IDPRO PION AMIDA Following the procedure of Example 2, making only the required variations to use 3-phenoxypropionic acid in place of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethylphenyl) methanone , the title compound was obtained as a white powder (52% Yield). 1 H NMR (300 MHz, CDCl 3) d 10.08, 8.40, 7.74, 7.61, 7.55, 7.34, 7.26-7.22, 7.05, 6.93, 6.88, 4.34, 4.01-3.96, 3.92-3.86, 3.68-3.60, 3.55-3.53, 3.29 -3.27, 3.08. MS (ES +) m / z 500.3 (M + 1).

EXAMPLE 2.11 3- (4-FLUOROFENLL) -N-. { 6-r4- (2-TRlFLUOROMETILBENZOIL) PIPERAZIN-1-IL > PIRLPAZIN-3-IL) PROPIONAMlDA Following the procedure of Example 2, making only the required variations to use 3- (4-fluorophenyl) propionic acid in place of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] ( 2-trifluoromethylphenol) methanone, the title compound was obtained as a white solid (58.5% Yield). 1 H NMR (300 MHz, CDCl 3) d 10.33, 8.40, 7.78, 7.67, 7.60, 7.36, 7.14, 7.08, 6.85, 3.90, 3.51, 3.20, 3.02, 2.92. MS (ES +) m / z 502.7 (M + 1).

EXAMPLE 2.12 2-BUTOXI-N-. { 6-r4- (2-TRlFLUOROMETILBENZOIL) PIPERAZIN-1-ILL PIRIDAZIN-3-IDACETAMlDA Following the procedure of Example 2, making only the variations required to use butoxyacetic acid in place of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethylphenyl) methanone, obtained the title compound as a white powder (40.8% Yield). H NMR (300 MHz, CDCl 3) d 9.19, 8.35, 7.72, 7.55, 7.33, 7.03, 4.05, 3.94, 3.60, 3.31, 1.64, 1.43, 0.93. MS (ES +) m / z 465.6 (M + 1).

EXAMPLE 2.13 CHLORIDE OF 2-METHYL-1 -. { 6-r4- (2-TRIFLUOROMETILBENZOIL) - PIPERAZIN-1-IL1 PYRIDAZI N-3-ILCARBAMOI DPROPILAMONIUM Following the procedure of Example 2, making only the required variations to use 2-amino-3-methyl-butyric acid instead of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2 -trifluoromethylphenyl) methanone and then treated with HCl, the title compound was obtained as a white powder of the HCl salt (48% Yield). 1 H NMR (300 MHz, DMSO-d 6) d 11.53, 8.50, 8.12, 7.84, 7.76, 7.68, 7.62, 7.54, 3.90, 3.36, 3.25, 2.20, 0.98. MS (ES +) m / z 451.2 (M + 1).

EXAMPLE 2.14 • f6-f4- (2-TRIFLUOROMETILBENZOIL) PIPERAZIN-1 -IL1 PIRIDAZIN-3-IDAMIDE OF ACID 5-f 1.21DITIOLAN-3-IL-PENTANOIC Following the procedure of Example 2, making only the variations required to use lipoic acid in place of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethylphenyl) methanone, obtained the title compound as a white solid (yield 8%). 1 H NMR (300 MHz, CDCl 3) d 10. 11, 8.37, 7.72, 7.61, 7.53, 7.35, 7.04, 4.08-3.84, 3.70-3.57, 3.56-3.46, 3.33-3.30, 3.17-3.02, 2.59.2.39, 1.84 , 1.78-1.56, 1.51-1.37. 13C NMR (300 MHz, CDCI3): 172.52, 167.57, 157.94, 150.00, 134.42, 132.38, 129.45, 127.79, 127.29, 127.14, 126.93, 126.88, 126.82, 121.92, 116.27, 56.34, 46.47, 45.65, 45.33, 41.25, 40.26 , 38.49, 37.05, 34.74, 28.85, 25.14. MS (ES +) m / e 540.1 (M + 1).

EXAMPLE 2.15 2- (2-CIC LOP ROPILETOXI) -N. { 6-r4- (2-TRIF LUORO METHYLBENZOYL) PIPERAZIN-1-IL1-PIRIDAZIN-3-IL > ACETAMID Following the procedure of Example 2, making only the required variations to use 5- (2-cyclopropylethoxy) acetic acid instead of benzyloxyacetic acid to react with [4- (6-aminopyridazin-3-yl) piperazin-1 -i I] (2-tri fluoro methyl nyl) meta nona, the title compound was obtained as a white solid (0.056 g, 41% Yield). H NMR (300 MHz, CDCI3) d 9.15, 8.32, 7.73-7.7, 7.61-7.53, 7.35-7.33, 7.0, 4.07, 3.97-3.89, 3.64, 3.57-3.54, 3.32-3.29, 1.57-1.51, 0.85-0.75 , 0.52-0.48, 0.09-0.07.3 13C NMR (75 MHz, CDCI3) d 168.8, 167.5, 158.3, 148.3, 134.4, 132.3, 129.3, 127.7, 127.5, 127.2, 127.1, 126.8, 126.7, 126.3, 125.4, 121.8 , 120.9, 115.5, 72.2, 70.2, 46.4, 45.5, 45.1, 41.2, 34.5, 7.8, 4.2. MS (ES +) m / z 478.3 (M + 1).

EXAMPLE 3 SYNTHESIS OF (3-METHYLBUTYL) AMID OF ACID 6-f4- (ISOXAZOL-5- CARBONIDPIPERAZIN-1-IL1 PIRIDAZI N-3-CARBOXYLIC To a stirred solution of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide (277 mg, 1 mmol) in 15 ml of dichloromethane was added isoxazole-5-carbonyl chloride (1.0 mmol). ) as a dichloromethane solution in the presence of 0.4 ml of triethylamine at room temperature. After 1 hour, the mixture was evaporated and the residue was subjected to column chromatography. The final product was isolated as a solid (0.107 g, 29% yield). 1 H NMR (300 MHz, CDCl 3) d 8.34, 8.05, 7.83, 7.00, 6.86, 3.90-3.84, 3.51-3.45, 1.75-1.62, 1.53-1.46, 0.92. MS (ES +) m / z 373.3 (M + 1).

EXAMPLE 3.1 (3-METHYLBUTYL) ACID AMID 6-r4-M-METHYL-5-TRI FLUORO METH L-1 H-PI RAZO L-4-CARBONIL) PIPERAZIN-1-IL1-PIRIDAZIN-3-CARBOXYLIC Following the procedure of Example 3, making only the required variations to use 1-methyl-5-trifluoromethyl-1 H-pírazole-4-carbonyl chloride in place of isoxazole-5-carbonyl chloride to react with (3-methylbutyl) 6-Piperazin-1-yl-pyridazine-3-carboxylic acid amide, the title compound was obtained as a white powder (47% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.04, 7.82, 7.54, 6.99, 3.97, 3.90-3.54, 3.51-3.44, 1.75-1.62, 1.53-1.46, 0.92. MS (ES +) m / z 454.3 (M + 1).

EXAMPLE 3.2 (3-METHYLBUTYL) ACID AMID 6-f4- (4-METHYLPIPERAZIN-1-CARBONIDPIPERAZIN-1-IL1 PYRIDAZINE-3-CARBOXYLIC Following the procedure of Example 3, making only the variations required to use 4-methylpiperazine-1-carbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1- (3-methylbutyl) -amide. pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (79% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.01, 7.83, 6.96, 3.77-3.73, 3.51-3.44, 3.42-3.38, 3.36-3.33, 2.44-2.41, 2.31, 1.75-1.62, 1.48, 0.92. MS (ES +) m / z 404.4 (M + 1).

EXAMPLE 3.3 6- (4-BENZOYLPIPERAZIN-1-IL) PYRIDAZINE-3-CARBOXYLIC ACID (2-CICLOPROPYLLATE) AMIDA Following the procedure of Example 3, making only the variations required to use benzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazin-3-cyclopropylethyl acid amide carboxylic acid, the title compound was obtained as a white solid (92% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.04, 7.97, 7.44, 6.98, 3.99-3.62, 3.55, 1.50, 0.80-0.66, 0.48-0.42, 0.11-0.06. MS (ES +) m / z 380.2 (M + 1).

EXAMPLE 3.4 (2-CICLOPROPILETLL) ACID AMID 6- [4- (2-ETHYLBUTYL) PIPERAZIN-1-IL1-PYRIDAZINE-3-CARBOXYLIC Following the procedure of Example 3, making only the variations required to utilize 2-ethylbutyryl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazin- (2-cyclopropylethyl) -amide. 3-carboxylic acid, the title compound was obtained as a white solid (71% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.07, 8.00, 7.00, 3.86-3.90, 3.76, 3.68, 3.57, 2.57, 1.70, 1.50-1.55, 0.90, 0.45, 0.10. MS (ES +) m / z 374 (M + 1).

EXAMPLE 3.5 (2-CICLOPROPYLTHYL) ACID AMID (4- C ICLOHEXANC ARBONILPI PERAZI N-1-I RID AZI N-3- CARBOXYLIC RDI Following the procedure of Example 3, making only the variations required to use cyclohexanecarbonyl chloride instead of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) -amide, the title compound was obtained as a white solid (58% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.06, 7.99, 6.99, 3.88, 3.79, 3.68, 3.56, 2.50, 1.67-1.84, 1.48-1.60, 1.24-1.34, 0.76, 0.47, 0.10 MS (ES +) m / z 386 (M + 1).

EXAMPLE 3.6 (3-METHYLBUTIDAMIDE OF ACID 6-r4- (2- TRI FLUORO METOXIBENZOI DPI PERAZI N-1 -I Ll PIRIDAZIN-3- CARBOXYLIC Following the procedure of Example 3, making only the required variations to use 2-trifluoromethoxybenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazin- (3-methylbutyl) -amide. 3-carboxylic acid, the title compound was obtained as a white solid (83% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.06, 7.85, 7.53-7.32, 7.01, 4.12-3.36, 1.75-1.66, 1.54-1.48, 0.98. MS (ES +) m / z 466.2 (M + 1).

EXAMPLE 3.7 (3-METILBUTID AMID ACID 6-r4- (5-CHLORO-2- TRI FLUORO METI LBENZOI DPI PERAZI N -1-1 L1P I RIDAZIN -3- CARBOXYLIC Following the procedure of Example 3, making only the required variations to use 5-chloro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-pi perazine (3-methylbutyl) -amide pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (80%). p.f. 148-151 ° C. 1 H NMR (400 MHz, CDCl 3) d 8.06, 7.85, 7.67, 7.54-7.50, 7.35, 7.01, 4.05-3.34, 1.73-1.46, 0.98. MS (ES +) m / z 484.3 (M + 1).

EXAMPLE 3.8 (2-CICLOPROPILETIDAMIDE OF ACID 6-T4- (2-TRIFLUOROMETILBENZOIDPIPERAZIN-1-IL1PIRIDAZIN-3-CARBOXÍLICO Following the procedure of Example 3, making only the required variations to use 2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine (2-cyclopropylethyl) amide 3-carboxylic acid, the title compound was obtained as a white solid (92%). p.f. 95-98 ° c. 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.96, 7.74, 7.65-7.52, 7.35, 6.99, 4.08-3.22, 1.55-1.46, 0.80-0.67, 0.48-0.42, 0.10-0.07. 13C NMR (75 MHz, CDCI3) d 167.6, 162.9, 160.0, 145.4, 134.2, 132.3, 129.5, 127.2, 127.1, 126.9, 121.8, 118.2, 112.5, 46.3, 44.5, 44.4, 41.2, 39.6, 34.5, 8.6, 4.2 . MS (ES +) m / z 448.2 (M + 1).

EXAMPLE 3.9 (2-CICLOPROPILETID AMID ACID 6-r4- (2-CHLORO-5- FLUOROBENZOIDPIPERAZIN-1-IL1 PYRIDAZI-3-CARBOXYLIC Following the procedure of Example 3, making only the variations required to use 2-chloro-5-fluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazine (2-cyclopropylethyl) amide n- - i-Pyridazin-3-carboxylic acid, the title compound was obtained as a white solid (94% Yield), mp 194-196 ° C. 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.96, 7.41-7.37, 7.11-7.03, 7.00, 4.07-3.34, 1.55-1.46, 0.79-0.68, 0.48-0.42, 0.11-0.06. 13 C NMR (75 MHz, CDCl 3) d 165.7, 163.0, 160.0, 159.7, 145.5, 136.7, 131.5, 127.1, 125.3, 117.8, 115.2, 112.5, 46.0, 44.8, 44.6, 41.2, 39.6, 34.5, 8.6, 4.2. MS (ES +) m / z 432.2 (M + 1).

EXAMPLE 3.10 (2-CICLOPROPILETID AMID ACID 6-r4- (3,3,3-TRIFLUORO-2-METHYL-2-TRIFLUOROMETILPROPIO IDPIPERAZIN -1-IL1PIRIDAZIN- 3-CARBOXYLIC Following the procedure of Example 3, making only the variations required to use (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropionyl chloride in place of isoxazole-5-carbonyl chloride to react with (2- cyclopropyl) letyl) 6-piperazin-1-yl-pyridazine-3-carboxylic acid amide, the title compound was obtained as a white solid (35% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.02, 7.96, 6.80 , 3.91-3.75, 3.58, 1.58-1.48, 0.78-0.63, 0.48-0.43, 0.11-0.04 MS (ES +) m / z 468.2 (M + 1).

EXAMPLE 3.11 (2-CICLOPROPILETID AMID ACID 6-f4- (2,2-DIMETHYLPROPIONIDPIPERAZIN-1-IL1PIR1DAZIN-3-CARBOXYLIC Following the procedure of Example 3, making only the required variations to use 2,2-dimethylpropionyl chloride in place of isoxazole-5-carbonyl chloride to react with (2-cyclopropi leti lo) 6-piperazin-1-yl acid amide pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (64% yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 8.01, 6.98, 3.86-3.73, 3.57, 1.57-1.48, 0.79-0.70, 0.52-0.45, 0.16-0.12. MS (ES +) m / z 360.0 (M + 1).

EXAMPLE 3.12 (2-CICLOPROPILETID AMID ACID 6-r4- (5-CHLORINE-2- TRI FLUO ROM ETILBENZOI DPI PERAZI N -1-1 L1PIRID AZI N -3- CARBOXYLIC Following the procedure of Example 3, making only the required variations to use 5-chloro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-p iperazi (2-cyclopropylethyl) amide 1-pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (58% Yield), mp 164-166 ° C. 1 H NMR (300 MHz, CDCl 3) d 8.07, 7.96, 7.69, 7.54, 7.02, 4.07-3.35, 1.52, 0.79-0.68, 0.48-0.43, 0.14-0.08. MS (ES +) m / z 482.1 (M + 1).

EXAMPLE 3.13 (2-CICLOPROPILETIDAMIDE OF ACID 6-r4- (5-FLUORO-2- TRIFLUOROMETILBENZOIDPI PERAZI -1-I L1PIRIDAZIN- 3- CARBOXÍLICO Following the procedure of Example 3, making only the required variations to use 5-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl (2-cyclopropylethyl) amide - pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (65% yield). 1 H NMR (400 MHz, CDCl 3) d 8.05, 7.98, 7.74, 7.27-7.24, 7.09-7.06, 7.00, 4.08-3.96, 3.94-3.68, 3.55, 3.36, 1.50, 0.79-0.69, 0.48-0.42, 0.11-0.09 .

EXAMPLE 3.14 (2-CICLOPROPILETID AMID OF ACID 6-r4- (2,6-DIFLUOROBENZOIDPIPERAZ1N-1-IL1PIRIPAZIN-3-CARBOXÍLICO Following the procedure of Example 3, making only the variations required to use 2,6-difluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-pi perazin-1 -i (2-cyclopropylethyl) -amide. I-pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (44% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.07, 8.07-7.99, 7.44-7.38, 7.02-6.96, 4.0-3.99, 3.86-3.83, 3.58-3.50, 3.39-3.38, 1.52, 1.15-1.10, 0.77-0.74, 0.49 -0.45, 0.11-0.08.

EXAMPLE 3.15 (2-CICLOPROPILETID AMID ACID 6-T4 (PIRROLIDIN-1-CARBONIDPIPERAZIN-1-IL1PIRIDAZIN-3-CARBOXYLIC) Following the procedure of Example 3, making only the variations required to use pyrrolidin-1-carbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl- (2-cyclopropyethyl) amide pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (54% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.04, 7.98, 6.99, 3.79, 3.56, 3.47-3.45, 3.40, 1.87-1.85, 1.52, 0.80-0.72, 0.48-0.46, 0.10-0.09.

EXAMPLE 3.16 (2-CICLOPROPILETIDAMIDE OF ACID 6-f4- (2,5-BIS-TRI FLUORO METILBENZOIDPIPERAZIN-1 -I L1PIRID AZI N-3- CARBOXYLIC Following the procedure of Example 3, making only the variations required to use 2,5-bis-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1- (2-cyclopropylethyl) -amide. pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (50% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.08, 7.99, 7.92-7.9, 7.85-7.84, 7.65, 7.02, 4.13-4.08, 3.95-3.71, 3.57-3.55, 3.38-3.36, 1.57-1.44, 0.8-0.7, 0.48 -0.46, 0.16-0.08.

EXAMPLE 3.17 (2-CICLOPROPILETID AMID OF ACID 6-f4- (2.4-BIS-TRI FLU PROMETI LBENZOI DPI PERAZI N-1 -l LIPIRID AZI -3- CARBOXYLIC Following the procedure of Example 3, making only the required variations to use chloride 2,4-bis-trifluoromethylbenzoyl in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide, the title compound was obtained as a white powder (29% yield) H NMR (400 MHz, CDCI3) d 8.08, 8.02-7.98, 7.91, 7.54, 7.03, 3.97-3.86, 3.85-3.72, 3.57, 3.36, 1.52, 0.77-0.74, 0.49- 0.46, 0.12-0.09.

EXAMPLE 3.18 (2-CICLOPROPILETID AMID ACID 6-r4- (2,5-DIFLUOROBENZOI DPI PERAZI N-1 -I L1PIRID AZI N-3-CARBOXYLIC Following the procedure of Example 3, making only the variations required to use 2,5-difluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl- (2-cyclopropylethyl) -amide. pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (53% Yield). H NMR (400 MHz, CDCI3) d 8.08, 8.0, 7.17-7.11, 7.03, 4.02-3.92, 3.85-3.83, 3.59-3.5, 1.52, 0.74-0.69, 0.46-0.40, 0.09-0.04.

EXEMPLP 3.19 (3-CICLPPRPPILPRPPID AMID OF ACID 6-r4- (5-FLUPRP-2-TRIFLUPRPMETILBENZPIDPIPERAZIN-1-IL1PIRIDAZIN-3-CARBPXYLIC Following the procedure of Example 3, making only the variations required to use 5-Fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl (3-cyclopropylpropyl) amide pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (28% yield). 1 H NMR (400 MHz, CDCl 3) d 8.07, 7.89, 7.76, 7.28-7.24, 7.10-7.08, 7.02, 4.06-4.03, 3.90-3.86, 3.82-3.72, 3.51, 3.37, 1.76-1.70, 1.30, 0.70-0.67 , 0.44-0.40, 0.03-0.003.

EXAMPLE 3.20 (2-CICLOPROPILETID AMID OF ACID 6-4- (2-CHLORO-4-TRIFLUORPMETILPIRIMI DI N-5-CARBPNIDPI PERAZI N-1-IL1 PYRIDAZI-3-CARBPXYLIC Following the procedure of Example 3, making only the required variations to use 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazine (2-cyclopropylethyl) amide -1-yl-pyridazin-3-carboxylic acid, the title compound was obtained as a white powder (35% Yield). 1H NMR (300 MHz, CDI3) d 8.77, 8.08, 7.97, 7.01, 4.06-3.68, 3.55, 3.39, 1.50, 0.76-0.71, 0.48-0.42, 0.10-0.05.

EXAMPLE 3.21 (2-CICLOPROPILETID AMID OF ACID 6-T4- (2-FLUOROBENZOI DPI PERAZI N-1 -I L1PIRID AZI N -3-C ARBOXÍ LIGO Following the procedure of Example 3, making only the required variations to use 2-fluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazin-3-cyclopropylethyl acid amide carboxyl, the title compound was obtained as a white powder (20.3% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.04, 7.98, 7.47-7.40, 7.26-7.21, 7.15-7.09, 6.99, 3.95-3.78, 3.58-3.5, 1.54-1.47, 0.78-0.69, 0.48-0.42, 0.11-0.05 .

EXAMPLE 3.22 (2-CICLOPROPILETID AMID OF ACID 6. -T4-Í3. • FLUPRP-2- TRI FLUO ROM ETILBENZOI DPI PERAZI N-1- IL1PIRIDAZIN-3- CARBPXILICO Following the procedure of Example 3, making only the required variations to use 3-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1- (2-cyclopropyloethyl) amide pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (31% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.97, 7.65-7.59, 7.29, 7.12, 6.99, 4.05-3.99, 3.89-3.72, 3.54, 3.35, 1.50, 0.76-0.71, 0.48-0.42, 0.10-0.05.

EXEMPLP 3.23 (3-CICLPPRPPILPRPPIL) ACID AMID 6-f4- (4-FLUPRP-2-TRIFLUOROMETILBENZOIDPIPERAZIN-1-IL1PIRIDAZIN-3-CARBOXYLIC Following the procedure of Example 3, making only the variations required to use 4-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1- (3-cyclopropylpropyl) amide 1-pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (49% yield). 1 H NMR (300 MHz, CDCl 3) d 8.04, 7.87, 7.45-7.3, 6.99, 4.09-3.98, 3.89-3.67, 3.49, 3.33, 1.75-1.66, 1.28, 0.69-0.62, 0.43-0.37, 0.04-0.03.

EXAMPLE 3.24 (3-CICLOPROPILPROPID AMID OF ACID 6-T4- (5-CLPRP-2-TRIFLUPRPMETILBENZPIDP1PERAZIN-1-I 1 PYRIDAZINE-3-CARBCXÍLICP Following the procedure of Example 3, making only the required variations to use 5-chloro chloride -2-trifluoromethylbenzoyl in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide, the title compound was obtained as a white solid ( 73% Yield) .1H NMR (300 MHz, CDCI3) d 8.05, 7.86, 7.68-7.65, 7.53-7.5, 7.35, 6.99, 4.05-3.99, 3.89-3.67, 3.52-3.46, 3.37-3.34, 1.75-1.6 , 1.31-1.24, 0.71-0.62, 0.43-0.37, 0.02-0.03, 13C NMR (75 MHz, CDCI3) d 165.9, 162.9, 159.9, 145.4, 138.8, 135.93, 135.9, 129.7, 128.6, 128.4, 121. 4, 112.6, 46.3, 44.5, 44.3, 41.3, 39.2, 31.9, 29.5, 10.5, 4.4 MS (ES +) m / z 496. 3 (M + 1).

EXAMPLP 3.25 (4-METILPENTID AMID OF ACID 6-r4- (5-FLUPRP-2- TRI FLUORO M ETI LB ENZOIDPIPERAZIN-1 -I L1PIRID AZI N-3- CARBOXYLIC Following the procedure of Example 3, making only the variations required to use 5-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1- (4-methylpentyl) -amide. pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (10% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.04, 7.86, 7.75-7.71, 7.26-7.22, 7.08-7.04, 6.98, 4.10-3.98, 3.90-3.70, 3.46-3.40, 3.36-3.33, 1.61-1.50, 1.28-1.20 , 0.85. 13C NMR (75 MHz, CDCI3) d 166.0, 162.9, 162.6, 159.9, 145.5, 136.8, 129.7, 127.6, 127.7, 127.2, 125.1, 123.3, 121.4, 116.8, 116.5, 114.9, 114.6, 113.9, 112.5, 46.3, 44.5 , 44.3, 41.3, 39.7, 36.0, 27.8, 27.4, 22.5. MS (ES +) m / z 482.4 (M + 1).

EXAMPLE 3.26 (4-METILPENTID AMID OF ACID 6-T4- (2-TRIFLUPRPMETILBENZPIDPIPERAZIN-1-IL1PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 3, making only the variations required to utilize 2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazin- (4-methylpentyl) -amide. 3-carboxylic acid, the title compound was obtained as a white solid (65.5% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.03, 7.86, 7.74-7.72, 7.62-7.54, 7.36-7.34, 6.98, 4.08-3.98, 3.92-3.65, 3.47-3.4, 3.35-3.31, 1.62-1.53, 1.28-1.21 , 0.86. 13C NMR (75 MHz, CDCI3) d 167.5, 162.9, 159.9, 145.3, 134.2, 132.3, 129.4, 127.0, 126.7, 126.2, 125.4, 121.7, 112.5, 46.3, 44.5, 44.3, 41.2, 39.6, 35.9, 27.7, 27.4 , 22.4. MS (ES +) m / z 464. 5 (M + 1).

EXAMPLE 3.27 (2-CICLOPROPILETID AMID ACID 6-r4- (4-FLUORO-2-TRIFLUOROMETILBENZOIDPIPERAZIN-1-IL1PIRIDAZIN-3-CARBOXÍLICO Following the procedure of Example 3, making only the variations required to use 4-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazoI-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropyl) -amide. , the title compound was obtained as a white solid (83.5% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.97, 7.46-7.42, 7.39-7.29, 6.97, 4.07-4.01, 3.89-3.67, 3.58-3. 51, 3.36-3.32, 1.53-147, 0.76-0.69, 0.48-0.42, 0.10-0. 06. 13C NMR (75 MHz, CDCI3) d 166.7, 163.9, 162.8, 160.6, 159.9, 145.4, 129.6, 129.5, 127.0, 119.7, 119.4, 114.8, 114.7, 114.4, 114.38, 112.5, 44.4, 44.5, 44.3, 41.3 , 39.6, 34.4, 8.6, 4.1. MS (ES +) m / z 466. 1 (M + 1).

EXAMPLE 3.28 (3-METILBUTID AMID ACID 6-r4- (2-NITROBENZOID PIPERAZIN-1-IL1 PYRIDAZINE-3-CARBOXYLIC Following the procedure of Example 3, making only the required variations to use 2-nitrobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with (3-methylbutyl) amide 6-piperazin-1-yl-pyridazin-3 carboxylic acid, the title compound was obtained as a white solid (72% Yield) .1 H NMR (500 MHz, CDCl 3) d 8.24, 8.07, 7.84, 7.76, 7.63, 7.44, 7.01, 4.12-4.26, 3.75-3.95 , 3.50, 3.41, 1.65-1.76, 1.52, 0.94. MS (ES +) m / z 427 (M + 1).

EXAMPLE 3.29 (3-METHYLBUTIP AMID ACID 6-r4- (2-CHLOROBENZOiP PIPERAZIN-1-IL1 PYRIDAZINE-3-CARBOXYLIC Following the procedure of Example 3, making only the variations required to use 2-chlorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-pyridazin-3-methylbutyl) -amide. carboxylic acid, the title compound was obtained as a white solid (94% yield). 1 H NMR (500 MHz, CDCl 3) d 8.05, 7.85, 7.43-7.46, 7.31-7.40, 7.00, 4.04-4.10, 3.75-3.94, 3.34-3.52, 1.65-1.75, 1.52, 0.94. MS (ES +) m / z 416 (M + 1).

EXAMPLE 3.30 (3-METHYLBUTIP AMID ACID 6-r4- (2.4-DICHLOROBENZOIP PI PERAZI N-1-I L1PIRIDAZIN-3-CARBOXYLIC Following the procedure of Example 3, making only the required variations to use 2,4-dicyrobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with (3-methyl-butyl I) 6-piperazin-1-yl acid amide pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (90% Yield) .1 H NMR (500 MHz, CDCl 3) d 8.07, 7.85, 7.47, 7.35, 7.28, 7.01, 4.02-4.09, 3.75 -3.93, 3.33-3.52, 1.65-1.75, 1.52, 0.94. MS (ES +) m / z 450 (M).

EXAMPLE 3.31 ESTER 2-r, 4-r6- (2-CICLOPROPILELLCARBAMOIL) PIRIDAZLN-3-IL, - PIPERAZIN-1-CARBONID PHENYLLE OF ACETIC ACID Following the procedure of Example 3, making only the required variations to use acetyl chloride Isal iciloi lo instead of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-pyridazin (2-cyclopropylethyl) amide -3-carboxylic acid, the title compound was obtained as a white solid (39% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.06, 8.00, 7.00, 7.47, 7.34-7.29, 7.18, 6.98, 4.00-3.72, 3.60-3.48, 2.28, 1.52, 0.76, 0.48, 0.10. MS (ES +) m / z 438 (M + 1).

EXAMPLE 3.32 (2-CICLPBUTILETIP AMID OF ACID 6-í4- (5-CLPRP-2-TRIFLUPRPMETILBENZPIPPIPERAZIN-1-IL1PIRIDAZIN-3-CARBOXÍLICO Following the procedure of Example 3, making only the variations required to use 5-chloro-2- (trifluoromethyl) benzoyl chloride in place of isoxazole-5-carbonyl chloride to react with (2-cyclobutyl-ethyl) 6-chloro-6-amide. -piperazin-1-ylpyridazine-3-carboxylic acid, the title compound was obtained as a white powder (71% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.07, 7.81, 7.66, 7.51, 7.34, 3.86-3.66, 3.40-3.34, 2.33, 2.03, 1.86-1. 57. 13 C NMR (75 MHz, CDCl 3) d 166.0, 162.8, 159.8, 145.5, 138.9, 135.9, 129.8, 128. 5.127. 5,127. 3.125. 6,125. 2,112. 7.46. 4.44. 6.44. 5,41. 3,37. 6.36. 5.33.7, 28.3, 18.6. MS (ES +) m / z 496.5 (M + 1).

EXAMPLE 3.33 (2-CYCLOBUTHYLLE) ACID AMID 6-r4- (5-FLUORO-2-TRIFLUOROMETILBENZOIPPIPERAZIN-1-IL1PIRIDAZIN-3-CARBOXYLIC Following the procedure of Example 3, making only the required variations to use 5-fluoro-2- (trifluoromethyl) benzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazine (2-cyclobutylethyl) -amide -1-yl-pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (71% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.03, 7.83-7.71, 7.20, 7.06, 6.95, 4.01, 3.88-3.67, 3.40-3.28, 2.35, 1.89-1.57. 13C NMR (300 MHz, CDCI3) d 166.0, 162.8, 162.6, 159.9, 145.5, 137.0, 19.7, 127.2, 125.1, 121.5, 116.9, 116.6, 115.0, 114.7, 112.6, 46.4, 44.6, 44.4, 41.3, 37.6, 36.5 , 33.7, 28.3, 18.6. MS (ES +) m / z 480. 5 (M + 1).

EXAMPLE 3.34 HEXYLAMIDE OF ACID 6-f4- (5-CHLORO-2-TRIFLUOROMETILBENZOIPPIPERAZIN-1-IL1PIRIDAZIN-3-CARBOXÍLICO Following the procedure of Example 3, making only the variations required to use 5-chloro-2- (trifluoromethyl) benzyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl hexyl amide pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (55% Yield) .1 H NMR (300 MHz, CDCl 3) d 8.07, 7.86, 7.66, 7.51, 7.34, 7.00, 4.00, 3.88-3.66, 3.47-3.33, 1.62-1.53, 1.38-1.27, 0.85. 3C NMR (75 MHz, CDCI3) d 166.0, 162.9, 159.9, 145.5, 138.9, 135.9, 129.8, 128.5, 127.5, 127.2, 125.6, 125.1, 121.5, 112.7, 46.4, 44.6, 41.3, 39.5, 31.5, 29.5, 26.6 , 22.6, 14.0. MS (ES +) m / z 498.2 (M + 1).

EXAMPLE 3.35 (2-CICLOPROPILETIP AMID ACID 6-r4- (5-FLUPRP-2- TRIFLUOROMETILBENZOIP-p.4lDIAZEPAN-1-IL1 PIRIPAZIN-3-CARBPXÍLICP Following the procedure of Example 3, making only the required variations to use 5-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6- (2-cyclopropylethyl) acid amide. ] diazepane-1-pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (60% yield). 1 H NMR (CDCl 3, 300 MHz) d 8.07-7.85, 7.71-7.6, 7.23-7.08, 6.94-6.88, 6.34-6.31, 4.24-4.12, 3.98-3.73, 3.67-3.36, 3.29-3.25, 2.19-1.73, 1.53 -1.46, 0.81-0.68, 0.48-0.4, 0.11-0.03. 13C NMR (CDCI3, 75 MHz) d 167.3, 167.2, 165.7, 163.1, 162.9, 162.3, 158.9, 158.4, 144.8, 144.6, 137.1, 129.7-129.2, 127.4, 127.2, 125.0, 121.4, 116.7, 116.6, 116.4, 116.3 , 114.9, 114.8, 114.6, 114.5, 111.5, 111.3, 48.8, 48.6, 47.6, 47.5, 45.8, 45.7, 44.1, 39.6, 34.5, 26.8, 25.4, 8.6, 4.2. MS (ES +) m / z 480.1 (M + 1).

EXEMPLP 4 SYNTHESIS OF (3-METILBUTIP AMIDA OF ACIDP 6- (4-BENZYLPI PERAZI N-1 -I PPIRID AZI N-3-CARBPXÍLlCP A stirred mixture of 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide (0.113 g, 0.5 mmol), 1-benzylpiperazine (90 mg, 0.5 mmol), tetrabutylammonium bromide (27 mg, 0.084 mmol) and 1 , 8-diazabicyclo [5.4.0] undec-7-ene (152 mg, 1.0 mmol) was heated under reflux in 10 ml of dioxane overnight. The solvent was evaporated. The residue was treated with 2% methanol in 25 ml of water. The solid, which was precipitated, was filtered and dried in vacuo to give 138 mg (0.376 mmol) of the title compound in 75% yield. 1 H NMR (300 MHz, CDCl 3) d 7.98, 7.87, 7.36-7.32, 6.94, 3.76-3.74, 3.57, 3.50-3.46, 2.60-2.58, 1.74-1.68, 1.52-1.48, 0.94. MS (ES +) m / z 368.2 (M + 1).

EXAMPLP 5 SYNTHESIS OF 1- (2-PHENYLCLCLOPROPID-3-f6-r4- (2-TRIFLUPRPMETILBENZPIDPIPERAZIN-1-I 1P1RIDAZIN-3-IL.) UREA To a solution of [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl-phenyl) methanone (123 mg, 0.35 mmol) in 20.0 ml of DMF was added (2-isocyanatocylclopropyl) benzene (111 mg, 0.7 mmol). The mixture was stirred at 60 ° C overnight. After cooling, the mixture was poured into 120 ml of water. The white solid, which was precipitated, was filtered and dried in vacuo to give the title product (162 mg) as a white solid in 90% yield. 1 H NMR (300 MHz, CDCl 3) d 8.01-7.97, 7.73, 7.60, 7.55, 7.32, 7.22-7.10, 7.06, 4.00-3.95, 3.87-3.86, 3.62-3.52, 3.43-3.41, 3.25-3.22, 2.85-2.82 , 2.14-2.10, 0.91-0.86. MS (ES +) m / z 511.2 (M + 1).

EXAMPLE 5.1 Ethyl Ester of ACID 3- (3 -f 6-T4- (2- TRI FLUORO METH LBENZOIPPI PERAZI N-1 -I L1-PIRID AZI N-3-ID-UREID) PROPIONIC Following the procedure of Example 5, making only the required variations to use 3-isocyanatopropionic acid ethyl ester in place of (2-isocyanatocylclopropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yI] (2-trifluoromethylphenyl) methanone , the title compound was obtained as a white powder (37% Yield), 1 H NMR (300 MHz, CDCl 3) d 8.12, 7.92, 7.74, 7.62, 7.55, 7.36, 7.11, 6.65, 3.95-3.90, 3.59, 3.49. -3.40, 3.28, 2.36-2.33, 1.63-1.61, 0.94-0.93.

EXAMPLP 5.2 1-PENTIL-3-f6-r4- (2-TRlFLUPRPMETILBENZPIDPIPERAZlN-1-IL1 PIRIDAZIN- 3-IDUREA Following the procedure of Example 5, making only the required variations to use pentylisocyanate in place of (2-isocyanatocyclopropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone, the title compound was obtained as a white solid (45.5% Yield). 1 H NMR (400 MHz, CDCl 3) d 10.60, 7.82, 7.74, 7.13, 7.63, 7.56, 7.52, 7.36, 7.08, 4.29, 4.0-4.09, 3.85-3.95, 3.50-3.70, 3.40-3.47, 3.25-3.36, 1.50 -1.60, 1.22-1.36, 0.80-0.92. MS (ES +) m / z 465 (M + 1).

EXAMPLE 5.3 1-BENCIL-3-f6-r4- (2-TRIFLUOROMETILBENZOID-PIPERAZIN-1 ILTPIRIDAZIN-3-IL) UREA Following the procedure of Example 5, making only the required variations to use benzyl isocyanate in place of (2-isocyanatocylcylpropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone, the title compound was obtained as a white solid (45.6% Yield). 1 H NMR (500 MHz, CDCl 3) d 12.0, 8.28, 7.80, 7.67, 7.62, 7.32, 7.23, 7.02-7.14, 4. 54, 3.85-3.91, 3.69-3.76, 3.28-3.40, 2.94-3.10.

EXAMPLE 5.4 1- (4-FLUOROFE ID-3-f6-r4- (2-TRIFLUOROMETILBENZOID PIPERAZIN-1-IL1-PIRIDAZI -3-IDUREA Following the procedure of Example 5, making only the required variations to use 4-fluorophenylisocyanate in place of (2-isocyanatocylclopropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2- trifluoromethylphenyl) -methanone, the title compound was obtained as a white solid (32.3% Yield). 1H NMR (500 MHz, CDCL3) d 12.0, 8.20, 7.53, 7.64, 7.59, 7.39, 7.33, 7.16, 6.91-6.98, 3.96-4.04, 3.83-3.90, 3.52-3.65, 3.37-3.45, 3.20-3.26. MS (ES +) m / z 489 (M + 1).

EXAMPLE 5.5 1- (2-FLUOROFENID-3-f6-r4- (2-TRIFLUOROMETILBENZOID PIPERAZIN-1-IL1-PIRIDAZIN-3-ID UREA Following the procedure of Example 5, making only the required variations to use 2-flurophenylisocyanate in place of (2-isocyanatocylclopropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2- trifluoromethylphenyl) -methanone, the title compound was obtained as a white solid (32% Yield). 1H NMR (500 MHz, CDCL3) d 7.90-8.30, 7.99, 7.75, 7.63, 7.57, 7.34, 7.10-7.17, 7.01-7.07, 3.94-4.01, 3.85-3.92, 3.56-3.66, 3.41-3.49, 3.24-3.29 .

EXAMPLE 5.6 1-FENETIL-3-. { 6-r4- (2-TRIFLUOROMETILBENZOID-PIPERAZIN-1 ILl-PIRIDAZIN-3-IL> UREA Following the procedure of Example 5, making only the variations required to use 2-phenylethylisocyanate in place of (2-isocyanatocylclopropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2- trifluoromethylphenyl) -methanone, the title compound was obtained as a white solid (19% Yield: 1 H NMR (500 MHz, CDCl 3) d 7.92, 7.60, 7.64, 7.58, 7.37, 7.13-7.24, 7.09, 3.96-4.03, 3.82-3.89, 3.40-3.56, 3.22-3.34, 2.86.

EXAMPLE 5.7 1- (4-FLUOROBENCID-3- {6-r4- (2-TRIFLUOROMETILBENZOID PIPERA IN-1-IL1-PIRIDAZIN-3-IL) UREA Following the procedure of Example 5, making only the required variations to use 4-fluorobenzylisocyanate in place of (2-isocyanatocylchloropropyl) benzene to react with [4- (6-aminoniridazin-3-yl) piperazin-1-1] (2-trifluoro methyl fyl nl) -methanone, the title compound was obtained as a white solid (56% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.13, 7.78, 7.66, 7.60, 7.33, 7.21, 7.09, 6.83, 4.50, 3.91-4.00, 3.73-3.80, 3.34-3.48, 3.05-3.22. MS (ES +) m / z 503 (M + 1).

EXAMPLE 5.8 1-BUTIL-3-. { 6-r4- (2-TRIFLUOROMETILBENZOIDPIPERAZIN-1-lL1 PIRIDAZIN-3-ID UREA Following the procedure of Example 5, making only the required variations to use butylisocyanate in place of (2-isocyanatocloclopropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone, the title compound was obtained as a white solid (92% Yield). 1H NMR (500 MHz, CDCI3) d 7.84, 7.74, 7.63, 7.56, 7.36, 7.08, 4.00-4.07, 3.88-3.94, 3.54-3.66, 3.42-3.46, 3.27-3.36, 1.51-1.57, 1.30-1.40, 0.89 . MS (ES +) m / z 451 (M + 1).

EXAMPLE 5.9 1 -CICLE PE NTIL-3-6-r4- (2-TRIFLUO RPM ETILBENZPID-PIPERAZIN.1-IL1PIRIDAZIN-3-IDUREA Following the procedure of Example 5, making only the required variations to use the cyclopentyl isocyanate in place of (2-isocyanatocyclopropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethylphenyl) -metanone, the title compound was obtained as a white solid (91% Yield). 1 H NMR (500 MHz, DMSO-d 6) d 9.02, 7.82, 7.75, 7.65, 7.58, 7.51, 7.34, 3.91-3.98, 3.67-3.80, 3.46-3.58, 3.36-3.44, 3.11-3.35, 1.80-1.88, 1.46 -1.67, 1.30-1.40. MS (ES +) m / z 451 (M + 1).

EXAMPLE 5.10 1-HEXIL-3-. { 6-r4- (2-TRIFLUOROMETILBENZOI DPI PERAZI N-1-IL1 PIRIDAZIN-3-IDUREA Following the procedure of Example 5, making only the required variations to use hexyl isocyanate in place of (2-isocyanatocyclopropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone, the title compound was obtained as a white powder (50% Yield). 1H NMR (300 MHz, CD3OD) d 7.83, 7.76, 7.69, 7.52, 7.44, 7.39, 3.87-4.00, 3.66, 3.50, 3.25-3.43, 1.53-1.67, 1.28-1.48, 0.84-0.98. MS (ES +) m / z 479 (M + 1).

EXAMPLE 5.11 1 -HEPTIL-3-f6-r4- (2-TRIFLUPRPMETILBENZPID-PI PERAZI N-1 - IL1PIRIDAZIN-3-IDUREA Following the procedure of Example 5, making only the variations required to use heptylisocyanate in place of (2-isocyanatocylcylpropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone, the title compound was obtained as a white powder (46% Yield). 1 H NMR (500 MHz, DMSO-d 6) d 9.12, 7.82, 7.75, 7.65, 7.50-7.57, 7.35, 3.69-3.80, 3.45-3.60, 3.38-3.43, 3.28-3.34, 3.20-3.26, 3.06-3.17, 1.45 , 1.15-1.28, 0.85.

EXAMPLE 5.12 1- (3, 4-DlCLOROBENCID-3-f6-, 4- (2-TRIFLUOROMETILBENZOID PIPERAZIN-1-IL1-PIRIDAZIN-3-IDUREA Following the procedure of Example 5, making only the required variations to use 3,4-dichlorobenzylisocyanate in place of (2-isocyanato-cyclopropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl ] (2-trifluoromethylphenyl) -methanone, the title compound was obtained as a white powder (44% Yield). 1 H NMR (500 MHz, DMSO-d 6) d 9.38, 8.30, 7.85, 7.77, 7.67, 7.59, 7.52-7.57, 7.39, 7.29, 4.38, 3.70-3.82, 3.50-3.62, 3.42-3.47, 3.34-3.38, 3.23 -3.29, 3.15-3.20. MS (ES +) m / z 553 (M + 1).

EXAMPLE 5.13 1 -CICLO HEXIL-3-. { 6-r4- (2-TRIFLUO ROM ETILBENZOI DPI PERAZI N-1 - IL1-PIRIDAZIN-3-ILIUREA Following the procedure of Example 5, making only the required variations to use cyclohexyl isocyanate in place of (2-isocyanatocyclopropyl) benzene to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethylphenyl) -metanone, the title compound was obtained as a white powder (34% yield). 1 H NMR (500 MHz, DMSO-d 6) d 9.05, 7.82, 7.74, 7.65, 7.55, 7.52, 7.35, 3.69-3.79, 3.44-3.58, 3.35-3.42, 3.20-3.26, 3.11-3.18, 1.75-1.84, 1.58 -1.67, 1.47-1.55, 1.10-1.35.

EXAMPLE 6 SYNTHESIS OF 2-FENPXI-N-f 6-T4- (2- TRIFLUPRPMETILBENZPIDPIPERAZIN-1-IL1PIRIDAZIN-3-I ACETAMIDE To a stirred solution of [4- (6-aminopyridazin-3-yl) -piperazin-1-yl] - (2-trifluoromethyl-phenyl) methanone (105 mg, 0.300 mmol) in 10 ml of dichloromethane was added phenoxyacetyl chloride (56 mg, 0.32 mmol) followed by the addition of 0.15 ml of triethylamine at 0 ° C. The mixture was stirred at room temperature overnight. Water was added and the mixture extracted with 2 portions is 15 ml of ethyl acetate. The combined organic layer was washed sequentially with dilute HCl, sodium bicarbonate and brine solution, then dried with Na 2 SO 4, and concentrated. The residue was redissolved in a small amount of dichloromethane and purified by column chromatography. The title compound was isolated as a white solid in 34% yield (50 mg). 1 H NMR (500 MHz, CDCl 3) d 9.28, 8.38, 7.75, 7.64, 7.56, 7.35, 7.04, 4.65, 4.01, 3.68, 3.34.

EXAMPLE 6.1 (2- FEN I LCIC LOP RO CARBON BREAD 1 Df 644- (2 TRIFLUOROMETILBENZOIDPIPERAZIN-1-IL1PIRIDAZIN-3-IL) AMIDA DE ACIDO 2-FENILCICLPPRPPAN-CARBPXÍLICP AND f6-T4- (2-TRIFLUOROMETILBENZQ1DPIPERAZIN-1-IL1PIRIDAZIN-3-IDA DE ACIDO FENILCICLOPROPAN-CARBOXILICO Following the procedure of Example 6, making only the required variations to use 2-phenylcylclopropanecarbonyl chloride in place of phenoxyacetyl chloride to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromet Lphenyl) -metanone, both compounds were obtained from the reaction. It was isolated (2-phenylcyclic propanecarbonyl). { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} 2-phenylcylclopropane carboxylic acid amide was isolated through column chromatography eluting with EtOAc: hexane = 40:60 and obtained as a white powder (20% Yield). 1 H NMR (300 MHz, CDCl 3) d 7.73, 7.62, 7.54, 7.34, 7.22, 7.16, 7.04, 6.84, 3.99, 3.82, 3.63, 3.28, 2.62, 2.31, 1.76, 1.38. MS (ES +) m / z 640.3 (M + 1). 2-. { 6- [4- (2-trifluoromethyl-benzoyl) piperazin-1-yl] pyridazin-3-yl} Phenylcycloclopane carboxylic acid amide was isolated through column chromatography eluting with EtOAc: hexane = 50:50 and obtained as a white powder (16% Yield). 1 H NMR (300 MHz, CDCl 3) d 8 10.36, 8.39, 7.76, 7.64, 7.57, 7.34, 7.18, 7.12, 3.92, 3.52, 3.37, 3.18, 2.64, 2.30, 1.34. MS (ES +) m / z 496.3 (M + 1).

EXAMPLE 6.2. { 6-r4- (2-TRIFLUOROMETlLBENZOIDPIPERAZIN-1-IL1PIRIDAZIN-3-ILLAMIDE OF HEXANOIC ACID Following the procedure of Example 6, making only the required variations to use hexanoyl chloride in place of phenoxyacetyl chloride to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone , the title compound was obtained as a white solid (30% Yield). 1 H NMR (300 MHz, CDCl 3) d 11.65, 8.62, 7.75, 7.65, 7.58, 7.46-7.53, 7.37, 4.08, 3.88, 3.52-3.78, 3.30-3.40, 2.63, 1.72-1.79, 1.24-1.40, 0.90. MS (ES +) m / z 449. 7 (M + 1).

EXAMPLE 6.3 4-FLUO RO-N. { 6-r4- (2-TRIFLUO ROM ETILBENZOI DPI PERAZI N -1-1 Ll - PIRIDAZIN-3-I BENZAMIDE Following the procedure of Example 6, doing only - the variations required to use 4-fluorobenzoyl chloride in place of phenoxyacetyl chloride to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone, the compound of title as a light yellow solid (62% yield). 1 H NMR (400 MHz, DMSO-d 6) d 7.78-7.85, 7.77, 7.66, 7.52, 7.44, 7.25-7.35, 3.10-3.80.

EXAMPLE 7 SYNTHESIS OF BUTYL ESTER OF ACID (6-r4- (2- TRIFLUOROMETILBENZOIDPIPERAZIN-1-IL1 PI IDAZIN-3-I CARBAMIC To a stirred solution of [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl-phenyl) methanone (100 mg, 0.285 mmol) in 5 ml of dichloromethane was added n-butyl chloroformate (0.285 mmole) in the presence of triethylamine (0. 313 mmole) at 0 ° C. The resulting mixture was stirred at room temperature for 24 hours and then quenched with 10 ml of water. The organic phase was washed with water, saturated NaCl, dried over MgSO4 and then concentrated in vacuo to give the desired product as a white solid (0.095 g, 74% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.10, 7.73, 7.63, 7.55, 7.36, 7.04, 4.19, 3.96-4.02, 3.89-3.95, 3.61-3.66, 3.52-3.56, 3.32, 1.64-1.70, 1.38-1.46, 0.95 .

EXAMPLE 7.1 PROPYLIC ESTER OF ACID-f 6-f4- (2-TRIFLUOROMETILBENZOIL) PIPERAZIN-1-IL1 PYRIDAZINE-3-IDCARBAMIC Following the procedure of Example 7, making only the required variations to use propyl chloroformate instead of n-butyl chloroformate to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone, the title compound was obtained as a white solid (72% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.10, 7.73, 7.62, 7.55, 7.37, 7.04, 4.14, 3.96-4.02, 3.88-3.94, 3.61-3.66, 3.52-3.56, 3.32, 1.66-1.75, 0.98. MS (ES +) m / z 438 (M + 1).

EXAMPLE 7.2 ISOBUTYL ESTER OF ACID (6-f4- (2- TRIFLUOROMETILBENZOID PI PERAZI N-1 -IL1PIRIDAZIN-3-1L1CARBAMIC Following the procedure of Example 7, making only the required variations to use 2-methylpropyl chloroformate instead of n-butyl chloroformate to react with [4- (6- aminopyridazin-3-yl) piperazin-1-yl] (2- trifluoromethyl) methanone, the title compound was obtained as a white solid (47% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.09, 7.73, 7.65, 7.63, 7.55, 7.36, 7.04, 3.96, 3.95-4.02, 3.88-3.94, 3.61-3.65, 3.52-3.56, 3.32, 1.94-2.04, 0.96. MS (ES +) m / z 452 (M + 1).

EXAMPLE 7.3 ETHYST ESTHER OF ACID (6-r4- (2-TRIFLUOROMETILBENZOID P1PERAZIN-1-IL1 PIRIDAZIN-3-IDCARBÁ ICO Following the procedure of Example 7, making only the required variations to use ethyl chloroformate instead of n-butyl chloroformate to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2- trifluoromethyl) methanone, the title compound was obtained a light yellow solid (35% Yield). 1 H NMR (300 MHz, DMSO-d 6) d 10.30, 7.82-7.85, 7.76, 7.67, 7.52, 7.37, 4.15, 3.15-3.85, 1.10. MS (ES +) m / z 424 (M + 1).

EXAMPLE 8 SYNTHESIS OF 1 - (3-CICLOPRPPILPRPPIL) -3- (6-r4- (2- TRI FLUO ROM ETI LBENZOI D PI PERAZI N-1 -I DPIRIDAZIN-3-I PUREA [4- (6-Aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone (200 mg, 0.57 mmol) was added slowly to a freezing solution of 1,1 '-carbonyldiimidazole (110 mg, 0.683). mmoles) in 15 ml of anhydrous dichloromethane. The temperature was then raised to room temperature and the reaction mixture was stirred for another 4 hours. Then 3-cyclopropylpropylamine (48.5 mg, 0.569 mmol) was added to the reaction mixture which was stirred at room temperature overnight under nitrogen. The reaction mixture was washed with saturated sodium bicarbonate and brine solution, concentrated and purified by flash column chromatography to yield the product as a white solid (23 mg, 8.5% Yield). 1 H NMR (300 MHz, CDCl 3) d 10.2, 7.68-7.83, 7.72, 7.65, 7.63, 7.55, 7.36, 7.04, 3.95-4.02, 3.83-3.95, 3.50-3.68, 3.40-3.50, 3.26-3.38, 1.60-1.72 , 1.17-1.30, 0.71-0.80, 0.44-0.50, -0.06-0.013. MS (ES +) m / z 477 (M + 1).

EXAMPLP 8.1 1- (6-r4- (2,6-P) FLUPRPBENZPIDPIPERAZ) N-1-IL1PIRIPAZIN-3-ID-3- (3-METHYLBUTYDRIDE) Following the procedure of Example 8, making only the required variations to use 3-methylbutylamine in place of 3-cyclopropylpropylamine to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yI] (2,5-difluorophenyl) ) methanone, the title compound was obtained as a white solid (27% Yield). 1 H NMR (300 MHz, CDCl 3) d 9.75, 7.68, 7.32-7.43, 7.07, 6.89-7.00, 3.85-4.00, 3.25-3.75, 1.40-1.65, 0.89. MS (ES +) m / z 432.8 (M + 1).

EXAMPLP 8.2 1-CICLPPRPPILMETILP-3- (6-r4- (2-TRIFLUPRPMETILBENZPID PIPERAZ1N-1-IL1PIRIDAZIN-3-IL1UREA Following the procedure of Example 8, making only the variations required to utilize cylcopropropylmethylamine in place of 3-cyclopropylpropylamine to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone, obtained the title compound as a white solid (50% Yield). 1 H NMR (400 MHz, CDCl 3) d 7.80-7.54, 7.37, 7.09, 4.07-3.18, 1.12-0.98, 0.52-0.46, 0.27-0.22. MS (ES +) m / z 449.9 (M + 1).

EXAMPLP 8.3 1- (3,3-DlMETILBUTID-3- {6-r4- (2-TRIFLUPRPMETlLBENZPlD PI PERAZI N-1 -I L1PIRIDAZIN-3-IL1UREA Following the procedure of Example 8, making only the required variations to use 3,3-dimethylbutylamine instead of 3-cyclopropylpropylamine to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) ) methanone, the title compound was obtained as a white solid (56% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.04-7.54, 7.37, 7.09, 4.08-3.6, 1.52-1.44, 0.88. MS (ES +) m / z 479. 3 (M + 1).

EXAMPLC 8.4 1 - (2-CICLP PRP PILETID-3- {6-r4- (2-TRIFLU PRP METH LBENZPl D- PIPERAZ1N-1-IL1 PIRIDAZIN-3-l PUREA Following the procedure of Example 8, making only the required variations to use 2-cyclopropyldiamine instead of 3-cyclopropylpropylamine to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone , the title compound was obtained as a yellow solid (65% yield). P.f. 300 ° C. 1 H NMR (300 MHz, CDCl 3) d 7.73, 7.62, 7.55, 7.36, 7.07, 4.04-7.00, 3.94-3.89, 3.64-3.56, 3.47-3.45, 3.40-3.32, 1.46, 0.69-0.66, 0.47-0.38, 0.06 -0.00. MS (ES +) m / z 463 (M + 1).

EXAMPLP 8.5 1- (2-ISPPRPPPXIETiP-3-f6-r4- (2-TRl FLUPRPMETILBE ZPIP PI PERAZI N-1 -I Ll PIRIDAZIN-3-l PUREA Following the procedure of Example 8, making only the required variations to use 2-isopropoxyethylamine in place of 3-cyclopropylpropylamine to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone , the title compound was obtained as a yellow solid (15% Yield). p.f. > 300 ° C. 1 H NMR (300 MHz, CDCl 3) d 7.69, 7.60-7.56, 7.51, 7.35, 3.98-3.92, 3.74-3.64, 3.45-3.44, 3.38-3.19, 3.09-2.97, 2.95-2.86, 2.84-2.77, 2.00-1.74 , 1.77-1.74, 1.38. MS (ES +) m / z 470 (M + 1).

EXAMPLP 8.6 1- (3-HIPRPXI-4.4-PLMETILPENTIL) -3- (6-r4- (2-TRIFLUPRPMETILBENZPIP-PIPERAZIN-1-IL1 Pl RIDAZIN-3-IP UREA Following the procedure of Example 8, making only the required variations to use 3-hydroxy-4,4-dimethylpentylamine instead of 3-cyclopropyropropylamine to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethylphenyl) -methanone, the title compound was obtained as a yellow solid (32% Yield), mp. 218-221 ° C. MS (ES +) m / z 470 (M + 1).

EXAMPLE 8.7 1- (2-ClCLOPROPILETiP-3- (6-r4- (2-FLUORO-6- TRIFLUOROMETILBENZOIP-P1PERAZIN-1-IL1 PYRIPAZI N-3-IP UREA Following the procedure of Example 8, making only the variations required to utilize 2-cyclopropylethylamine in place of 3-cyclopropylpropylamine to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-f 6-trif luoromethylf in i I) -metanone, the title compound was obtained as a white powder (48% Yield) .1 H NMR (400 MHz, CDCl 3) 5 8.14, 7.58-7. 54.7. 43.7 38-7.34, 7.10-7. 05.4. 01-3.94, 3. 58-3. 32.1. 46.0. 72-0.67, 0.45-0. 39.0. 08-0.02.

EXAMPLP 8.8 1- (2-CICLPPRPPILETIL) -3-. { 6-f4- (5-FLUPRP-2- TRIFLUPRPMETILBENZPIP-PIPERAZIN-1-IL1PIRIDAZI -3-IP UREA Following the procedure of Example 8, making only the required variations to use 2-cyclopropylethylamine instead of 3-cyclopropylpropylamine to react with [4 ~ (6-aminopyridazin-3-yl) piperazin-1-yl] (5-fluoro-2) -trifluoro methylphenyl) -metanone, the title compound was obtained as a white powder (30% Yield). H NMR (400 MHz, CDCl 3) d 8.30, 7.76-7.71, 7. 23, 7.10-7.06, 4.00-3.97, 3.91-3.87, 3.65-3.45, 3.88-3.40, 1.26- 1.24, 0.74-0.68, 0.44-0.43, 0.05-0.04.

EXAMPLP 8.9 1- (2-CICLPPRPPILETIL) -3-. { 6-r4- (2.6-DIFLUPRPBENZPIP PI PERAZI N-1 -l Ll-PIRIDAZIN-3-ILIUREA Following the procedure of Example 8, making only the variations required to use 2-cyclopropylethylamine in place of 3-cyclopropylpropylamine to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2,6-difluorophenyl) ) methanone, the title compound was obtained as a white powder (14.1% Yield). 1 H NMR (300 MHz, CDCl 3) d 9.16, 7.89, 7.62-7.52, 7.37, 7.26-7.21, 3.81-3.78, 3.58-3.52, 3.44-3.37, 3.32-3.28, 3.24-3.18, 1.36, 0.70-0.65, 0.42 -0.37, 0.07-0.03.

EXAMPLP 8.10 1- (3-CICLPPRPPlLPRPPIL) -3-. { 6-r4- (5-FLUPRP-2- TRIFLUPRPMETILBENZPIP-PI PERAZI N-1 -I L1PIRID AZI N-3-ID UREA Following the procedure of Example 8, making only the required variations to use [4- (6-aminopyridazin-3-yl) piperazin-1-yl] (2-trifluoromethyl) methanone instead of [4- (6-aminopyridazine-3 -yl) piperazin-1-yl] (5-fluoro-2-trifluoromethylphenyl) methanone to react with 3-cyclopropylpropylamine, the title compound was obtained as a white powder (15% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.32-8.31, 7.76-7.73, 7.76-7.73, 7.25-7.22, 7.13-7.06, 4.14-3.98, 3.95-3.85, 3.68-3.52, 3.40-3.32, 1.70-1.60, 1.28 -1.21, 0.65-0.62, 0.40-0.36, 0.03-0.02.

EXEMPLP 8.11 1- (4-METlLPENTID-3-6-r4- (2-TRlFLUPRPMETlLBENZPlD PI PERAZI N-1 -I L1PIRIDAZIN-3-I PUREA Following the procedure of Example 8, making only the required variations to use 4-methylpentylamine in place of 3-cyclopropylpropylamine to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yI] (2-trifluoromethyl) methanone , the title compound was obtained as a white solid (0.039 g, 29% Yield). 1 H NMR (300 MHz, CDCl 3) d 10.7-10.2, 7.85-7.77, 7.73, 7.65-7.5, 7.35, 7.1-7.07, 4.08-3.95, 3.94-3.83, 3.64-3.52, 3.48-3.38, 3.35-3.21, 1.6 -1.45, 1.25-1.12, 0.83. 13C NMR (75 MHz, CDCI3) d 167.5, 156.8, 155.8, 151.7, 134.4, 132.3, 129.4, 127.2, 126.8, 126.7, 125.4, 121.8, 121.3, 118.4, 46.4, 46.02, 45.8, 40.3, 36.1, 28.3, 27.8 , 22.5. MS (ES +) m / z 479.4 (M + 1).EXAMPLP 9 SYNTHESIS OF (3-METHYLBUTIP AMID OF ACID 6-í4- (2.5- DICLPRPBENZPIPPIPERAZIN-1-IL1PIRIDAZIN-3-CARBPXÍLICP A mixture of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide (0.255 mmol), 2,5-dichlorobenzoic acid (0.31 mmol), 1,8-diazabicyclo [5.4.0] undec-7-ene (0.51 mmole) and 1-hydroxybenzotriazole hydrate (0.31 mmole) in 2 ml of DMF was stirred at room temperature for 15 minutes. Then 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide (0.31 mmol) was added. The mixture was stirred at room temperature overnight, and then diluted with 50 ml of EtOAc and washed with 2 portions of 20 ml of saturated aqueous NaHCO 3 and two 20 ml portions of brine. The organic extract was dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography to give the title compound as a white solid (102 mg, 89% Yield). H NMR (500 MHz, CDCI3) d 8.07, 7.85, 7.32-7.40, 7.01, 4.01-4.08, 3.77-3.93, 3.35-3.55, 1.65-1.75, 1.52, 0.94. MS (ES +) m / z 450 (M).

EXAMPLE 9.1 (2-CICLOPROPILETIP AMID ACID 6-T4- (5-METHYL-2-TRIFLUPRPMETILFURAN-3-CARBPNIPPIPERAZIN-1-IL1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 5-methyl-2-trifluoromethylfuran-3-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazine- (2-cyclopropylethyl) amide 1-pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (53% Yield), mp 128-130 ° C. 1 H NMR (500 MHz, CDCl 3) d 8.08, 7.99, 7.01, 6.15, 3.89-3.94, 3.77-3.82, 3.52-3.60, 2.39, 1.52, 0.71-0.80, 0.45-0.49, 0.08-0.13. MS (ES +) m / z 452 (M + 1).

EXAMPLC 9.2 (2-CICLPPRPPILET1P AMID OF ACIDP 6-r4- (2-CLPRPPIRIDIN-3-CARBPNIPPIPERAZIN-1-IL1PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 2-chloropyridine-3-carboxylic acid instead of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-ylpyridazin (2-cyclopropylethyl) -amide. -3-carboxylic acid, the title compound was obtained as a white solid (44% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.50, 8.08, 7.99, 7.71, 7.37, 7.02, 4.05-4.13, 3.78-3.95, 3.34-3.60, 1.51, 0.71-0.80, 0.45-0.49, 0.08-0.12. MS (ES +) m / z 415 (M + 1).

EXAMPLP 9.3 (2-CICLPPRPPILETIP AMID ACID 6-f4- (2-METHYL-5-TRIFLUPRPMETILPXAZPL-4-CARBPNIPPIPERAZIN-1-IL1-PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to utilize 2-methyl-5-trifluoromethyloxazole-4-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazine- (2-cyclopropylethyl) -amide. 1-yl-pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (58% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.98, 6.99, 3.75-3.95, 3.50-3.59, 2.55, 1.51, 0.71-0.80, 0.45-0.49, 0.06-0.12. MS (ES +) m / z 453 (+1).

EXAMPLP 9.4 (2-CICLPPRPPILETIP AMID OF ACID 6-f4- (2,6-D1CLPRPPIRIDIN-3-CARBPNIPPIPERAZIN-1-IL1PIR1DAZIN-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 2,6-dichloropyridine-3-carboxylic acid instead of 2,5-dichlorobenzoic acid to react with 6-piperazin-1- (2-cyclopropylethyl) -amide. pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (19% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.06, 7.97, 7.65, 7.37, 7.01, 3.70-4.10, 3.29-3.61, 1.52, 0.68-0.80, 0.42-0.49, 0.06-0.13. MS (ES +) m / z 449 (M).

EXAMPLC 9.5 (3-METHYLBUTLP AMID OF ACIPP 6-Í4-M-BENClL-5- TRIFLUPRPMETIL-1H-p.2.31TRIAZPL-4-CARBPNiP-PIPERAZIN-1- IL1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 1-benzyl-5-trif luoromethyl-1 H- [1, 2,3] triazole-4-carboxylic acid instead of 2,5-dichlorobenzoic acid to react with 6- piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) -amide, the title compound was obtained as a white powder (32% Yield). 1 H NMR (300 MHz, DMSO-de) d 8.03, 7.81, 7.33-7.27, 6.86, 5.92, 5.39, 3.71, 3.47, 3.05, 2.63, 2.43, 1.65, 1.48, 0.92. MS (ES +) m / z 531.2 (M + 1).

EXAMPLE 9.6 (3- METHYLBUTYL) ACID AMID 6-, 4- (3-BENZYL-5-TRIFLUORPMETIL-3H-p, 2.31 TRIAZPL-4-CARBPNIPPIPERAZIN-1-IL1PIRIDAZIN-3-CARBPXYLICP Following the procedure of Example 9, making only the required variations to use 3-benzyl-5-trifluoromethyl-3H- [1, 2,3] triazole-4-carboxylic acid instead of 2,5-dichlorobenzoic acid to react with ( 3-methylbutyl) 6-piperazin-1-yl-pyridazine-3-carboxylic acid amide, the title compound was obtained as a white powder 37% Yield). 1 H NMR (300 MHz, DMSO-d 6) d 8.04, 7.83, 7.36, 7.28, 6.99, 5.69, 3.94, 3.84, 3.70, 3.46, 1.75-1.61, 1.49, 0.91. MS (ES +) m / z 531.2 (M + 1).

EXAMPLE 9.7 (3- METILBUTIP AMID OF ACID 6-, 4- (2-METHYL-5- TRIFLUPRPMETIL-2H-p.2,31TRIAZPL-4-CARBPNiPPPERAPIN-1 IL1PIRI AZ1N-3-CARBPXYLICP Following the procedure of Example 9, making only the required variations to use 2-methyl-5-trifluoromethyl-2H- [1, 2,3] triazole-4-carboxylic acid instead of 2,5-dichlorobenzoic acid to react with ( 3-methylbutyl) 6-piperazin-1-yl-pyridazine-3-carboxylic acid amide, the title compound was obtained as a white powder (15% Yield). 1 H NMR (300 MHz, DMSO-d 6) d 8.05, 7.83, 7.00, 4.28, 3.97-3.67, 3.51-3.45, 1.75-1.68, 1.49, 0.92. MS (ES +) m / z 455.2 (M + 1).

EXAMPLE 9.8 (3-METHYLBUTIP AMIDA PE ACID 6-r4- (5-TRIFLUOROMETHYL-3H-1MIPAZPL-4-CARBCN1PPI PERAZI N-1-I L1P1RIPAZIN-3-CARBCXYLICC Following the procedure of Example 9, making only the required variations to use 5-trifluoromethyl-3H-imidazole-4-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazine- (3-methylbutyl) -amide. 1-ylpyridazine-3-carboxylic acid, the title compound was obtained as a white powder (48% Yield). 1 H NMR (300 MHz, DMSO-d 6) d 8.03, 7.86, 7.70, 6.99, 3.80, 3.46, 1.75-1.62, 1.48, 0.92. MS (ES +) m / z 440.2 (M + 1).

EXAMPLE 9.9 (3-METHYLBUTIP AMID OF ACID 6-T4- (2- M ETAN SU LFONILBENZOIPPI PERAZI N -1-1 L1PIRID AZI N -3- CARBOXYLIC Following the procedure of Example 9, making only the required variations to use 2-methanesulfonylbenzoic acid instead of 2,5-dichlorobenzoic acid to react with 6-piperazine n-1-yl-pyridazin-3 (methylbutyl) -amide. carboxyl, the title compound was obtained as a white solid (97% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.11, 8.03, 7.85, 7.74-7.62, 7.38, 4.32-3.33, 3.27, 1.73-1.62, 1.52-1.46, 0.94. MS (ES +) m / z 484.3 (M + 1).

EXAMPLE 9.10 (2-C1CLOPROPILETIP AMID ACID 6-f4- (2,2-DIMET1LBUT1RIDP1PERAZIN-1-1L1PIRIDAZIN-3-CARBOXYLIC Following the procedure of Example 9, making only the required variations to use 2,2-dimethylbutyric acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-ylpyridazin-3-cyclopropylethyl acid amide carboxylic acid, the title compound was obtained as a white solid (46% Yield) 1 H NMR (300 MHz, CDCl 3) d 8.05, 8.01, 6.98, 3.86-3.73, 3. 57, 1.68, 1.52, 0.92, 0.80-0.72. , 0.49-0.45, 0.14-0.08.

MS (ES +) m / z 374.3 (M + 1).

EXAMPLE 9.11 (2-CICLOPROP1LETIP AMID ACID 6-T4- (2.2- Dl METH LPENTANOIPPI PERAZI -1-I Ll PIR1DAZIN-3-CARBOXYL1CO Following the procedure of Example 9, making only the required variations to use 2,2-dimethylpentanoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazin- (2-cyclopropylethyl) -amide. 3-carboxylic acid, the title compound was obtained as a white solid (61% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.96, 6.98, 3.85-3.72, 3.56, 1.64-1.45, 1.23, 0.96, 0.82-0.62, 0.49-0.45, 0.12-0.07. MS (ES +) m / z 388.2 (M + 1).

EXAMPLE 9.12 (2-CICLOPROPILETIP AMID ACID 6-r4- (5-FLUORO-2-METOXIBENZOIPPIPERAZ1N-1-1L1PIRIDAZIN-3-CARBOXÍLICO Following the procedure of Example 9, making only the required variations to use 5-fluoro-2-methoxybenzoic acid instead of 2,5-dichlorobenzoic acid to react with 6-pi perazin-1 (2-cyclopropylethyl) -amide. pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (61% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.03, 7.96, 7.10-6.98, 6.86-6.84, 4.03-3.37, 1.51, 0.80-0.72, 0.49-0.44, 0.15-0.10. MS (ES +) m / z 428.1 (M + 1).

EXAMPLE 9.13 (2-CICLOPROPILETIP AMIDA FROM ÁCIPP 6-T4- (2- Dl METÍ LAMÍ NPBENZPIPP1 PERAZI N-1 -l L1PIRID AZI N-3- CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 2-dimethylaminobenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazin-3-cyclopropylethyl acid amide carboxylic acid, the title compound was obtained as a white solid (61% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.04, 7.96, 7.36-7.25, 7.05-6.94, 4.17-3.40, 2.80, 1.51, 0.80-0.73, 0.47-0.42, 0.12-0.07.

EXAMPLP 9.14 (2-CICLPPRPPILETIP AMID OF ACID 6-f4- (2-CLPRP-5- DI METÍ LAMÍ NPBENZPIPP1 PERAZI N-1 -I L1PIRI D AZI N -3- CARBPXYL1CP Following the procedure of Example 9, making only the variations required to use 2-chloro-5-dimethylaminobenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl (2-cyclopropylethyl) -amide. pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (53% yield). 1 H NMR (300 MHz, CDCl 3) d 8.04, 7.96, 7.39, 6.94, 6.66, 6.55, 4.14-3.32, 2.93, 1.52, 0.75-0.69, 0.48-0.42, 0.11-0.05. MS (ES +) m / z 457.4 (M + 1).

EXAMPLP 9.15 (2-CICLPPRPPILETIP AMID OF ACID 6-r4- (2,5-DIMETHYLENZPIPPIPERAZIN-1-IL1 P1RIDAZIN-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 2,5-dimethylbenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazin- (2-cyclopropylethyl) -amide. 3-carboxylic acid, the title compound was obtained as a white solid (56% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.96, 7.16-7.11, 7.03-6.97, 4.12-3.67, 2.23, 2.22, 1.52, 0.82-0.69, 0.48-0.42, 0.11-0.05. MS (ES +) m / z 408.3 (M + 1).

EXAMPLP 9.16 (2-CICLPPRPPILETIP AMID OF ACID 6-T4- (2.5- DICLPRPBENZPIPPIPERAZIN-1-IL1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 2,5-dichlorobenzoic acid instead of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine (2-cyclopropyl ethyl) amide -3-carboxylic acid, the title compound was obtained as a white solid (56% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.96, 7.38-7.30, 6.97, 4.12-3.23, 1.50, 0.80-0.67, 0.51-0.38, 0.16-0.06. MS (ES +) m / z 448.2 (M + 1).

EXAMPLP 9.17 (2-CICLPPRPPLETIL) AMID OF ACID 6-T4- (1 -METIL-1 H-PYRRPL-2-CARBPNIPPIPERAZIN-1-1L1 P1RIDAZIN-3-CARBPXYL1CP Following the procedure of Example 9, making only the required variations to use 1-methyl-1H-pyrrole-2-carboxylic acid instead of 2,5-dichlorobenzoic acid to react with 6- (2-cyclopropylethyl) -amide. piperazin-1-yl-pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (51.8% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.07, 8.01, 7.00, 6.75, 6.40, 6.12, 4.00-3.80, 3.58, 1.52, 0.76, 0.48, 0.10. MS (ES +) m / z 383 (M + 1).

EXAMPLP 9.18 (2-CICLPPRPPILETIP AMIDA PE ACIDP 6-, 4- (4,4,4-TRI FLUPRPB UT-2-ENPIPPI PERAZI N -1-1 L1PIRIP AZI N -3- CARBCXYL1CP Following the procedure of Example 9, doing only the variations required to use 4,4,4-trifluorobut-2-enoic acid instead of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide , the title compound was obtained as a white powder (19.6% Yield), 1 H NMR (500 MHz, CDCl 3) d 8.09, 8.00, 7.00, 6.81, 3.96-3.88, 3.78, 3.57, 1.53, 0.76, 0.48, 0.10. MS (ES +) m / z 398 (M + 1).

EXAMPLP 9.19 (2-CICLPPRPPILETIP AMID OF ACID 6-i4- (1- H1DRPXICICLPPRPPANCARBPNIPPIPERAZIN-1-IL1PIRIDAZIN-3-CARBPXYLICC Following the procedure of Example 9, making only the required variations to use 1-hydroxycyclopropane carboxylic acid instead of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazin-3-cyclopropylethyl acid amide carboxyl, the title compound was obtained as a white powder (53.4% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.07, 8.03, 7.01, 3.98-3.73, 3.58, 1.53, 1.16, 1.02, 0.76, 0.48, 0.10. MS (ES +) m / z 360 (M + 1).

EXAMPLP 9.20 (2-CICLOPROPILETIP AMID ACID 6-r4- (4,4,4-TRIFLUPRP-3-HIDRPXI-3-TRIFLUPRPMETILBUTIRIPPIP RAZIN-1-IL1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 4,4,4-trifluoro-3-hydroxy-3-trifluoromethylbutyric acid in place of 2,5-dichlorobenzoic acid to react with (2-cyclopropylethyl) acid amide 6-piperazin-1-yl-pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (45.6% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.08, 8.03, 7.98, 7.00, 3.95-3.71, 3.56, 2.89, 1.55, 0.75, 0.48, 0.10. 13C NMR (CDCI3) d 168.5, 162.8, 159.8, 145.8, 127.3, 112.5, 45.5, 44.5, 44.1, 41.3, 39.7, 34.5, 27.2, 8.6, 4.2. MS (ES +) m / z 484 (M + 1).

EXEMPLP 9.21 (2-C1CLPPRPPILETIP AMID ACID 6-f4- (4,4,4-TRIFLUPRP-3-HYDROXY-3-METHYLBUTYRIPP1PERAZIN-1-IL1-PIRIDAZ1N-3-CARBPXYLICP Following the procedure of Example 9, making only the required variations to use 4,4,4-trifluoro-3-hydroxy-3-methylbutyric acid in place of (2-cyclopropylethyl) acid amide 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (50.1% Yield). H NMR (300 MHz, CDCl 3) d 8.07, 7.96, 6.98, 6.23, 4.05-3.52, 2.90, 2.47, 1.53-1.43, 0.76, 0.46, 0.09. MS (ES +) m / z 430 (M + 1).

EXAMPLP 9.22 (2-CICLCPRPPILETIL) AMIDA PE ACIPP 6- (4-CICLPBUTANCARBCNILPIPERAZIN-1-IDPIRIPAZIN-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 4-cyclobutane carboxylic acid instead of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazin-3-cyclopropylethyl acid amide carboxyl, the title compound was obtained as a white powder (45. 6% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.03, 7.97, 6.97, 3.82-3.64, 3.57-3.49, 3.26, 2.43-2.27, 2.22-2.05 2.02-1.81, 1.50, 0.75, 0.46, 0.08. MS (ES +) m / z 358 (M + 1).

EXEMPLP 9.23 (2-CICLPPRPPPLETIP AMID OF ACID 6-t4- (2-TRIFLUPRPMET1LCICLPPRPPANCARBPNIPPIPERAZIN-1-IL1- P I R I DAZIN-3-CARBPX INDEP Following the procedure of Example 9, making only the variations required to utilize 2-trifluoromethylcyclopropane carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazin-3-cyclopropylethyl acid amide carboxyl, the title compound was obtained as a white powder (30.9% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.03, 7.98, 7.00, 3.97-3.57, 2.20, 1.65, 1.50, 1.26, 0.75, 0.46, 0.09. MS (ES +) m / z 412 (M + 1).

EXEMPLP 9.24 (2-CICLPPRPPILETIP AMID OF ACID 6-f4- (4.4,4-TRIFLUPRP-3-TRI FLUPRPMETILB UT-2-ENPIPPI PERAZI N -1-1 L1PIR1DAZI N-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 4,4,4-trifluoro-3-trifluoromethylbut-2-enoic acid instead of 2,5-dichlorobenzoic acid to react with (2-cyclopropylethyl) acid amide 6-piperazin-1-yl-pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (45.4% Yield). 1H NMR (CDCI3) d 8.07, 7.97, 7.10, 7.01, 3.87-3.74, 3.58-3.50, 1.54-1.47, 0.78-0.68, 0.48-0.42, 0.10-0.05. 13C NMR (CDCI3) d 162.8, 161.1, 159.8, 145.8, 135.2, 135.1, 127.3, 124.5, 112.7, 45.5, 44.4, 44.3, 40.9, 39.7, 34.5, 8.6, 4.2. MS (ES +) m / z 466 (M + 1).

EXAMPLE 9.25 ACID CYCLOPBUTAMETHYLAMIDE 6-f4- (2-TRIFLUPRPMETILBENZPIPPIPERAZIN-1-IL1PIRIDAZIN-3-CARBCXYL1CP Following the procedure of Example 9, making only the variations required to use 2-trifluoromethylbenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid cyclobutylmethylamide, the compound of the title as a white powder (45.0% Yield). 1 H NMR (CDCl 3) d 8.04, 7.83, 7.72, 7.64-7.51, 7.32, 7.00, 4.10-4.01, 3.90-3.66, 3.49-3.27, 2.63-2.47, 2.11-1.67. 13C NMR (CDCI3) d 167.7, 162.9, 159.8, 145.4, 134.2, 132.4, 129.6, 127.4, 126.9, 126.8, 125.4, 121.8, 112.8, 46.4, 44.6, 41.2, 35.1, 25.7, 18.3. MS (ES +) m / z 448 (M + 1).

EXEMPLP 9.26 (2-CICLPPRPPILETIPAMIDE OF ACID 6-t4-T2- (2-TRIFLUPRPMETILFENIDACETIL1PIPERAZ1N-1-IL1PIRIDAZ1N-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use (2-trifluoromethylphenyl) acetic acid instead of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-ylpipdazin- (2-cyclopropylethyl) -amide. 3-carboxylic acid, the title compound was obtained as a white solid (78.7% Yield). 1H NMR (300 MHz, CDCI3) d 8.03, 7.97, 7.67-7.64, 7.53-7.48, 7.39-7.35, 6.96, 3.91, 3.87-3.67, 3.66-3.6, 3.58-3.51, 1.53-1.46, 0.78-0.64, 0.48 -0.42, 0.10-0.06. 13C NMR (75 MHz, CDCI3) d 168.8, 162.9, 159.9, 145.3, 133.2, 132.0, 131.5, 128.5, 128.2, 127.2, 127.0, 126.3, 126.2, 125.5, 112.3, 45.0, 44.7, 44.2, 41.2, 39.6, 37.13 , 37.11, 34.4, 8.6, 4.2. MS (ES +) m / z 462.2 (M + 1).

EXEMPLP 9.27 (2-CICLPPRPPILETIPAMIDE OF ACID 6-T4- (2- CYANPBENZPIPP1 PERAZI N-1 -I L1-PIRIDAZIN -3-C ARBPXÍLICP Following the procedure of Example 9, making only the variations required to use 2-cyanobenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazin-3-cyclopropylethyl acid amide carboxylic acid, the title compound was obtained as a white solid (25.8% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.97, 7.76-7.72, 7.69-7.66, 7.58-7.55, 7.53-7.43, 6.99, 4.3-3.94, 3.88-3.85, 3.58-3.51, 1.49, 0.78- 0.65, 0.48 -0.37, 0.16-0.02. 13C NMR (75 MHz, CDCI3) d 166.5, 162.8, 159.9, 145.3, 139.3, 133.3, 133.04, 129.9, 127.6, 127.03, 116.8, 112.4, 109.9, 46.4, 44.7, 44.6, 41.6, 39.6, 34.4, 8.6, 4.1 . MS (ES +) m / z 405.2 (M + 1).

EXAMPLE 9.28 (3-METHYLBUTIP AMIDA PE ACIPP 6-T4- (4-TRIFLUPRPMETILPIRIPIN-3-CARBPNIPPIPERAZIN-1-IL1 PIRIPAZIN-3-CARBPXYL1C0 Following the procedure of Example 9, making only the variations required to use 4-trifluoromethylpyridine-3-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl- (3-methylbutyl) -amide. pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (69% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.87, 8.69, 8.05, 7.82, 7.62, 7.00, 4.10-3.69, 3.51-3.44, 3.38-3.35, 1.75-1.61, 1.52-1.45, 0.90. MS (ES +) m / z 451.3 (M + 1).

EXAMPLE 9.29 (3-METHYLBUTYL) ACID AMID 6-f4- (4,4,4-TRIFLUPRP-3-METHYLBUT-2-ENPIDPIPERAZIN-1-IL1-PIRIDAZIN-3-CARBPXYL1CP Following the procedure of Example 9, making only the required variations to use to use 4,4,4-trifluoro-3-methylbut-2-enoic acid instead of 2,5-dichlorobenzoic acid to react with (3-methylbutyl) amide of 6-piperazin-1-yl-pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (62% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.83, 7.00, 6.55, 3.86-3.83, 3.80-3.73, 3.62-3.60, 3.48, 2.01, 1.75-1.62, 1.49, 0.92. MS (ES +) m / z 414. 4 (M + 1).

EXAMPLC 9.30 (3-METILBUTIP AMIDA OF ACIDP 6-r4- (1- TRIFLUPRPMETILCICLPPRPPANCARBPNIPP1PERAZIN-1-IL1- PIRIPAZIN-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 1-trifluoromethylcylcyclopropane carboxylic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) -amide, the title compound was obtained as a white powder (72% yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.83, 6.98, 3.90-3.80, 3.48, 1.66, 1.48, 1.39-1.35, 1.18-1.14, 0.92. MS (ES +) m / z 414.2 (M + 1).

EXAMPLP 9.31 (2-CICLPPRPPILETIP AMID OF ACID 6-r4- (PIRIDIN-2-CARBPNIP PIPERAZIN-1-IL1 PIRIDAZIN-3-C ARBPXÍLICP Following the procedure of Example 9, making only the variations required to use pyridine-2-carboxylic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide, the compound was obtained of the title as a white powder (70% yield). 1 H NMR (300 MHz, CDCl 3) d 8.60-8.58, 8.03, 7.98, 7.86-7.79, 7.73-7.71, 7.39-7.35, 6.98, 3.96-3.83, 3.54, 1.50, 0.78-0.69, 0.47-0.41, 0.08-0.05 . MS (ES +) m / z 381.2 (M + 1).

EXAMPLP 9.32 (2-CICLPPRPPILETlL) AMID OF ACIDP 6-T4- (2-TRIFLUPRPETHYLPHURAN-3-CARBPNIP PI PERAZI N-1 -l Ll PIRIDAZLN-3-CARBPXÍLICP Following the procedure of Example 9, making only the required variations to use 2-trifluoromethyl-furan-3-carboxylic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) -amide, the compound of the title as a white powder (71% yield). 1 H NMR (300 MHz, CDCl 3) d 8.04, 7.96, 7.56, 7.00, 6.54, 3.9-3.7, 3.6-3.5, 1.49, 0.79-0.66, 0.47-0.41, 0.09-0.04. 13 C NMR (300 MHz, CDCl 3) d 161.78, 160.01, 145.60, 145.05, 138.14, 137.57, 127.15, 121.74, 120.54, 112.54, 110. 88, 46.33, 44.59, 41. 43.39. 67.34. 52.8. 64.4. 23. MS (ES +) m / z 438.2 (M + 1).

EXAMPLE 10 SYNTHESIS OF (3-METHYLBUTIP AMIPA PE ACIDP 6-T4- (5- TRIFLUPRPMETIL-3HM, 2.31 TRIAZPL-4-CARBPNIPPIPERAZI -1-IL1-PIRIDAZIN-3-CARBPXYL1CP) (3-Methylbutyl) acid amide was dissolved 6- [4- (3-Benzyl-5-trifluoromethyl-3H- [1,2,3] triazole-4-carbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (0.4 g, 0.75 mmol) in 10 ml of MeOH with 3 drops of acetic acid and 0.2 g of 10% Pd / C were added.The reaction mixture was kept under normal pressure of H2 at room temperature overnight.After filtration the reaction mixture was evaporated under pressure reduced and the residue was recrystallized from 3 ml of EtOH to give 120 mg (36% Yield) of 6- (4- (5-trifluoromethyl-3H- (1,3-trifluoromethyl) -3- (3-methylbutyl)) ] triazole-4-carbonyl) -piperazin-1-yl] pyridazine-3-carboxylic acid as a white powder 1H NMR (500 MHz, Acetone-d6) d 8.18, 7.91, 7.32, 3.92-3.72, 3.45, 1.67, 1.52 , 0.92.

EXAMPLE 11 SYNTHESIS OF (3-METHYLBUTYL) AMID OF ACID 6-T4- (2- TRI FLUOROMETILBENCIPPI PERAZI N-1-I Ll PIRIDAZLN-3- CARBOXYLIC A mixture of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide (0.255 mmol), 2-trifluoromethylbenzyl chloride (0.255 mmol), and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.77 mmol) was stirred and heated at 60 ° C overnight. The reaction mixture was then diluted with 100 ml of EtOAc and washed with 2 portions of d2 20 ml of saturated aqueous NaHCO3 and 2 portions of 20 ml of brine. The organic layer was dried over anhydrous Na 2 SO 4, concentrated, and purified by flash chromatography to give the title compound as a white solid (80 mg, 72% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.00, 7.86, 7.82, 7.65, 7.55, 7.37, 6.95, 3.74-3.79, 3.73, 3.46-3.52, 2.62, 1.65-1.76, 1.52, 0.94. MS (ES +) m / z 436 (M + 1).

EXAMPLE 11.1 (2-CICLOPROPILETIP AMID ACID 6-T4- (2- TRIFLUOROMETILBENCIPPIPERAZIN-1-IL1PIRIDAZIN-3-CARBOXYLIC Following the procedure of Example 11, making only the required variations to use 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide in place of 6- (3-methyl-butyl) -amide piperazin-1-yl-pyridazine-3-carboxylic acid to react with 2-trifluoromethylbenzyl chloride, the title compound was obtained as a white solid (32% Yield), mp 106-108 ° C. 1 H NMR (500 MHz, CDCl 3) d 7.97-8.04, 7.83, 7.65, 7.55, 7.37, 6.96, 3.77, 3.73, 3.56, 2.63, 1.52, 0.71-0.80, 0.45-0.49, 0.08-0.13. MS (ES +) m / z 434 (M + 1).

EXAMPLE 11.2 (2-CICLOPROPILETIP AMID ACID 6-í4- (5-FLUPRP-2- TRI FLUORO M ETILB IN CIPPI PERAZI N-1 -I Ll PIRIDAZIN-3- CARBOXYLIC Following the procedure of Example 11, making only the variations required to use 5-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazin (2-cyclopropylethyl) -amide. -3-carboxylic acid, the title compound was obtained as a white solid (40% Yield). 1 H NMR (300 MHz, CDCl 3) d 7.95-8.01, 7.57-7.68, 7.04, 6.95, 3.79, 3.71, 3.56, 2.64, 1.51, 0.68-0.82, 0.43-0.51, 0.06-0.13. MS (ES +) m / z 452 (M + 1).

EXAMPLE 11.3 (2-CICLPPRPPILETIL) ACID AMID 6-T4- (4-FLUPRP-2- TRI FLUPRPMET1LBENCIP-PI PERAZI N-1 -I L1PIRIDAZIN-3-CARBCXYLICC Following the procedure of Example 11, making only the variations required to use 4-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-ylpyridazin-3-cyclopropylethyl) -amide. carboxylic acid, the title compound was obtained as a white solid (38% Yield). 1 H NMR (300 MHz, CDCl 3) d 7.96-8.04, 7.81, 7.36, 7.20-7.29, 6.96, 3.76, 3.68, 3.56, 2.61, 1.51, 0.68-0.84, 0.43-0.51, 0.06-0.13. MS (ES +) m / z 452 (M + 1).

EXEMPLP 11.4 (2-CICLPPRPPLETIL) AMID OF ACID 6-f4- (5-CLPRP-2- TR1 FLUPRP METI LB IN CIP PI PERAZI N -1-1 L1PIRI D AZI N -3- CARBPXÍLICP Following the procedure of Example 11, making only the variations required to use 5-chloro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with (2-cyclopropi leti I) 6-piperazin-1-acid amide pyridazin-3-carboxylic acid, the title compound was obtained as a white solid (48% Yield). 1 H NMR (300 MHz, CDCl 3) d 7.96-8.05, 7.87, 7.58, 7.34, 6.97, 3.80, 3.70, 3.56, 2.64, 1.53, 1.51, 0.70-0.83, 0.43-0.51, 0.07-0.13. MS (ES +) m / z468 (M + 1).

EXAMPLP 11.5 (2-CICLPPRPPILETIP AMID OF ACID 6-r4- (2-CLPRP-4- FLUPRPBENCIP PI PERAZI N-1 -I Ll PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 11, making only the required variations to use 2-chloro-4-fluorobenzyl chloride in place of 2-trifluoromethyl-benzyl chloride to react with 6-piperazin-1-yl-pyridazin- (2-cyclopropylethyl) -amide. 3-carboxylic acid, the title compound was obtained as a white solid (26% Yield). 1 H NMR (300 MHz, CDCl 3) d 7.92-8.03, 7.38-7.50, 7.06-7.14, 6.88-7.03, 3.68-3.78, 3.62, 3.46-3.58, 2.55-2.69, 1.42-1.54, 0.68-0.80, 0.40-0.49 , 0.02-0.13. MS (ES +) m / z 418 (M + 1).

EXAMPLP 11.6 (2-CICLPPRPPILETIP AMID OF ACID 6-T4- (2.5- DICLPRPBEN CIPPI PERAZI N-1 -I L1PIRIDAZIN-3-CARBPXÍLICC Following the procedure of Example 11, making only the required variations to use 2,5-dichlorobenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with (2-cyclopropylethyl) amide 6-piperazin-1-yl-pyridazin-3 acid carboxyl, the title compound was obtained as a white solid (43% yield). 1 H NMR (300 MHz, CDCl 3) d 7.96-8.04, 7.53, 7.16-7.33, 6.96, 3.75-3.84, 3.64, 3.56, 2.62-2.70, 1.53, 1.51, 0.70-0.83, 0.43-0.51, 0.06-0.13. MS (ES +) m / z 434 (M).

EXAMPLP 11.7 (3-METHYLBUTYPAMIDE FROM ACIPP 6-r4- (5-FLUPRP-2- TRI FLU PRP M ETI LB ENCIPPI PERAZI N-1-I Ll PIRI AZIN-3 'CARBPXÍLICP Following the procedure of Example 11, making only the required variations to use 5-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl- (3-methylbutyl) -amide. pyridazin-3-carboxylic acid, the title compound was obtained as a white solid (34% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.02, 7.82-7.92, 7.57-7.68, 7.00-7.09, 6.96, 3.79, 3.71, 3.50, 2.64, 1.64-1.78, 1.51, 0.94. MS (ES +) m / z 454 (M + 1).

EXAMPLP 11.8 (2-C1CLPPROPILET1P AMID OF ÁCIPP 6-, 4- (2,4- PICLPRPBENCIP-PIPERAZIN-1-IL1 PIRLPAZIN-3-CARBPXÍLICP Following the procedure of Example 11, making only the required variations to use 2,4-dichlorobenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with (2-cyclopropi leti I) 6-piperazin-1-yl- pyridazine-3-carboxylic acid, the title compound was obtained a light yellow solid (75% yield). 1 H NMR (300 MHz, CDCl 3) d 7.95-8.02, 7.44, 7.38, 7.23, 6.93, 3.70-3.77, 3.60-3.63, 3.54, 2.60-2.65, 1.50, 0.74, 0.45, 0.08. MS (ES +) m / z 434 (M + 1).

EXAMPLE 11.9 (3-C1CLOPROPILPROPIP AMID ACID 6-r4- (5-FLUORO-2- TRI FLUO ROM ETILBENCIPPI PERAZI N -1-1 L1PIRID AZI N -3- CARBOXYLIC Following the procedure of Example 11, making only the required variations to use 5-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl- (3-cyclopropylpropyl) -amide. pyridazine-3-carboxylic acid, the title compound was obtained a light yellow solid (34% yield). 1 H NMR (300 MHz, CDCl 3) d 7.98, 7.88, 7.55-7.65, 7.2, 6.3, 3.68-3.85, 3.50, 2.60, 1.70, 1.25, 0.65, 0.40, 0.09. MS (ES +) m / z 466 (M + 1).

EXEMPLP 11.10 SYNTHESIS OF PENT-4-ACID ENILAMIDE 6-r4- (5-FLUPRP-2-TRIFLUPRPMETILBENZP1PPIPERAZIN-1-IL1PIR1DAZ1 -3- CARBPXÍLICC Following the procedure of Example 11, making only the required variations to use 5-fIuoro-2- (trifluoromethyl) benzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1- pent-4-enylamide ilpyridazine-3-carboxylic acid, the title compound was obtained as a white powder (17.3% Yield). 1 H NMR (300 MHz, CDCl 3) d 7.99, 7.92, 7.77, 7.27, 7.11, 7.00, 5.91-5.78, 5.09-4.95, 4.08-3.65, 3.47-3.27, 2.18-2.11, 1.75-1.65. 3C NMR (300 MHz, CDCI3) d 166.1, 165.7, 162.9, 162.7, 160.2, 145.5, 138.0, 129.3, 129.6, 129.5, 116.7, 114.9, 114.8, 114.6, 112.4, 46.4, 44.4, 44.2, 31.1, 28.9 . MS (ES +) m / z 466.3 (M + 1).

EXAMPLP 12 SYNTHESIS OF (3-METHYLBUTIP AMID OF ACID 6-T4- (2-AMINPBENZPIPPIPERAZIN-1-IL1 PIRIDAZIN-3-CARBPXYL1CP 6 - [4- (2-Nitrobenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methyl-butyl) -amide (100 mg, 0.235 mmol) was hydrogenated with 10 mg 10% Pd / C as a catalyst at room temperature under 1 atmosphere for 24 hours. The mixture was filtered through a celite cake. The filtrate was concentrated and purified by flash chromatography (ethyl acetate) to give a white solid (83% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.05, 7.86, 7.19-7.23, 7.10-7.13, 6.99, 4.40, 3.74-3.88, 3.50, 1.65-1.75, 1.52, 0.94. MS (ES +) m / z 397 (M + 1).

EXEMPLP 13 SYNTHESIS OF ESTER 3.3-DIMETIBUTÍLICP OF ÁCIPP (6-f4- (2-TRIFLU RPMETILBENZPIPPIPERAZIN-1-1L1PIRIDAZIN-3-1L.} CARBÁMICP To a solution of [4- (6-aminopyridazin-3-yl) piperazin- 1 -yl] - (2-trifluoromethyl-phenyl) methanone (200 mg, 0.57 mmol) in 10 ml of dioxane was added trichloromethyl chloroformate (112.7 mg, 0.57 mmol) and stirred at room temperature. 3,3-dimethylbutan-1 -ol (175.5 mg, 1.71 mmol) and triethylamine (57.6 mg, 0.57 mmol) and the temperature was raised to 80 ° C. The mixture was stirred for 3 hours under N2, and then concentrated. The residue was dissolved in 100 ml of dichloromethane, and washed with 2 portions of 20 ml of 1N HCl, 2 portions of 20 ml of saturated NaHCO 3 and finally with 2 portions of 20 ml of brine The combined organic extract was dried over Na2SO0 anhydrous, concentrated, and then purified through column chromatography eluted with hexane: ethyl acetate (1: 2). vo as a white solid (30 mg, 11% yield). 1H NMR (300 MHz, DMS0-d6) d 10.38, 7.89, 7.83, 7.77, 7.67, 7.54, 7.47, 4.14, 3.10-3.90, 1.55, 0.95.

EXAMPLE 13.1 2-CICLOPROPYLLETULIC ESTER OF ACID (6-f4- (2- TRI FLUORO M ETHYLENZOIPPIPERAZ1N-1 -I L1PIRIP AZI N-3-CARBAMIC ID Following the procedure of Example 13, making only the variations required to use 2-cyclopropyl ethanol in place of 3,3-dimethylbutan-1-ol to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl] ( 2-trifluoromethyl) methanone, the title compound was obtained as a white solid (8.3% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.11, 7.73, 7.65, 7.63, 7.55, 7.36, 7.04, 4.25, 3.95-4.02, 3.88-3.94, 3.61-3.65, 3.52-3.56, 3.32, 1.58, 0.71-0.80, 0.44 -0.50, 0.05-0.013. MS (ES +) m / z 464 (M + 1).

EXAMPLE 14 SYNTHESIS OF (3-METHYLBUTLL) ACID AMID 6-T4- (4.4.4- TRIFLUORO-2-METHYLBUTYRIPP1PERAZIN-1-IL1P1RIDAZIN-3-CARBOXYLIC A TFA salt mixture of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methyl-1-butyl) -amide (100 mg, 0.25 mmol), 4,4,4-trifluoro-2-methylbutyric acid (47.8 mg, 0.31 mmol), 1,8-diazabicyclo [5.4.0] undec-7-ene (77.8 mg, 0.51 mmol) and 1-hydroxy-benzotriazole hydrate (41.4 mg, 0.31 mmol) in 2 ml of DMF it was stirred at room temperature for 15 minutes. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide (47.6 mg, 0.31 mmol) was added to this solution. The reaction mixture was stirred at room temperature overnight and then diluted with 50 ml of ethyl acetate and washed with 2 portions of 20 ml of saturated aqueous NaHCO 3 and finally with 2 portions of 20 ml of brine. The organic extract was dried over anhydrous Na2SO4., concentrated, and then purified by column chromatography eluted with hexanes: ethyl acetate (1: 2). The product was obtained as a white flaky solid (80 mg, 75% yield). 1 H NMR (300 MHz, CDCl 3) d 8.07, 7.85, 7.01, 3.60-4.00, 3.50, 3.15, 2.80, 2.21, 1.70, 1.50, 1.25, 0.95. MS (ES +) m / z 416 (M + 1).

EXAMPLE 14.1 (3-METHYLBUTIP AMID ACID 6-r4- (4,4,4-TRIFLUORO-3-METHYLBUTYRIP PIPERAZIN-1-IL1 PYRIDAZINE-3-CARBOXYL1CO Following the procedure of Example 14, making only the required variations to use 4,4,4-trifluoro-3-methylbutyric acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with (3-methylbutyl) amide of 6-piperazin-1-pyridazine-3-carboxylic acid, the title compound was obtained as a white, squamous solid (63% yield). 1 H NMR (300 MHz, CDCl 3) d 8.07, 7.85, 7.00, 3.69-3.98, 3.67, 3.50, 3.00, 2.71, 2.35, 1.70, 1.50, 1.20, 0.95. MS (ES +) m / z 415 (M + 1).

EXAMPLE 14.2 (3-METHYLBUTIP AMID ACID 6-r4- (4,4,4-TRIFLUOROBUTIRlL) PIPERAZIN-1-IL1 PIRIDAZI N-3-CARBOXÍLICO Following the procedure of Example 14, making only the required variations to use 4,4,4-trifluorobutyric acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-methyl (3-methylbutyl) -amide: piperazin-1-yl-pyridazine-3-carboxylic acid, the title compound was obtained as a white flaky solid (49% yield). 1 H NMR (300 MHz, CDCl 3) d 8.07, 7.85, 7.00, 3.91, 3.82, 3.72, 3.67, 3.50, 2.50-2.67, 1.70, 1.50, 0.95. MS (ES +) m / z 402 (M + 1).

EXAMPLE 14.3 (3-METHYLBUTIP AMID ACID 6-r4- (6-CHLOROPYRIDIN-2-CARBONIPPIPERAZIN-1-IL1-PYRIDAZINE-3-CARBOXYLIC Following the procedure of Example 14, making only the variations required to use 6-chloropyridine-2-carboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6- (3-methylbutyl) -amide. piperazin-1-pyridazine-3-carboxylic acid, the title compound was obtained as a white flaky solid (12% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.87, 7.82, 7.70, 7.43, 7.00, 3.80-4.00, 3.50, 1.70, 1.53, 0.95. MS (ES +) m / z 417 (M + 1).

EXAMPLE 14.4 (2-CICLOPROPILETIPAMIDE OF ACID 6-r4- (2-METHYLCYCLOH EXANCARBONIPPI PERAZI N-1-I Ll PLRIDAZIN-3-CARBOXYLIC Following the procedure of Example 14, making only the variations required to use 2-methylcyclohexanecarboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1- (2-cyclopropylethyl) -amide. pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (60% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.08, 8.00, 7.00, 3.50-4.00, 2.70, 2.05, 1.20-1.90, 0.90, 0.75, 0.45, 0.10. MS (ES +) m / z 400 (M + 1,).

EXAMPLE 14.5 (2-CICLOPROPILETIP AMID ACID 6-r4- (3- M ETI LCI C LOHEXAN CARBON! DPI PERAZI N-1 -l LIPIRIPAZIN -3- CARBOXYLIC Following the procedure of Example 14, making only the required variations to use 3-methylcyclohexane carboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1 (2-cyclopropylethyl) -amide. -yl-pyridazine-3-carboxylic acid, the title compound was obtained as a white solid (27% yield). 1 H NMR (300 MHz, CDCl 3) d 8.06, 7.99, 6.99, 3.89, 3.79, 3.65-3.72, 3.56, 2.55, 1.20-1.86, 0.99, 0.92, 0.75, 0.47, 0.10. MS (ES +) m / z 400 (M + 1).

EXAMPLE 14.6 (2-CICLOPROPILETID AMID ACID 6-T4- (4-METHYLCYCLPHEXANCARBPNI PERAZI N-1-I-LlPlRIDAZIN-3-CARBPXILICP Following the procedure of Example 14, making only the required variations to use 4-methylcyclohexane carboxylic acid instead of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide, the title compound was obtained as a white solid (43 % Yield) H NMR (300 MHz, CDCI3) d 8.07, 7.09, 7.05, 3.89, 3.79, 3.64-3.70, 3.56, 2.40-2.60, 1.65-1.88, 1.50-1.62, 0.99, 0.91, 0.75, 0.48, 0.10 MS (ES +) m / z 400 (M + 1).

EXAMPLP 14.7 METHYL ESTER PEACLE 2-. { 4-r6- (2- C IC LOP ROP I LETILCARBAMPIP PIRIPAZIN-3-I PPI PERAZI N-1- CARBONIPBENZOICO Following the procedure of Example 14, making only the variations required to use monomethyl ester of phthalic acid in place of 4,4,4-trifluoro-2-methylbutypic acid to react with 6-piperazic acid (2-cyclopropylethyl) amide 1-I-pyridazine-3-carboxylic acid, the title compound was obtained a light yellow solid (97% yield). 1 H NMR (300 MHz, CDCl 3) d 8.02-8.06, 7.96, 7.88, 7.60, 7.48, 7.30, 6.98, 3.72-4.02, 3.54, 3.33, 1.49, 0.74, 0.45, 0.08. MS (ES +) m / z 438 (M + 1).

EXAMPLE 14.8 (2-CICLOPROPILETIP AMID ACID 6-f4- (3.3.3-TRIFLUORO-2-HYDROXY-2-METHYLPROPIONIPPIPERAZIN-1-IL1 PIRIDAZLN-3-CARBOXYLIC Following the procedure of Example 14, making only the required variations to use 3,3,3-trifluoro-2-hydroxy-2-methylproplonic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with (3 -methylb uti I) 6-Piperazin-1-yl-pyridazine-3-carboxylic acid amide, the title compound was obtained as a white solid (55% Yield), mp. 181-183 ° C. 1 H NMR (300 MHz, CDCl 3) d 8.07, 7.98, 7.01, 4.86, 3.92-3.81, 3.55, 1.74, 1.51, 0.81-0.68, 0.46, 0.09. 13C NMR (75 MHz, CDCI3) d 167.2, 163.1, 160.0, 145.4, 127.1, 126.3, 122.5, 112.5, 76.8-75.6 (q, J = 117 Hz, C-19F), 44.6, 39.7, 35.3, 20.5, 8.5 , 4.8. MS (ES +) m / z 416 (M + 1).

EXAMPLE 15 SYNTHESIS OF (2-CYCLOPROPYL-2-HYDROXYTEP AMID ACID 6-T4- (2-TRI FLUOROMETILB ENZOIPPI PERAZI N -1-1 L1PIRID AZI N-3- CARBOXYLIC To a solution of (2-cyclopropyl-2-hydroxyethyl) acid amide 6-chloropyridazine-3-carboxylic acid (58 mg, 0.24 mmol) in 10 ml of DMF was added 1,8-diazabicyclo [5.4.0] undec-7-ene (0.109 g), piperazin-1-yl- (2- trifluoromethylphenyl) methanone (86.7 mg, 0.33 mmol) and Bu4NI (4 mg, 0.01 mmol). The mixture was heated at 80 ° C overnight. Water was added and the mixture was extracted with 2 15 ml portions of ethyl acetate. The organic extract was washed with dilute HCl, followed by sodium bicarbonate solution and brine, then dried over Na 2 SO 4 and concentrated. The residue was dissolved in a small amount of dichloromethane and purified by column chromatography eluted with ethyl acetate to yield the product as a white solid (35.5 mg, 32% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.24, 8.02, 7.73, 7.58, 7.34, 6.98, 4.04, 3.85, 3.52, 3.33, 3.10, 2.60-2.41, 0.95, 0.52, 0.32. MS (ES +) m / z 464.3 (M + 1).

EXAMPLE 15.1 METHYL ESTER OF 4-METHYL-2 ( {6-R4- (2- TRIFLUOROMETILBENZOIPPIPERAZIN-1-IL1-PIRIPAZIN-3-CARBONlL.}. AMINO) PENTANOlCO Following the procedure of Example 15, making only the required variations to use 2 - [(6-chloropyridazine-3-carbonyl) amino] -4-methylpentanoic acid ethyl ester in place of (2-cyclopropyl-2-hydroxyethyl) amide 6-chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) -methanone, the title compound was obtained as a white solid (36% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.16, 8.04, 7.85, 7.66-7.53, 7.28, 7.00, 4.82-4.77, 4.14-3.68, 3.58-3.51, 1.83-1.60, 1.03-0.95. EXAMPLE 15.2 CYCLOPROPYLMETHYLAMIDE OF ACID6 6-, 4- (2-TRIFLUPRPMETILBENZPIPPIPERAZIN-1-1L1P1RIDAZIN-3-CARBCXÍLICC Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid cyclopropylmethylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to react with piperazine -1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white solid (31% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.16-7.88, 7.75, 7.68-7.46, 7.18, 7.00, 4.17-3.64, 3.21-3.12, 1.07-1.00, 0.61-0.44, 0.26-0.20.

EXEMPLP 15.3 G2- (4-METPXYPHENIPETYLAMIDE OF ACID 6-T4- (2-TRIFLUPRPETYLBENZPIPPIPERAZIN-1-IL1 PIRIPAZIN-3-CARBPXYLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid [2- (4-methoxyphenyl) ethyl] amide in place of (2-cyclopropyl-2-hydroxyethyl) amide 6. Chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white solid (12% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.04, 7.93, 7.74, 7.63, 7.56, 7.36, 7.12, 6.92, 6.81, 4.08-3.46, 3.33, 2.87.

EXAMPLP 15.4 (3-FENILPRPPIL) ACID AMID 6-r4- (2-TRIFLUPRPMETILBENZPIP-PIPERAZIN-1-IL1PIRIDAZIN-3-CARBCXÍLICC Following the procedure of Example 15, making only the required variations to use (3-f in i I propi I) 6-chloropyridazine-3-carboxylic acid amide in place of (2-cyclopropyl-2-hydroxyethyl) 6-hydroxyethyl amide. -chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethyl-phenyl) methanone, the title compound was obtained as a white solid (15% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.05, 7.93, 7.74, 7.63, 7.56, 7.39, 7.29-7.13, 6.92, 4.12-3.29, 2.68, 2.02-1.83.

EXEMPLC 15.5 F2- (4-CLPRPFENPXI) ETILl AMIDA PE ACIPP 6-T4- (2- TRI FLUP RPM ETILBENZPIPPI PERAZI N -1-1 L1PIRIPAZIN -3- CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use [ 6-Chloropyridazine-3-carboxylic acid 2- (4-chlorophenoxy) ethyl] amide in place of 6-chloro-pyridazin-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to react with piperazin-1- il- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white solid (13% Yield) 1 H NMR (400 MHz, CDCl 3) d 8.27, 8.05, 7.74, 7.64, 7.57, 7.37, 7.25-7.20 , 7.00, 6.85-6.82, 4.02-3.32.

EXAMPLP 15.6, 2- (4-FLUPRPFENPXI) ETIL1 ACID AMID 6-f4- (2-TRIFLUPRPMETILBENZPIPPIPERAZIN-1-IL1PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid [2- (4-fluorophenoxy) ethyl] amide in place of (6-cyclopropyl-2-hydroxyethyl) -amide Chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) -methanone, the title compound was obtained as a white solid (49% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.28, 8.05, 7.74, 7.63, 7.56, 7.35, 7.03-6.92, 6.87-6.81, 4.02-3.30.

EXEMPLP 15.7 G2- (2,4-DIFLUPRPFENIPETYL1AMIDE OF ACID 6-f4- (2-TRIFLUPRPMETILBENZPIPPIPERAZIN-1-IL1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid [2- (2,4-difluorophenyl) ethyl] amide instead of (2-cyclopropyl-2-hydroxyethyl) amide of 6-chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white solid (33% Yield), mp 179-181 ° C. 1 H NMR (400 MHz, CDCl 3) d 8.04, 7.91, 7.75, 7.61, 7.37, 7.30-6.89, 4.09-3.66, 3.38-3.32, 2.88. MS (ES +) m / z 520 (M + 1).

EXAMPLP 15.8 (3,3-DIMETHYLBUTYP AMID OF ACID 6-T4- (2-TRIFLUPRPMETILBENZPIPPIPERAZIN-1-IL1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (3,3-dimethylbutyl) amide in place of 6-chloropyridazine- (2-cyclopropyl-2-hydroxyethyl) amide 3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white solid (17% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.05, 7.83-7.72, 7.64, 7.57, 7.38, 6.98, 4.09-3.66, 3.50-3.45, 3.37-3.34, 1.57-1.52, 0.96. MS (ES +) m / z 464.6 (M + 1).

EXEMPLP 15.9 (2-FENILCICLPPRPPILMETIP AMID OF ACID 6-T4- (2-TRIFLUPRPETYLBENZPIPPIPERAZIN-1-IL1 PIRLDAZIN-3-CARBCXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (2-phenylcyclopropylmethyl) amide in place of 6-chloropyridazin-3- (2-cycloproplo-2-hydroxyethyl) amide To react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white solid (25% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.09-8.03, 7.76, 7.64, 7.57, 7.36, 7.28-7.21, 7.17-7.12, 7.07-6.96, 4.09-3.32, 1.92-1.86, 1.47-1.38, 1.01-0.96. MS (ES +) m / z 510.4 (M + 1).

EXAMPLP 15.10 (3-CICLPPRPPILPRPPIP AMID OF ACID 6-r4- (2-TRIFLUPRPMETILBENZPIPPIPERAZIN-1-IL1 PIRIDAZIN-3-CARBPXÍLICP) Following the procedure of Example 15, making only the required variations to use (3-cyclopropylpropyl) 6-acid amide chloropyridazine-3-carboxylic acid in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to react with piperazin-1-yl- (2-trifluoromethylphenol) methanone, the compound of the title as a white solid (28% yield) 1 H NMR (400 MHz, CDCl 3) d 8.04, 7.89, 7.73, 7.65, 7.58, 7.38, 6.99, 4.08-3.67, 3.54-3.46, 3.39-3.31, 1.77-1.66 , 1.34-1.23, 0.72-0.62, 0.45-0.36, 0.06-0.04 MS (ES +), m / z 462.2 (M + 1).

EXEMPLC 15.11 ESTER T-BUTIICP OF ACIDP 4-T6- (2- C1CLPPRPPILETILCARBAMPIPPIRIDAZIN-3-IL1PIPERAZIN-1-CARBCXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide in place of 6-chloropyridazine-3- (2-cyclopropyl-2-hydroxyethyl) amide carboxylic acid to react with piperazine-1-carboxylic acid t-butyl ester, the title compound was obtained as a white solid (47% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.04-7.95, 6.97, 3.62-3.54, 1.59-1.44, 1.34-1.23, 0.72-0.62, 0.45-0. 36.0. 06-0.04. MS (ES +) m / z 376.3 (M + 1).

EXEMPLC 15.12 (2-ClCLPPRPPILETIL) AMIDA PE ACIPP 6-T4- (TETRAHIPRPFURAN-2-CARBPNIPPIPERAZIN-1-IL1 PIRIPAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide in place of 6-chloropyridazin-3- (2-cyclopropyl-2-hydroxyethyl) amide To react with piperazin-1-yl- (tetrahydrofuran-2-yl) methanone, the title compound was obtained as a white solid (47% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.12-7.88, 6.97, 4.64-4.60, 3.93-3.42, 2.56-2.35, 2.10-1.93, 1.52-1.38, 0.84-0.62, 0.50-0.38, 0.17-0.05. MS (ES +) m / z 374.3 (M + 1).

EXEMPLP 15.13, 2- (3-FLUPRPFEN! P ETIL1 ACID AMID 6- [4- (2- TRI FLUPRP METÍ LBENZPIPP1 PERAZI N -1-1 L1PIRID AZI N -3- CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid [2- (3-fluorophenyl) ethyl] amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. -chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethyphenyl) methanone, the title compound was obtained as a white solid (71% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.05, 7.93, 7.74, 7.64-7.56, 7.37-7.35, 7.26-7.24, 7.01-6.90, 4.10-4.03, 3.89-3.70, 3.36-3.33, 2.92.

EXEMPLP 15.14 r2- (4-FLUPRPFENIP ETIL1 AMID OF ACID6 6- T4- (2- TRIFLUPRPMETILBENZPIP PIPERAZIN-1 -IL1 PIRIDAZIN-3- CARBCXÍLICP Following the procedure of Example 15, making only the required variations to use [2- (4-fluorophenyl) ethyl] amide 6-chloropyridazine-3-carboxylic acid instead of 6- (2-cyclopropyl-2-hydroxyethyl) amide Chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (59.8% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.05.0, 7.92, 7.72-7. 76, 7.66-7. 54.7. 38-7.34, 7.20-7. 14.7. 0-6.94, 4.10-4. 02.3. 92-3.84, 3.80-3. 68.3. 37-3.36, 2.90.

EXAMPLP 15.15 r2- (2-FLUPRPFEN! ACID6-T4-TEPYLAMIDE (2- TRIFLUPRPMET1LBENZPIPP1PERAZIN-1-IL1 PIRlDAZlN-3-CARBCXÍLICP Following the procedure of Example 15, making only the required variations to use [2- (2-fluorophenyl) ) ethyl 6-chloropyridazine-3-carboxylic acid amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to react with piperazin-1-yl- (2-trifluoromethylphen) methanone , the title compound was obtained as a white powder (70.7% Yield), 1 H NMR (400 MHz, CDCl 3) d 8.04, 7.95, 7.75-7.72, 7.63, 7.55, 7.36, 7.22-7.15, 7.05-6.97, 4.07 -4.02, 3.89-3.83, 3.79-3.67, 3.35-3.32, 2.96.

EXEMPLP 15.16 r2- (4-CLPRPPENHYL) ETHYLAMIDE OF ACIPP 6-i4- (2-TRIFLUPRPMETILBENZPIPPIPERAZIN-1-IL1 PIRIPAZlN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid [2- (4-chlorophenyl) ethyl] amide in place of 6-chloropyridyl-2-hydroxyethyl) -amide. Chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a light yellow powder (46.5% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.10, 7.95, 7.75, 7.65, 7.58, 7.35, 7.25, 7.15, 7.00, 4.10, 3.95-3.66, 3.38, 2.90.

EXEMPLP 15.17 F2-Í3-CLPRPFENIPETIL1 AMID OF ÁCIPP 6-T4- (2-TRIFLUPRPMET1LBENZPIPPIPERAZIN-1-IL1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use chloropyridazine-3-carboxylic acid [2- (3-chlorophenyl) ethyl] amide in place of 6-chloropyridazine (2-cyclopropyl-2-hydroxyethyl) amide -3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a light yellow powder (59.6% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.05, 7.94, 7.75, 7.64, 7.57, 7.37, 7.26, 7.24-7.19, 7.12, 7.00, 4.10, 3.95-3.66, 3.38, 2.90.

EXEMPLP 15.18 (2-PHENYLPRPPIPAMIDE OF ACID 6-r4- (2- TRI FLUP RPM ETILBENZPIPPI PERAZI N-1 -I Ll PIRIDAZIN-3- CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (2-phenylpropyl) -amide in place of 6-chloropyridazine- (2-cyclopropyl-2-hydroxyethyl) -amide. 3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (63.2% Yield). 1 H NMR (500 MHz, CDCl 3) d 7.97, 7.80, 7.68, 7.57, 7.50, 7.30, 7.24, 7.20-7.12, 6.92, 3.98, 3.80, 3.74-3.60, 3.53, 3.28, 3.00, 1.28.

EXEMPLP 15.19 (2-BIFENIL-4-1L-ETIP AMID OF ÁCIPP 6-T4- (2-TRIFLUPRPETYLBENZPIPPIPERAZ1N-1-IL1PIRIDAZI -3- CARBCXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (2-biphenyl-4-yl-ethyl) in place of (2-cyclopropyl-2-hydroxyethyl) acid amide 6-chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (63.2% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.07, 7.98, 7.76, 7.64, 7.60-7.52, 7.44, 7.38-7.30, 7.00, 4.06, 3.88, 3.82-3.68, 3.36, 2.98.

EXEMPLP 15.20 (3-METHYLBUTIP AMID OF ACID6 6- \ 4- (2- TRIFLUPRPMETILBENZPIP PIPERAZIN-1 -ILIPLRIDAZIN-3- CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide in place of 6-chloropyridazin-3- (2-cyclopropyl-2-hydroxyethyl) amide carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (63.2% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.05, 7.98, 7.75, 7.64, 7.57, 7.37, 7.00, 4.06, 3.89, 3.82-3.64, 3.49, 3.36, 1.70, 1.50, 0.95.

EXEMPLP 15.21 (4-HIDRPXIBUTIP AMID OF ACID 6-f4- (2-TRIFLUPRPMETILBENZPIP PIPERAZIN-1 -IL1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use (4-h id roxy butyl) 6-chloropyridazine-3-carboxylic acid amide in place of 6- chloropyridazine (2-cyclopropyl-2-hydroxyethyl) amide -3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (30% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.05, 7.98, 7.75, 7.63, 7.57, 7.37, 6.99, 4.06, 3.88, 3.82-3.67, 3.52, 3.36, 1.70.

EXEMPLP 15.22 (2-HIDRPXI-2-FENILETIP AMID OF ACID (R) -6-f4- (2-TRIFLUPRPMETILBENZP1PPIPERAZIN-1-1L1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use (2 (R) -6-chloropyridazine-3-carboxylic acid (hydroxy-2-phenylethyl) amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to react with piperazin-1 - il- (2-trifluoromethylphen) methanone, the title compound was obtained as a white powder (64.5% Yield). 1 H NMR (500 MHz, CDCl 3) d 8. 28, 8.05, 7.76, 7.64, 7.58, 7.44-7.32. , 7.29, 7.00, 4.96, 4.08, 3.92-3.68, 3.61, 3.36.

EXEMPLP 15.23 (2-HIDRPXI-2-FENILETIP AMID OF ACID (S) -6-f4- (2-TRIFLUPRPMETILBENZPIL) PIPERAZIN-1 -IL1 PIRIDAZIN-3-CARBCXÍLICP Following the procedure of Example 15, making only the required variations to use (S) -6-chloropyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) amide in place of (2-cyclopropyl-2-hydroxyethyl) amide of 6-chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (64.5% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.28, 8.05, 7.76, 7.64, 7.58, 7.44-7.32, 7.29, 7.00, 4.96, 4.08, 3.92-3.68, 3.61, 3.36. MS (ES +) m / z 500 (M + 1).

EXEMPLC 15.24 ACIDIC ETÍLICP ESTER 4- ( { 6-r4- (2-TRIFLUPRPMETILBENZPIP PIPERAZIN-1-IL1 PYRIDAZINE-3-CARBPNIL > AMI P) BUTÍRICP Following the procedure of Example 15, making only the required variations to use 2 - [(6-chloropipdazin-3-carbonyl) amino] butyric acid ethyl ester in place of 6- (2-cyclopropyl-2-hydroxyethyl) -amide Chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (37.8% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.05, 7.96, 7.75, 7.65, 7.57, 7.37, 7.00, 4.16-4.04, 3.92-3.70, 3.56, 3.36, 2.40, 1.25. MS (ES +) m / z 494 (M + 1).

EXAMPLP 15.25 (3-HIDRPXI-4,4-DIMETHYLPENTLL) ACID AMID 6-T4- (2- TRI FLUPRP METHYLBENZPIPPI PERAZI N-1-I Ll PIRIDAZIN-3-CARBCXÍLICP Following the procedure of Example 15, making only the required variations to use (3-hydroxy-4, 4-d imethylpenti I) 6-chloropyridazine-3-carboxylic acid amide in place of (2-cyclopropyl-2-hydroxyethyl) amide of 6-chloroplridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (39% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.18, 8.05, 7.74, 7.63, 7.56, 7.36, 6.99, 4.05, 3.92-3.67, 3.45-3.32, 3.26, 1.76, 1.55, 0.88. MS (ES +) m / z 494 (M + 1).

EXEMPLP 15.26 (3-HIDRPXI-3-METILBUTIP AMID OF ACID 6-T4- (2-TRIFLUPRPMETILBENZPIP PIPERAZIN-1 -IL1 PLRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (3-hydroxy-3-methylbutyl) amide in place of 6- (2-cyclopropyl-2-hydroxyethyl) -amide. Chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (46.4% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.30, 8.05, 7.75, 7.65, 7.57, 7.37, 6.98, 4.06, 3.88, 3.81-3.69, 3.64, 3.40-3.32, 1.80, 1.64, 1.30. MS (ES +) m / z 466 (M + 1).

EXEMPLP 15.27 (2-ETPXlETIP AMID OF ACID 6-f4- (2-TRIFLUPRPMETILBENZPIPP1PERAZIN-1-IL1 PIRIDAZI -3- CARBPXÍLICP Following the procedure of Example 15, making only the variations -required to use 6-chloropyridazine-3-carboxylic acid (2-ethoxyethyl) amide in place of 6-chloropyridazin-3 (2-cyclopropyl-2-hydroxyethyl) amide carboxylic to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (24.8% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.18, 8.07, 7.76, 7.65, 7.58, 7.38, 7.00, 4.07, 3.90, 3.83-3.65, 3.60, 3.52, 3.36, 1.20. MS (ES +) m / z 452 (M + 1).

EXEMPLP 15.28 ACID PENTILAMIDE 6-r4- (2-TRIFLUPRPMETILBENZPIL) PIPERAZIN-1-IL1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the variations required to use 6-chloropyridazine-3-carboxylic acid pentylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to react with piperazine -1-yl- (2-tpfluoromethylphenyl) methanone, the title compound was obtained as a white solid (94% Yield), mp. 123-125 ° C. 1 H NMR (300 MHz, CDCl 3) d 8.03, 7.85, 7.62, 7.54, 7.35, 6.97, 4.06-3.99, 3.91-3.69, 3.44, 3.33, 1.62-1.55, 1.37-1.33, 0.95-0.81. 3 C 1 H NMR (75 MHz, CDCl 3) d 167.6, 162.9, 160.0, 145.5, 132.4, 129.5, 127.2, 127.1, 126.9-127.8, 112.5, 77.2, 46.4, 44.6, 44.4, 41.3, 39.4, 29.3, 29.1, 22.4, 14.0. MS (ES +) m / z 450.2 (M + 1), 472.2 (M + Na).

EXEMPLP 15.29 (2-HIDRPXI-3,3-DIMETHYLBUTYL) ACIDIC AMID 6- [4- (2- TRI FLUPRP METH LBENZPIPPI PERAZI N -1-1 L1P1RID AZI -3- CARBPXÍLICC Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl) amide in place of (2-cyclopropyl-2-hydroxyethyl) acid amide 6-chloropyridazine-3-carboxylic acid to react with piperazi n-1-l- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a brown solid (75% yield), mp. 236-240 ° C. 1 H NMR (300 MHz, CDCl 3) d 7.90, 7.83-7.79, 7.75-7.73, 7.69-7.65, 7.54-7.52, 7.30, 4.29, 3.91-3.73, 3.43-3.32, 3.20-3.11, 2.81, 2.77, 0.95. MS (ES +) m / z 480 (M + 1).

EXAMPLP 15.30 (2-HIDRPX1-3, 3-DIMETHYLBUTYL) AMID OF ACID 6-f4- (5-FLUPRP-2-TRIFLUPRPMETILBENZPIP PIPERAZIN-1-IL1 PYRIDAZINE-3-CARBPXYLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl) amide in place of (2-cyclopropyl-2-hydroxyethyl) acid amide 6-chloropyridazine-3-carboxylic acid to react with piperazin-1-yl- (5-fluoro-2-trifluoromethylphenyl) methanone, the title compound was obtained as a brown solid (51% Yield), mp: 186-189 ° C. 1 H NMR (300 MHz, CDCl 3) d 8.20, 8.04, 7.75, 7.22, 7.07, 6.98, 4.06-3.98, 3.91-3.71, 3.47-3.23, 2.45, 0.96. 13 C NMR (75 MHz, CDCl 3) d 166.3, 164.1, 160.1, 160.0, 130.1, 127.2, 116.9, 116.6, 115.0, 114.7, 112.4, 79. 4, 46.4, 44.5, 44.3, 41.9, 41.3, 34.4, 25.7. MS (ES +) m / z 498 (M + 1).

EXAMPLP 15.31 (2-CICLPPRPPLETIL) AMID OF ACID6 6- f4- (2-METHYLCYCLPPRPPANECARBPNIP PIPERAZIN-1 -IL1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide in place of 6-chloropyridazin-3- (2-cyclopropylo-2-hydroxyethyl) amide To react with piperazin-1-yl- (2-methylcyclopropyl) methanone, the title compound was obtained as a white solid (88% Yield. 13 C NMR (75 MHz, CDCl 3) d 177.1, 163.5, 159.5, 144.9, 131.3, 126.4, 115.1, 49.7, 45.2, 39.5, 37.5, 37.2, 35.3, 34.6, 29.9, 28.5, 26. 5, 23.4, 8.6, 4.2. MS (ES +) m / z 360 (M + 3).

EXEMPLP 15.32 PENTILAMIPA PE ÁCIPP 6-r4- (5-FLUPRP-2- TRIFLUPRPMETILBENZPIPPI PERAZI -1-I LIPIRIPAZIN- 3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid pentylamide in place of 6-cyoropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) -amide to react with piperazine -1-yl- (5-fluoro-2-trifluoromethylphenyl) methanone, the title compound was obtained as a white solid (31% Yield), mp. 162-164 ° C. 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.87, 7.24, 7.07, 6.99, 4.08-3.99, 3.90-3.66, 3.45, 3.35, 1.65-1.55, 1.37-1.30. 13 C NMR (75 MHz, CDCl 3) d 166.1, 162.9, 160.0, 145.7, 129.7, 127.2, 116.9, 116.6, 115.0, 114.7, 112.6, 77. * 2, 46.4, 44.6, 44.4, 41.3, 39.4, 29.3, 29.1, 22.4, 14.0.

EXAMPLP 15.33 (4-METILPENTIP AMID OF ACID 6-T4- (2-TRIFLUPRPETYLBENZPIPPIPERAZIN-1-1L1 PIRLDAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (4-methylpentyl) amide in place of 6-chloropyridazin-3- (2-cyclopropyl-2-hydroxyethyl) amide To react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white solid (36% Yield), mp. 43-45 ° C. 1 H NMR (300 MHz, CDCl 3) d 7.71, 7.66-7.52, 7.34, 6.96, 4.06-3.98, 3.87-3.68, 3.63, 3.53, 3.19, 3.25, 3.09, 1.65-1.58, 1.36-1.33, 1.26-1.12, 0.85 , 13 C NMR (75 MHz, CDI3) d 167.6, 166.9, 166.2, 159.0, 158.9, 149.5, 149.4, 134.4, 132.4, 129.5, 129.2, 127.2, 126.9, 126.8, 112.6, 112.5, 51.4, 48.8, 46.4, 44.7 , 44.4, 41.3, 37.8, 34.8, 34.0, 29.7, 29.0, 28.7, 27.1, 26.7, 22.5, 22.3, 14.0, 13.9. MS (ES +) m / z 464.2 (M + 1), 486.2 (M + Na).

EXAMPLP 15.34 (3-METHYLBUTYP AMIDA PE ACIPP 6- r4- (5-FLUPRP-2-RIFLUPRPMETILBENZPIL) PIPERAZIN-1-IL1 PIRIPAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide in place of 6-chloropyridazin-3- (2-cyclopropyl-2-hydroxyethyl) amide To react with piperazin-1-yl- (5-fluoro-2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (28.3% Yield). 1H NMR (400 MHz, -CDCI3) d 8.05, 7.86, 7.78-7.75, 7.28-7.22, 7.12-7.08, 7.02, 4.08-4.01, 3.91-3.86, 3.82-3.68, 3.55-3.46, 3.38, 1.73-1.65, 1.56-1.48, 0.94.

EXAMPLP 15.35 (3-METILBUTIP AMIPA PE ÁCIPP 6-f4- (4-FLUPRP-2-TRIFLUPRPMETILBENZPIPPIPERAZIN-1-IL1PIRIPAZIN-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide in place of 6-chloropyridazin-3- (2-cyclopropylo-2-hydroxyethyl) amide To react with piperazin-1-yl- (4-fluoro-2-trifluoromethylpheni) methanone, the title compound was obtained as a white powder (63.8% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.08, 7.85, 7.48-7.46, 7.41-7.32, 7.02, 4.08-4.05, 3.95-3.88, 3.80-3.68, 3.52-3.45, 3.35, 1.73-1.68, 1.51, 0.94.

EXAMPLP 15.36 (3-METHYLBUTYL) ACID AMID 6-r4- (2-FLUPRP-6-TRI FLUPRPMETILBENZPIPPI PERAZI N-1-I P PYRIDAZIN-3-CARBPXYLICP Following the procedure of Example 15, making only the required variations to use (3-methylbutyl) acid amide 6-chloropyridazine-3-carboxylic acid in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to react with piperazin-1-yl- (6-fluoro-2-trifluoromethylphenyl) methanone; obtained the title compound as a white powder (16.8% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.06, 7.85, 7.57-7.55, 7.39-7.36, 7.01, 4.04-3.94, 3.86-3.79, 3.49, 3.44-3.36, 1.73-1.68, 1.52, 0.94.

EXEMPLC 15.37 (3-METHYLBUTYPAMIDE OF ACID 6-T4- (2, 6-DIFLUPRPBENZPIP PIPERAZIN-1-IL1PIRIDAZ1N-3-CARBPXÍLICP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide in place of 6-chloropyridazin-3- (2-cyclopropyl-2-hydroxyethyl) amide To react with piperazin-1-yl- (2,6-dif-Iodophenyl) methanone, the title compound was obtained as a white powder (42.2% Yield). 1 H NMR (400 MHz, CDCU) d 8.07, 7.85, 7.44-7.38, 7.03-6.97, 4.0-3.99, 3.86-3.83, 3.52-3.48, 1.73-1.67, 1.51, 0.94.

EXAMPLP 15.38 (2-CICLPPRPPLETIL) AMID OF ACID 6-r4- (2,2,3 3-TETRAMETILCICLPPRPPANCARBPNIPPI PERAZI N-1 IL1- PLRLDAZIN-3-CARBPXÍLlCP Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropyloethyl) in place of 6-chloropyridazine-3- (2-cyclopropyl-2-hydroxyethyl) amide carboxylic acid to react with piperazin-1-yl- (2,2,3,3-tetramethylcyclopropyl) methanone, the title compound was obtained as a white solid (35% Yield). 1 H NMR (400 MHz, CDCl 3) d 8.07, 8.01, 7.01, 3.91-3.89, 3.81-3.65, 3.57, 1.21, 1.19, 0.79-.072, 0.49-0.46, 0.11-0.10. MS (ES +) m / z 400 (M + 1).

EXAMPLE 15.39 (2-MET1LCICLOPROPILMETIP AMID ACID 6-T4- (2- TRI FLUORO METILBENZOIPPI PERAZI N-1 -I Ll PLRIDAZIN-3- CARBOXYLIC Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (2-methyl-cyclopropylmethyl) amide in place of 6-chloropyridazin-3- (2-cyclopropyl-2-hydroxyethyl) amide To react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white solid (26% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.06, 7.96, 7.75, 7.65, 7.58, 7.38, 7.01, 4.04-4.10, 3.86-3.93, 3.69-3.83, 3.25-3.42, 1.12, 1.05, 0.71-0.80, 0.64-0.72 , 0.39-0.45, 0.25-0.30. MS (ES +) m / z 448 (M + 1).

EXAMPLE 15.40 T-BUTYLIC ESTER OF ACID 4-r6- (3-METHYLBUTLLCARBAMOIP P I RIDAZIN-3-IL1PIPERAZIN-1 -CARBOXYLIC Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide in place of 6-chloropyridazin-3- (2-cyclopropyl-2-hydroxyethyl) amide carboxylic acid to react with piperazine-1-carboxylic acid tert-butyl ester, the title compound was obtained as a white solid (83% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.03, 7.86, 6.97, 3.75, 3.56-3.63, 3.49, 1.65-1.76, 1.52, 0.94. MS (ES +) m / z 378 (M + 1).

EXAMPLE 15.41 (2-C1CLOBUTILETIP AMID ACID 6-G4- (2-TR1FLUOROMETILBENZOIPPIPERAZIN-1-IL1 PYRIDAZI-3-CARBOXYLIC Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (2-cyclobutylethyl) amide in place of 6-chloropyridazin-3- (2-cyclopropyl-2-hydroxyethyl) amide carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (47% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.02, 7.74, 7.73, 7.57, 7.35, 6.98, 4.03, 3.89-3.66, 3.40-3.31, 2.36, 2.09-2.00, 1.92-1.57. 13C NMR (75 MHz, CDCI3) 2 167.6, 134.3, 132.4, 129.5, 127.2, 127.0, 126.9, 126.8, 126.7, 125.5, 121.8, 112.6, 46.4, 44.6, 44.5, 41.3, 37.6, 36.5, 33.7, 28.3, 18.6 . MS (ES +) m / z 462.3 (M + 1).

EXAMPLE 15.42 6-AXIS HEXILAMIDE r4- (2-TRIFLUOROMETILBENZOID PIPERAZIN-1-IL1PIRIDAZ1N-3-CARBOXYLIC) Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid hexylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to react with piperazine -1-yl- (2-trifluoromethyl-phenyl) methanone, the title compound was obtained as a white powder (35% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.02, 7.85, 7.72, 7.56, 7.34, 6.97, 4.00, 3.90-3.64, 3.48-3.28, 1.58, 1.29, 0.85. 13C NMR (75 MHz, CDCI3) d 167.6, 162.9, 160.0, 145.5, 134.3, 132.8, 129.5, 127.6, 127.2, 126.9, 125.4, 46.4, 44.6, 44.4, 44.4, 41.3, 39.4, 31.5, 29.5, 26.6, 22.6, 14.0 . MS (ES +) m / z (%) 464 (M + 1).

EXAMPLE 15.43 (3-CICLOBUTILPROPIP AMIDA OF ACID 6-T4- (2- TRI FLUORO METILBENZOIPPI PERAZI N-1 -I Ll PIRIDAZIN-3- CARBOXÍLICO Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid (3-cyclobutylpropyl) in place of 6-chloropyridazine-3- (2-cyclopropyl-2-hydroxyethyl) amide carboxylic acid to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone, the title compound was obtained as a white powder (28% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.03, 7.85, 7.73, 7.57, 7.34, 6.99, 4.05, 3.89-3.65, 3.45, 3.33, 2.27, 1.99, 1.76, 1.58-1.39. 13C NMR (75 MHz, CDCI3) d 167.6, 162.8, 159.9, 145.4, 134.2, 132.4, 129.5, 127.2, 126.9, 126.7, 112. 7, 46.4, 44.6, 44.5, 41.2, 39.4, 35.7, 34.1, 28.3, 27.2 , 18.4. MS (ES +) m / z 475.9 (M + 1).

EXAMPLE 15.44 ACID HEPTILAMIDE 6- T4- (2- TRI FLUORO METILBENZOIPPIPERAZIN-1 -I Ll PIRIDAZLN-3- CARBOXÍLICO Following the procedure of Example 15, making only the required variations to use 6-chloropyridazine-3-carboxylic acid heptylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to react with piperazine -1-yl- (2-trifluoromethyl-phenol) methanone, the title compound was obtained as a white powder (41% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.05, 7.85, 7.72, 7.58, 7.34, 6.98, 4.03, 3.94-3.64, 3.47-3.28, 1.58, 1.32-1.25, 0.84. 13C NMR (75 MHz, CDCI3) d 167.6, 162.9, 160.0, 145.5, 134.3, 132.4, 129.5, 126.9, 126.3, 125.4, 121.8, 112.6, 46.4, 44.5, 41.3, 39.4, 31.7, 29.6, 29.0, 26.9, 22.6 , 14.1. MS (ES +) m / z 478.2 (M + 1).

EXAMPLE 15.45 (4-CICLOPROPILBUTIP AMID ACID 6-T4- (2- TRIFLUOROMETILBENZOIPPIPERAZIN-1-IL1 PIRIDAZIN-3-CARBOXYLIC Following the procedure of Example 15, making only the variations required to use 6-chloropyridazine-3-carboxylic acid (4-cyclopropylbutyl) amide in place of 6-chloropyridazine-3-carboxylic acid (3-cyclobutyl-propyl) -amide to react with piperazin-1-yl- (2-trifluoromethyl-phenyl) methanone, the title compound was obtained as a white powder (21% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.03, 7.86, 7.72, 7.58, 7.34, 6.98, 4.05, 3.89-3.62, 3.48-3.31, 1.64-1.41, 1.20, 0.60, 0.39-0.30, -0.04. 13C NMR (75 MHz, CDCI3) d 167.6, 162.9, 160.0, 145.4, 134.3, 132.4, 129.5, 127.2, 126.9, 126.7, 125.4, 121.8, 112.6, 46.4, 44.6, 44.4, 41.2, 39.5, 34.4, 29.4, 27.0 , 10.7, 4.4. MS (ES +) m / z 476.1 (M + 1).

EXAMPLE 16 SYNTHESIS OF 4-METHYL-2- ( {6-r4- (2- TRI FLUORO METH LBENZOIPPI PERAZI N-1 -I LIPIRIDAZIN -3- CARBONYL AMINO) PENTANOIC Lithium hydroxide monohydride (25 mg, 0.595 mmol) was added to a solution of 4-methyl-2- (. {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine ethyl ester. -3-carbonyl.} -amino) pentanoic acid (130 mg, 0.256 mmol) in 3 ml of tetrahydrofuran and 1.5 ml of water, the reaction mixture was stirred at room temperature for 3 hours, the THF was removed by evaporation , the residue was adjusted with 5% citric acid to a pH of about 6, and diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and concentrated to give 4-methyl-2- acid. (. {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carbonyl} amino) pentanoic acid (94 mg, 74%), 1 H NMR (400 MHz, CDCl 3) d 8.17, 8.02, 7.78, 7.66-7.53, 7.38, 6.99, 6.72, 4.88-4.73, 4.25-3.60, 3.44-3.21, 1.79-1.06, 1.33-1.19, 1.03, 0.99.

EXAMPLE 17 SYNTHESIS OF CHLORHYDRATE OF (2-CICLOPROPI LETIL) AMIDA OF ACID 6-. { 4-ri1- (2-TRIFLUPRPMETILFENiPETILlPIPERAZIN-1-iP-PIRIDAZIN-3-CARBPXÍLlCP Titanium isopropoxide (0.6 ml, 2.0 mmol) was added to a solution of 6-piperazin-1-yl-pyridazine-3-carboxylic acid 2- (cyclopropylethyl) -amide (282 mg, 1.02 mmol) and 2- (trifluoromethyl) acetophenone (0.23 ml, 1.53 mmol) in 3 ml THF. The resulting mixture was stirred at room temperature for 4 hours. Sodium cyanoborohydride (130 mg, 1.96 mmol) was added, and stirring continued for another 13 hours. Aqueous sodium hydroxide (2.0 ml, 1.0 M) was added. After stirring for 5 minutes at room temperature, the reaction mixture was diluted with 50 ml of ethyl acetate, and then washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. Purification through flash chromatography gave 126 mg of 6- (2-cyclopropylethyl) -amide. { 4- [1- (2-trifluoromethylphenyl) ethyl] piperazin-1-yl} -pyridazine-3-carboxylic acid. This product was dissolved in 2 ml of CH2Cl2 and then HCl in ether (7M, 0.2 ml, 1.4 mmol) was added. This mixture was kept at room temperature for 2 hours. The white precipitate was collected by filtration and washed with ether and dried under vacuum to yield the title compound as a white solid (104 mg, 21% Yield), m.p. 158-163 ° C 1H NMR (300 MHz, DMS0-d6) d 12.10, 8.81, 8.67, 7.90-7.81, 7.64, 7.40, 4.70-2.85, 1.69, 1.38, 0.72-0.58, 0.40-0.32, 0.023-0.02. MS (ES +) m / z 374.3 (M + 1-HCl).

EXAMPLE 18 SYNTHESIS OF (2-OXO-2-PHENYLETIP AMID ACID 6-T4- (2- TRI FLUORO METILBENZOIPPIPERAZ1N-1 -I Ll PIRIDAZIN-3-CARBOXYLIC To a solution of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) (0.517 g, 1. 03 mmoles) in 10 ml of dichloromethane, 0.53 g of 1, 1, 1-triacetoxy-1,1-dihydrogen-1, 2-benzydoxy-3 (1 H) -one in a portion under stirring in a cold water bath. After stirring in a cold water bath for 15 minutes and then at room temperature for 2 hours, the reaction mixture was diluted with 20 ml of diethyl ether. The mixture was emptied in a solution of sodium thiosulfate (1176 g, 7.44 mmol) in 29 ml of saturated aqueous sodium bicarbonate. The mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed with 2 portions of 15 ml of saturated aqueous NaHCO 3 and 2 portions of 15 ml of water. The combined aqueous washes were then extracted with 2 80 ml portions of ethyl acetate. The combined organic phase was dried over Na2SO4 and filtered, the solvent was then removed under vacuum. The crude product was purified by column chromatography, which was eluted sequentially with hexane: ethyl acetate (1: 1), hexane: ethyl acetate (1: 2) and pure ethyl acetate. The product was obtained as a white powder (0.261 g, 51% Yield), m.p. 196-198 ° C. 1 H NMR (300 MHz, CDCl 3) d 8.72, 7.97-8.06, 7.74, 7.47-7.66, 7.36, 6.99, 4.96, 4.02-4.11, 3.70-3.92, 3.27-3.42. 13C NMR (CDCI3) d 193.4, 167.7, 163.4, 160.0, 145.1, 134.6, 134.2, 134.0, 132.4, 129.6, 128.9, 128.0, 127.2, 126.9, 126.8, 112.3, 46.4, 44.7, 44.4, 41.3. MS (ES +) m / z 498 (M + 1).

EXAMPLE 19 SYNTHESIS OF ETHYL ESTER OF ACID 1-PHENYL-2- ( {6-r4- (2- TRIFLUOROMETHYL-BENZOIPP1PERAZIN-1-IL1PIRIDAZIN-3-CARBONYL AMINO) ACETIC To a solution of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) -amide in 2 ml chloroform, they added 0.25 ml of acetic anhydride, 0.25 ml of triethylamine and 18 mg of 4-dimethylaminopyridine. After stirring at room temperature for 6 hours, the reaction mixture was diluted with 100 ml of ethyl acetate, washed with 3 portions of 10 ml of water and dried over Na 2 SO 4. The crude product obtained after the solvent removal was purified through column chromatography eluted sequentially with hexane: ethyl acetate = 1: 1 and 1: 2 to give a white powder (49.6 mg, 91.5% Yield). 1 H NMR (500 MHz, CDCl 3) d 8.10, 8.04, 7.75, 7.65, 7.57, 7.40-7.28, 7.00, 5.92, 4.07, 3.98, 3.90, 3.82-3.68, 3.36, 2.10. MS (ES +) m / z 508 (M + 1).

EXAMPLE 19.1 PROPOLIC ACID ESTER 1.1-DIMETHYL-3 - (- f 6-T4- (2- TRI FLUORO METILBENZOI DPI PERAZI N-1 -I Ll-PIRID AZI N-3- CARBONI PAM I NO) ACETIC Following the procedure of Example 19, making only the required variations to use 6- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-hydroxy-3-methylbutyl) -amide in place of 6- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) -amide for reaction with acetic anhydride, the title compound was obtained as a white powder ( 80% of Performance). 1 H NMR (500 MHz, CDCl 3) d 8.05, 8.01, 7.75, 7.65, 7.57, 7.37, 6.99, 4.06, 3. 88, 3.81-3.67, 3.58, 3.36, 2.06, 2.01, 1.52. MS (ES +) m / z 508 (M + 1).

EXAMPLE 20 SYNTHESIS OF (2-METOXY-3.3-DIMETILBUTIP AMID ACID 6- r4- (2-TRIFLUOROMETILBENZOiPPIPERAZlN-1-ILL PLRIDAZIN-3-CARBOXYLIC To a solution of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl) amide of (81.6 mg, 0.17 mmol) in 1.0 mL THF was added sodium hydride (5.0 mg, 0.19 mmol), followed by methyl iodide (15 mL, 0.26 mmol). The reaction mixture was stirred at room temperature for 16 hours and then the solvent was removed. The gummy material was diluted with 5 ml dichloromethane, washed with 2 portions of 2 ml water, dried over MgSO4 and the solid filtered. After the solvent was concentrated to dryness, the crude material was subjected to column chromatography eluted sequentially with ethyl acetate: hexane (1: 1) and ethyl acetate to obtain 25.3 mg (30%) of the product as a solid. P.f. 65-68 ° C. H NMR (300 MHz, CDCI3) d 7.73-7.69, 7.62, 7.53, 7.33, 6.98-6.93, 4.18-3.59, 3.48, 3.41, 3.37-3.26, 3.18, 3.03-2.98, 1.76, 0.98, 0.75. 13C NMR (75 MHz, CDCI3) d 167.6, 166.4, 158.9, 149.8, 149.3, 134.3, 132.4, 129.5, 129.4, 129.3, 129.1, 127.2, 126.9-126.7, 112.7, 88.1, 61.7, 61.4, 52.7, 52.0, 46.4 , 44.7, 44.6, 44.5, 44.4, 41.3, 41.2, 40.5, 35.8, 35.3, 35.0, 26.0, 25.9, 25.7. MS (ES +) m / z 508 (M + 1).

EXAMPLE 21 SYNTHESIS OF (2-CICLOPROPILETIDAMIDA PE ACIPO 6-r3,5- PIMETlL-4- (2-TRIFLUOROMETlLBENZOID P1PERAZIN-1 -IL1 PIRIPAZIN-3-CARBOXYLIC To a solution of 6- (3,5-dimethylpiperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) (0.40 g, 1.33 mmol) in 15 ml dichloromethane was added diisopropyl ethylamine (0.34 g, 0.46 g). ml, 2.66 mmol) followed by 2-trifluoromethylbenzoyl chloride (0.31 g, 0.22 mL, 1.46 mmol) at room temperature. The reaction solution was stirred for 16 hours and emptied into 10 ml of cold water.

The organic layer was extracted with 50 ml dichloromethane and washed with 2 portions of 10 ml of saturated NaHCO 3 solution and dried over MgSO 4. After filtration, the filtrate was concentrated in vacuo. The crude material was purified by column chromatography eluting with ethyl acetate (100%) to obtain 0.18 g of a colorless solid (28% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.03-7.91, 7.70, 7.63-7.49, 7.32, 6.99-6.95, 5.00, 4.39-4.22, 3.64, 3.55-3.47, 3.39-3.17, 1.51-1.38, 1.24-1.14, 0.76 -0.67, 0.42, 0.05. 13 C NMR (75 MHz, CDCI3) d 168.0, 163.0, 160.9, 144.9, 132.3, 131.9, 129.4, 129.3, 127.2, 127.0, 126.8, 111.5, 50.4, 49.1, 48.7, 48.5, 48.2, 45.5, 45.3, 39.6, 34.6, 20.2, 19.5, 8.6, 4.2.

EXAMPLE 22 SYNTHESIS OF ACID PENTILAMIDE 6-r2,5-DIMETHYL-4- (2- TRI FLUOROMETILBE NZPI DPI PERAZI N -1-1 L1PIRIDAZIN -3- CARBPXÍLICP To a mixture of 6-chloropyridazine-3-carboxylic acid pentylamide (304 mg, 1.00 mmol) in 12 ml of 2-propanol was added 2,5-dimethylpiperazine (1.37 g, 12.0 mmol). The reaction mixture was refluxed for 2 days. Another 0.25 g of 2,5-dimethylpiperazine and 1.0 ml of triethylamine were added to the reaction mixture and heating continued for another 24 hours. Then the reaction mixture was cooled to room temperature and the solvent was removed through a rotary evaporator. To the dichloromethane solution was added 20 ml of crude material of 2-trifluoromethylbenzoyl chloride (0.63 g, 3.00 mmol) in 20 ml of dichloromethane and the reaction mixture was stirred at room temperature for 16 hours. The organic layer was diluted with 50 ml of dichloromethane and then washed with 10% HCl, dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The crude material was purified by column chromatography eluting with ethyl acetate (100%) to give 300 mg (31% Yield) of the product as a colorless solid. 1 H NMR (300 MHz, CDCl 3) d 7.74-7. 43.3.36-7. 24, 5.17-5.04, 4.91-4.79, 4.52, 4.52, 3.68-3.57, 3.54-3.44, 3.39-3.11, 2.93, 2.85-2.71, 1.36-1.31, 1.27-1.15, 1.23-1.05.

EXAMPLE 23 SYNTHESIS OF ACCOUNT 2-. { 4-r6- (2-ClCLOPROPILETlLCARBAMOID P1RIPAZ1N-3- IL1 PIPERAZIN-1 -CARBONIL.}. BENZOIC Lithium hydroxide monohydrate (0.066 g, 1.57 mmol) was added to 0.230 g of a solution of 2-ethyl ester. { 4- [6- (2-Clyclopropylethylcarbamoyl) pyridazin-3-yl] piperazin-1 -carbonyl} benzoic acid in 10 ml of tetrahydrofuran and 5 ml of water, and stirred at room temperature overnight. The THF was removed in vacuo, the residue was dissolved in 100 ml of ethyl acetate, neutralized through the addition of 5% HCl solution, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was recrystallized from dichloromethane and hexanes to yield 0.107 g of the title compound (42% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.67, 9.07-7.87, 7.54, 7.41, 7.26-7.24, 6.95, 4.12-3.27, 1.55-1.40, 0.77-0.64, 0.50-0.34, 0.13-0.01; 13 C NMR (75 MHz, CDCl 3) d 170.7, 168.2, 163.2, 159.9, 145.0, 137.7, 133.1, 131.2, 129.2, 127.9, 127.2, 126.6, 112.6, 46.2, 44.1, 41.4, 39.7, 34.4, 8.6, 4.2; MS (ES +) m / z 424.2 (M + 1).

EXAMPLE 24 SYNTHESIS OF 2,2-DIMETHYL CYCLOPROPYLIMET AMIDA PE ACIPO 6-T4-IF2-TRIFLUOROMETILBENZOID PIPERAZIN- -1-IL1PIRIPAZIN-3- CARBOXYLLONE To a solution of 1.00 mmol of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid in 20 ml dichloromethane was added diisopropylethylamine (0.8 ml, 4.60 mmol), 1-hydroxybenzotriazole hydrate ( 0.203 g, 1.50 mmol) and 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (0.384 mg, 2.00 mmol). The resulting mixture was stirred for 15 minutes, then 2,2- (dimethylcylpropyl) methylamine (0.149 mg, 1.5 mmol) was added.

Agitation continued for another 24 hours. The reaction mixture was diluted with 100 ml of dichloromethane, washed sequentially with water and brine, then dried over anhydrous Na2SO4 and concentrated. Purification through flash chromatography on silica gel (ethyl acetate) and recrystallization from ethyl acetate and hexanes gave the title compound (0.089 g, 19%). p.f. 132-134 ° C. 1 H NMR (500 MHz, CDCl 3) d 8.06-8.02, 1.90-7.80, 7.75, 7.64-7.52, 7.34, 6.98, 4.05-3 33, 1.11, 1.04, 0.89-0.79, 0.50-0.46, 0.16-0.13; 13C NMR (75 MHz, CDCl3) d 167.6, 162.7, 159.9, 145.4, 134.2, 132.3, 129.5, 127.2, 126.8, 125.4, 121.8, 112.5, 46.3, 44.6, 44.4, 40.5, 27.1, 23.5, 19.9, 18.7, 15.9; MS (ES +) m / z 462 (M + 1).

EXAMPLE 24.1 (2-THIOPHEN-2-IL-ETHYL) ACID AMID 6-T4- (2- TRIFLUOROMETILBENZOID PIPERAZIN-1-IL1 PYRIDAZINE-3-CARBOXYLIC Following the procedure of Example 24, making only the required variations to use 2-thiophen-2-yl-ethylamine instead of 2, 2- (dimethylcylpropyl) methylamine to react with 6- [4- (2-trifluoromethylbenzoyl) plperazin-1-yl acid} pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (40% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.01, 7.73, 7.58, 7.34, 7.12, 6.98, 6.90, 6.84, 4.03, 3.89-3.55, 3.33, 3.12. 13C NMR (75 MHz, CDCI3) d 167.6, 163.1, 160.0, 145.2, 141.1, 134.2, 132.4, 129.5, 127.2, 127.0, 126.9, 125.3, 123.9, 121.8, 112.5, 46.4, 44.6, 44.4, 41.3, 40.9, 30.9 . MS (ES +) m / z 490.0 (M + 1).

EXAMPLE 24.2 (6-CHLOROPIRIDAZIN-3-ID AMIDA PE ACIPP 6-f4- (2-TRIFLUPRPMETILBENZPIDPIPERAZIN-1-IL1 PIRIPAZIN-3-CARBCXÍLICC Following the procedure of Example 24, making only the required variations to use 3-amino-6-chloropyridazin instead of 2,2- (dimethylcyl-cyclic) methylamine to react with 6- [4- (2-trifluoromethylbenzoyl) piperazine-1- acid pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (8% yield). 1 H NMR (300 MHz, CDCl 3) d 10.75, 8.62, 8.06, 7.75-7.50, 7.36, 7.03, 4.12-3.76, 3.36. 13C NMR (75 MHz, CDCI3) d 167.7, 162.2, 160.1, 154.0, 152.3, 143.8, 134.1, 132.4, 129.7, 129.6, 127.3, 127.2, 126.94, 126.88, 126.7, 120.7, 112.2, 46.3, 44.6, 44.3, 41.3 . MS (ES +) m / z 492.1 (M + 1).

EXEMPLP 25 SYNTHESIS OF (2-CICLPPRPPIL-2-PXPETIL) AMID OF ACID6 6- f4- (2-TRIFLUPRPMETILBENZPIL) PIPERAZI N-1 -IL1 PIRIDAZIN-3-CARBPXÍLICP Dess-Martin periodianin (0.55 g, 1.3 mmol) was added to a solution of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-cyclopropyl-2-hydroxyethyl) amide. carboxylic acid (0.50 g, 1.07 mmol), the resulting reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate, sequentially washed with 10% Na2S203 solution, saturated NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography and recrystallized from ethyl acetate-hexanes to give the title compound in 87% yield (0.43 g). 1 H NMR (300 MHz, CDCl 3) d 8.45-8.41, 8.02, 7.72, 7.63-7.51, 7.34, 7.00, 4.48, 4.47-3.28, 2.00-1.94, 1.18-1.11, 1.10-0.82. 13C NMR (75 MHz, CDCI3) d 204.4, 167.6, 163.1, 159.8, 144.9, 134.2, 132.3, 129.5, 129.0, 127.5, 127.2, 126.9, 121.8, 118.1, 112.4, 49.5, 46.3, 44.6, 44.4, 41.2, 18.7 , 11.4. MS (ES +) m / z 462.0 (M + 1).

EXAMPLE 26 SYNTHESIS OF (3-METHYLBUTYLAMIDE OF ACID 6-f4- (2- S U LFAMOILBENZOI DPI PERAZI N-1-I Ll PIRIDAZIN-3-CARBPXÍLICP To an ice-cold solution of 6- [4- (2-methanesulfonylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methylbutyl) -amide (0.078 g, 0.17 mmol) in 5 mL of cooled THF was added Methyl magnesium chloride (0.071 ml, 0.212 mmol). The resulting mixture was stirred for 15 minutes at 0 ° C, and then 30 minutes at room temperature. The reaction mixture was cooled to 0 ° C again, then tributylborane (0.255 ml, 0.255 mmol) was added. The mixture was stirred at room temperature for 30 minutes, then heated to reflux for 18 hours. The mixture was then cooled to 0 ° C, and sodium acetate, water and hydroxylamine-o-sulfonic acid (0.067 g) were added. The mixture was stirred for 3 hours, and then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried and concentrated in vacuo. The residue was purified by flash column chromatography using 20% methanol in ethyl acetate to yield the title product (0.033 g, 42% Yield). 1 H NMR (300 MHz, CDCl 3) d 8.58, 7.98, 7.81, 7.75-7.68, 7.64-7.58, 7.43, 7.19, 4.03-3.88, 3.78-3.59, 3.21-3.20, 3.152-3.147, 1.65-1.50, 1.46-1.35 , 0.85. 13C NMR (75 MHz, CDCI3) d 170.1, 165.5, 161.7, 146.3, 139.1, 137.3, 135.5, 131.3, 130.9, 128.8, 127.9, 114.4, 45.6, 45.2, 44.96, 42.6, 39.5, 38.8, 27.1, 22.9. MS (ES +) m / z 460.1 (M + 1).

EXEMPLP 27 SYNTHESIS OF (4-CLPRPFENID AMID OF ACID 6-T4- (2-TRIFLUPRPMETILBENZPIDPIPERAZIN-1-IL1 PIRIDAZLN-3-CARBPXÍLICP 2-Chloro-4,6-dimethoxy-1, 3,5-triazine (0.105 g, 0.60 mmol) was added to a cooled solution (0 ° C) of 6- [4- (2-trifluoromethylbenzoyl) piperazine-1 acid. -yl] pyridazine-3-carboxylic acid (0.190 g, 0.50 mmol) and methylmorpholine (0.07 ml, 0.63 mmol) in 10 ml of THF. The reaction mixture was stirred at 0 ° C for 15 minutes, and then at room temperature for 1 hour. Then 4-chloroaniline (0.0765 g, 0.60 mmol) was added. After stirring at room temperature for 20 hours, the reaction mixture was diluted with 100 ml of ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 and concentrated. Purification through flash chromatography and recrystallization from ethyl acetate / hexanes gave the title compound in 67% yield (0.164 g). 1 H NMR (300 MHz, CDCl 3) d 9.79, 8.08, 7.82-7.55, 7.36-7.28, 7.02, 4.10-4.00, 3.93-3.68, 3.35. 13C NMR (75 MHz, CDCI3) 2 167.6, 160.7, 160.0, 144.8, 136.2, 134.2, 132.4, 129.5, 129.2, 129.1, 127.2, 126.9, 126.8, 126.7, 125.4, 121.8, 120.7, 112.6, 46.3, 44.5, 44.3 , 41.2. MS (ES +) m / z 490.1 (M + 1).

EXAMPLE 27.1 (5-CLOROPIRIPIN-2-ID AMIPA OF ACID 6-f4- (2- TRI FLUORO METILBENZOIDPIPERAZIN-1 -I Ll PIRIDAZIN-3- CARBOXÍLICO Following the procedure of Example 27, making only the required variations to use 2-amino-5-chloropyridine in place of 4-chloroaniline, the title compound was obtained as a white powder (36% Yield). '1 H NMR (300 MHz, CDCl 3) d 10.32, 8.32, 8.27, 8.08, 7.83-7.47, 7.36, 7.02, 4.11-4.03, 3.92-3.71, 3.36. 13c NMR (75 MHz, CDCI3) d 167.6, 161.4, 160.0, 149.4, 146.9, 144.4, 137.8, 134.1, 132.4, 129.5, 127.2, 126.9, 126.8, 126.7, 125.4, 121.8, 114.5, 112.2, 46.3, 44.5, 44.3 , 41.2. MS (ES +) m / z 491.0 (M + 1).

EXAMPLE 27.2 (2.2-DIFLUORO-2-PIRIDIN-2-ILETID ACID AMID 6-T4- (2- TRIFLUOROMETILBENZOID P1PERAZIN-1-IL-PIRLDAZIN-3- CARBCXÍLICP Following the procedure of Example 27, making only the required variations to use 2,2-difluoro-2-pyridin-2-ylethylamine in place of 4-chloroaniline, the title compound was obtained as a white powder (49%). 1 H NMR (300 MHz, CDCl 3) d 8.65, 8.27, 8.01, 7.81-7.46, 7.38-7.32, 6.96, 4.43-4.31, 4.12-3.64, 3.32. 13C NMR (75MHz, CDCI3) d 167.6, 163.3, 159.9, 153.4, 153.1, 149.4, 144.8, 137.2, 134.2, 132.3, 129.5, 127.4, 127.2, 126.9, 126.8, 126.7, 126.3, 125.4, 125.2, 121.95, 121.81, 120.6, 120.5, 118.7, 115.5, 112.4, 46.3, 44.5, 44.4, 43.4, 43.0, 42.6, 41.2; MS (ES +) m / z 521.2 (M + 1).

EXEMPLP 27.3 (2.2-DIFLUPRP-2-FENILETIL) ACID6 AMID 6-, 4- (2-TRIFLUPRPMETILBENZPIDPIPERAZIN-1-IL1 PIRIDAZIN-3-CARBPXÍLICP Following the procedure of Example 27, making only the required variations to use 2,2-difluoro-2-phenylethylamine in place of 4-cyanoaniline, the title compound was obtained as a white powder (53%). 1 H NMR (300 MHz, CDCl 3) d 8.17, 8.00, 7.71, 7.64-7.50, 7.41-7.27, 6.97, 4.17-4.01, 3.89-3.66, 3.33. 13C NMR (75MHz, CDCI3) d 167.6, 163.2, 159.9, 144.6, 134.6, 134.1, 132.3, 130.3, 129.5, 128.5, 127.3, 127.2, 126.8, 125.3, 121.8, 120.3, 117.1, 112. 4, 46.3, 45.3, 44.5, 44.3; MS (ES +) m / z 520.2 (M + 1).

EXEMPLP 27.4 r2- (3-FLUPRPFENID-2-HYDROPYELYL ACID AMID 6-T4- (2- TRI FLUP RPM ETILBENZPI DPI PERAZI N-1 -I Ll PIRIDAZIN-3- CARBPXÍLICP Following the procedure of Example 27, making only the required variations to use 2-amino-1- (3-fluorophenyl) ethanol in place of 4-chloroaniline, the title compound was obtained as a white powder (34%). p.f. 117-119 ° C. H NMR (300 MHz, CDCl 3) d 8.25, 8.98, 7.72, 7.64-7.52, 7.35-7.23, 7.14-7.10 6.97-6.78, 4.93, 4.05-3.31, 3.31. 13C NMR (75MHz, CDCI3) d 167.6 164. 5, 164.3, 161.3, 159.9, 144.8, 144.6, 144.5, 134.1, 132.3, 130.0 129.9, 129.5, 127.5, 127.2, 127.1, 126.9, 126.8, 126.7, 125.4, 121.8 121. 4, 114.7, 114.4, 113.0, 112.7, 112.4, 73.1, 47.5, 47.0, 46.3 44.5, 44.3, 41.2; MS (ES +) m / z 518.3 (M + 1).

EXEMPLP 28 SYNTHESIS OF PIRIDIN-2-ILAMIPA PE ÁCIPP 6- | 4- (2- TRIFLUPRPMETILBENZPID PIPERAZ1N-1 -IL1PIRIDAZIN-3-CARBPXÍLICP To a solution of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (0.400 g, 1052 mmol) was added 0.03 ml of DMF and 0.5 ml of thionyl chloride. The reaction mixture was refluxed at 70 ° C for 17.5 hours. The mixture was evaporated and the residue was dried overnight. The dried residue was dissolved in 8 ml of dichloromethane as a concentrated solution of acid chloride in the next reaction step. To a solution of 2-aminopyridine (0.038 g, 0.395 mmole) and 0.1 ml of triethylamine in 2 ml of dichloromethane was added the above acidic concentrated solution (0.1315 M, 2 ml, 0.263 mmole) dropwise at room temperature. The reaction mixture was stirred at room temperature for 4 hours and then diluted with 100 ml ethyl acetate, washed sequentially with water and brine. The organic layer was dried over Na2SO4 and evaporated. The crude product was purified through column chromatography to give the title compound in 37% yield (0.044 g). 1 H NMR (300 MHz, CDCl 3) d 10.30, 8.35, 8.09, 7.75-6.69, 7.65-7.52, 7.35, 7.09-6.96, 4.10-4.02, 3.92-3.71, 3.35. 13C NMR (75MHz, CDCI3) d 167.7, 161.5, 160.1, 151.1, 148.3, 144.8, 138.2, 134.2, 132.4, 129.6, 127.2, 126.9, 126.8, 125.5, 121.8, 119.9, 114.0, 112.2, 46.4, 44.6, 44.3, 41.3. MS (ES +) m / z 457.3 (M + 1).

EXAMPLE 28.1 PYRIDAZINE-3-ILAMIDE PE ACCIDUS 6- | 4- (2- TRI FLUORO METILBENZOI DPI PERAZI N-1 -I Ll PIRIPAZIN-3- CARBOXYLIC Following the procedure of Example 28, making only the required variations to use pyridazin-3-ylamine in place of 2-aminopyridine to react with 6- [4- (2-tpfluoromethylbenzoyl) ~ piperazin-1-yl] pyridazin-3 chloride. -carbonyl, the title compound was obtained as a white powder (17.3% Yield). 1 H NMR (300 MHz, CDCl 3) d 10.81, 9.05, 8.70, 8.13, 7.87-7.57, 7.39, 6.95, 4.16-3.80, 3.40. 13C NMR (75MHz, CDCI3) d 167.7, 162.3, 160.1, 148.6, 144.1, 132.4, 129.6, 128.1, 127.2, 126.9, 118.3, 112.1, 43.4, 44.6, 44.3, 41.3. MS (ES +) m / z 458.3 (M + 1).

EXAMPLE 28.2 (2-PYRIDINE-2-ILETID AMIPA PE ACID 6-IF4- (2- TRIFLUOROMETILBENZOIDP1PERAZIN-1-IL1 PYRIPAZIAN-3-CARBOXYLIC Following the procedure of Example 28, making only the required variations to use 2-pyridin-2-ylethylamine in place of 2-aminopyridine to react with 6- [4- (2-trifluoromethyl-benzoll) piperazin-1-yl] chloride] pyridazin-3-carbonyl, the title compound was obtained as a white powder (30%). p.f. 151-154 ° C. 1 H NMR (300 MHz, DMSO-d 6) d 9.07, 8.78, 8.43, 7.99-7.61, 7.52, 7.34, 3.79-3.60, 3.35-3.14. MS (ES +) m / z 485.3 (M + 1).

EXAMPLE 29 SYNTHESIS DEBENZO M, 31 DIOXOL-5-lL-METHYL) ACID AMID 6- G4- (2-TRIFLUOROMETILBENZOIDP1PERAZIN-1-1L1 PIRLDAZIN-3- CARBOXÍLICO A. A solution of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (0.300 g, 0.789 mmol) in 12 mL of dichloromethane and 6 mL of THF was cooled to 0 ° C. . N-Methylmorpholine (0.806 g, 0.789 mmol) was charged, followed by the dropwise addition of isobutyl chloroformate (0.109 g, 0.789 mmol). After stirring at 0 ° C for 20 minutes and at room temperature for 1.5 hours, the mixture was evaporated. The residue was dissolved in 60 ml of dichloromethane and the solution was cooled to 0 ° C, 5 ml of water was added to the solution with stirring. The mixture was then transferred to a 100 ml separatory funnel. After it was quickly separated from the water, the organic layer was evaporated at 10 ° C. The residue was then dried and dissolved in 15 ml of dry dichloromethane and ready for the reaction of the next step. B. To the concentrated mixed anhydride solution above (0.053 M, 5 mL, 0.263 mmol) a solution of piperonylamine in dichloromethane (0.5 M, 0.52 mL, 0.26 mmol) was added dropwise at room temperature in 5 minutes. The reaction was stirred at room temperature for 16 hours. The mixture was evaporated and dried under reduced pressure to give the title compound in 93% yield (0.136 g).

EXAMPLE 30 SYNTHESIS OF (P1R1D1N-2-IL-METID AMID ACID 6-14- (2- TRIFLUOROMETILBENZOIDPIPERAZIN-1-IL1 PIRIDAZIN-3-CARBOXYLIC A mixture of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid ethyl ester (0.099 g, 0.25 mmol), 0.7 ml of pyridin-2-yl-methylamine and sodium cyanide (0.245 g, 0.5 mmol) was stirred at room temperature overnight and purified by column chromatography to yield the title compound in 48% yield (0.057 g). p.f. 179-181 ° C. H NMR (300 MHz, CDCI3) d 8.81, 8.59, 8.12, 7.78-7.50, 7.37, 7.21-7.13, 6.93, 4.83, 4.17-3.66, 3.37. 13C NMR (75MHz, CDCI3) d 167.6, 163.3, 160.0, 156.5, 149.0, 145.3, 137.0, 134.2, 132.4, 129.5, 127.2, 122.5, 121.9, 112.3, 46.4, 44.6, 44.4, 41.3. MS (ES +) m / z 471 (M + 1).

EXAMPLE 30.1 (2-BENZ? Ri.31DIOXOL-5-lL-ETID AMIPA PE ACID 6-T4- (2- TRI FLUORO METILBENZOIDPIPERAZIN-1 -I Ll PIRIPAZI -3- CARBOXÍLICO Following the procedure of Example 30, making only the required variations to use 2-benzo [1, 3] dioxol-5-ylethylamine in place of pyridin-2-ylmethylamine, the title compound was obtained as a white powder (99%) . p.f. 162-164 ° C. 1 H NMR (300 MHz, CDCl 3) d 8.02, 7.89, 7.72, 7.64-7.51, 7.34, 6.97, 6.72-6.63, 5.89, 4.10-3.63, 3.34-3.31, 2.81. 13C NMR (75MHz, CDCI3) d 167.6, 163, 159.9, 147.7, 146.1, 145.2, 134.2, 132.4, 132.3, 129.5, 127.2, 127.1, 126.9, 126.8, 126.7, 121.6, 112.4, 109.0, 108.4, 100.8, 46.3, 44.5, 44.4, 41.2, 40.8, 35.5. MS (ES +) m / z 528.2 (M + 1).

EXAMPLE 31 SYNTHESIS OF (2-CICLOPROPYLTHYL) AMID OF 6-, 4- (2- TRIFLUOROMETILTILOBENZOID PIPERAZIN-1 -IL1- PIRIDAZLN-3-CARBOXYLIC) A. A mixture of 4- (2-trifluoromethylbenzoyl) piperazine-1-carboxylic acid tert-butyl ester (3.58 g, 10.0 mmol) and Lawesson's reagent (2.12 g, 5.2 mmol) in toluene was heated to reflux for 4 hours, and then concentrated. The residue was purified by flash column chromatography to produce 4- (2-trifluoromethylthiobenzoyl) peperazine-1-carboxylic acid tert -butyl ester (2.87 g, 76%). 1 H NMR (300 MHz, CDCl 3) d 7.64, 7.54, 7.42, 7.21, 4.53-4.45, 4.27-4.19, 3.71-3.25, 1.42. B. A solution of 4- (2-trifluoromethylthiobenzoyl) piperazine-1-carboxylic acid tert-butyl ester (2.1 g, 5.61 mmol) in dichloromethane and trifluoroacetic acid (30 mL, 2: 1) was stirred at room temperature during overnight, the solvent was removed through evaporation. The residue was dissolved in ethyl acetate, and washed with saturated aqueous NaHCO 3 and brine, dried over anhydrous Na 2 SO 4 and concentrated to give piperazin-1-N- (2-trifluoromethylphenyl) methanethione (1.47 g, 5.36 mmole) which It was used directly in the next step without further purification. C. A mixture of piperazin-1-yl- (2-trifluoromethylphenyl) methanethione (1.1 g, 4.0 mmol), 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide (0.98 g, 3.98 mmol), K2CO3 (0.83 g, 6.0 mmol) and 0.010 g of n-Bu4NI in 10 mL of dioxane was heated to reflux for 21 hours, and then concentrated. The residue was purified through column chromatography and recrystallization from ethyl acetate and hexanes to give the title compound in 76% yield (1.42 g). p.f. 117-120 ° C. H NMR (300 MHz, CDCI3) d 8.05-7.93, 7.65, 7.55, 7.44, 7.24, 6.98, 4.61-4.40, 3.98-3.40, 1.51- 1.47, 0.73-0.64, 0.44-0.35, 0.07-0.01. 13C NMR (75MHz, CDCI3) d 197.0, 162.8, 159.6, 145.6, 140.2, 132.4, 128.8, 127.2, 127.0, 126.9, 125.5, 124.8, 124.4, 124.0, 121.8, 112.5, 50.4, 47.6, 44.2, 43.6, 40.0, 39.6, 34.4, 8.6, 4.2. MS (ES +) m / z 464.0 (M + 1).

EXAMPLE 32 The following compounds were synthesized through synthetic processes as described above: 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-phenoxyethyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid [3- (4-fluorophenyl) propyl] -amide; 1- [1- (4-Fluorophenyl) ethyl] -3-. { 6- [4- (2-trifluoromethylbenzoyl) pipe razin-1-yl] pyridazin-3-yl} urea; 1- [3- (4-Fluorophenyl) propyl] -3-. { 6- [4- (2-trifluoromethylbenzoyl) pipe razin-1-yl] pyridazin-3-yl} urea; 3-Cyclopentyl-N-. { 6- [4- (2-trifluoromethyl-benzoyl) piperazin-1-yl] pyridazin-3-yl} propionamide; phenethylamide 6- [4- (2-rifluoromethylbenzoyl) piperazin-1-yl acid} pyridazine-3-carboxylic acid; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-trifluoromethylpyridin-2-yl) -amide; (4- carbamoylphenol) -6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-carbamoylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid m-tolylamide; 6- [4- (2-Rifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid p-tolylamide; o- 6- (4- (2-Trifluoromethyl-Ibenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid o-tolylamide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-propylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] -pyridazine-3-carboxylic acid (4-propylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) plperazin-1-yl] pyridazine-3-carboxylic acid (4-isopropy-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-isopropylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-chloro-phenyl) -amide; 6- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyano-3-fluorophenyl) -amide.; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,4-dimethylphenyl) amide; 6- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,5-dimethylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,6-dimethylphenyl) amide; 6- (4- (2-Trifluoromethylbenzoyl) p iperazi n-1-yl] pyridazine-3-carboxylic acid (2,3-dimethylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3,5-dimethylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3,4-dimethyl-phenyl) -amide; (4- (2-Trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (4-ethyl-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-ethyl-phenyl) amide; 3-Fluoro-2-methylphenyl) 6- [4- (2-Tri fluoro methyl Ibenzo i l) p i perazi n-1-yl] pyridazine-3-carboxylic acid amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-fluoro-4-methylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-fluoro-2-methylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) p iperazin-1-yl] pyridazine-3-carboxylic acid (2-fluoro-5-methyphenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-flubo-5-methylphenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-fluoro-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-fluoro-phenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-fluoro-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,4-difluorophenyl) amide; (6- 2,5- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,5-difluorophenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3,4-difluorophenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) pi perazin-1-yl] pyridazine-3-carboxylic acid (2,3-difluorophenyl) amide; 6-4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,6-difluorophenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (7H-purin-6-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid pyrazin-2-ylamide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid indan-1-ylamide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (1 H-tetrazol-5-yl) -amide; 6- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2H- [1,2,4] triazol-3-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methyl-isoxazol-5-yl) -amide; 6- [4- (2-Trifluoromethylbenzoll) piperazin-1-yl] pyridazine-3-carboxylic acid (5-methyI-isoxazol-3-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (1 H-pyrazol-3-yl) amide; (5-methi 1-1 H-plrazol-3-yl) 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid amide; pyrimidin-2-ylamide 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid pyrazin-2-ylamide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-methyl-pyrimidin-2-yl) -amide; 6- (4- (2-Trif luoromethyl benzoyl) piperazin-1-yl] pyridyl-3-ca-phenyl acid (2-oxo-2, 3-dihydropyrimidin-4-yl) amide; 6- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazoline-3-carboxylic acid (6-oxo-1,6-dihydropyrimidin-2-yl) amide; (6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-OXO-1, 3-diazabicyclo [3.1.0] hex-3-en-4-yl) -amide; (5- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-oxo-4, 5-d- hydro-1 H -pyrazol-3-yl) -amide; [1, 3,4] thiadiazol-2-ylamide of 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid; thiazol-2-ylamide of 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid indan-5-ylamide; 6- [4- (2-Tpfluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid pyridin-2-ylamide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid pyridin-3-ylamide; 6- [4- (2-Trifluoromethylbenzoyl) pi perazi n-1-yl] pyridazine-3-carboxylic acid pyridin-4-ylamide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (6-oxo-1,6-dihydro [1,3,5] triazin-2-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-fluoro-pyridin-2-yl) -amide; 6- (4- (2-Trifluoromethylbenzoyl) p iperazi n-1 -i I] pyridazine-3-carboxylic acid (4-cyano-phenyl) amide; (2-cyano-phenyi) 6- [4- (2-Trifluoromethylbenzoyl) -piperazin-1-yl] pyridazine-3-carboxylic acid amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-cyano-phenyl) amide; 6- [4- (2-Trifluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-cyano-pyridin-2-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4,6-dimethylpyrimidin-2-yl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carboxylic acid (2-chloro-pyridin-4-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (1H-indol-6-yl) -amide; (1- H -indol-4-yl) 6- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carboxylic acid (1 H-indazoI-5-yl) amide; (1- H -indazol-6-yl) 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-methyl-thiazol-2-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carboxylic acid (5-methyl-thiazol-2-yl) -amide; 5- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5- [thioxo-4,5-dihydro-1H- [1,2,4] triazol-3-yl) -amide).; 6- [4- (2-Trofluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (1 H-benzoimidazol-2-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (6-methylpyridazin-3-yl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (6-methoxypyridazin-3-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-chloro-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-chloro-2-methylphenyl) -amide; (2- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-chloro-3-met lphenyi) acid amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,5-dichlorophenyl) amide; 6- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-chloro-5-methylphenyl) -amide.; 6- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclo-6-methylphenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-chloro-2-methylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-chloro-3-methylphenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-chloro-4-methylphenyl) amide; 6- [4- (2-Tpfluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-chloro-4-methylphenyl) -amide; (2- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclo-5-fluorophenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-chloro-2-fluorophenyl) -amide; 6- (4- (2-Trifluoromethylbenzoyl) pi perazi n-1-yl] pyridazine-3-carboxylic acid (2,5-difluorophenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,6-dichlorophenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-trifluoromethylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-trifluoromethylphenyl) amide; 6- (4- (2-Trifluoromethylbenzoyl) -piperazin-1-yl] pyridazine-3-carboxylic acid (3-trifluoromethylphenol); 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid phenylamine; (6-Chloro-2-methoxyphenyl) -6- [4- (2-Trifluoro-methyl-benzoyl-1-yl) -pyridin-3-carboxylic acid (5-cyclo-2-methoxyphenyl) -amide; (2,5-dimethoxyphenyl) amide of 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-chloro-4-methoxyphenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) -piperazin-1-yl] pyridazine-3-carboxylic acid (4-methoxyphenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-methoxyphenyl) amide; 6- [4- (2-Trifluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methoxyphenyl) -amide; 4- (. {6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carbonyl) amino) -benzoic acid methyl ester; 4- (. {6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carbonyl} amino) -benzoic acid; 2- (. {6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carbonyl] amino) -benzoic acid methyl ester; 2- (. {6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carbonyl} amino) -benzoic acid; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3,4-dichlorophenyl) amide; 1- [1- (4-Fluorophenyl) ethyl] -3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] -pyridazin-3-yl} urea.

EXAMPLE 33 MEASUREMENT OF THE ACTIVITY PE INHIBITION PE PESATURASA PE ESTEAROILP-CPA PE A CPMPUESTP PE TEST USING MICRPSPMAS PE HIGAPP PE RATPN The identification of the compounds of the invention as SCD inhibitors was easily achieved using SCD enzymes and the microsomal assay described in Brownie et al., PCT published patent application WO 01/62954.

Preparation of Mouse Liver Microsomes: Male ICR mice were sacrificed, with a low-fat, high-carbohydrate diet, under anesthesia with haloten light (15% in mineral oil) through exsanguination during periods of high enzyme activity. The livers were immediately rinsed with cold 9% NaCl solution, weighed and shredded with scissors. All procedures were carried out at 4 ° C, unless otherwise specified. The livers were homogenized in a solution (1: 3 w / v) containing 0.25M sucrose, 62 mM potassium pH buffer (pH 7.0), 0.15M KCl, 1.5 mM N-acetylcysteine, 5 mM MgCl2, and 0.1 mM EDTA using 4 traces of a Potter-Elvehjem tissue homogenizer. The homogenate was centrifuged at 10,400 x x portions for 20 minutes to eliminate the mitochondria and cell waste. The supernatant was filtered through a three layer gauze and centrifuged at 105,000 portions x g for 60 minutes. The microsomal pellet was slightly resuspended in the same homogenization solution with a small glass / teflon homogenate and stored at -70 ° C. The absence of mitochondrial contamination was evaluated enzymatically. The concentration of the protein was measured using bovine serum albumin as the standard.

Incubation of Mouse Liver Microsomes with Test Compounds: Reactions were initiated through the addition of 2 ml of microsomal protein in pre-incubator tubes containing 0.20 μCi of the substrate fatty acid (1-14C palmitic acid) at a concentration final 33.3 μM in 1.5 ml of homogenization solution, containing 42 mM NaF, 0.33 mM niacinamide, 1.6 mM ATP, 1.0 mM NADH, 0.1 mM coenzyme A and a concentration of 10 μN of the test compound. The tubes were vigorously vortexed and after 15 minutes incubation in a shaking water bath (37 ° C), the reactions were stopped and the fatty acids were analyzed. The fatty acids were analyzed as follows: The reaction mixture was saponified with 10% KOH to obtain free fatty acids that were also mutilated using BF3 in methanol. The methyl esters of the fatty acid were analyzed through high performance liquid chromatography (HPLC) using a Hewlett Packard 1090 Series II chromatograph, equipped with a diode test detector set at 205 nm, a radioisotope reactor (Model 171, Beckman, CA) with a solid scintillation cartridge (97% efficiency by 14C-detection) and a reverse phase ODS column (C-18) Beckman (250 mm x 4.6 mm id; particle size 5 μm) attached to a pre-column with a μBondapak C-18 insert (Beckman). The fatty acid methyl esters were separated with acetonitrile / water (95: 5 v: v) at a flow rate of 1 ml / minute and identified by comparison with authentic standards. Alternatively, the fatty acid methyl esters can be analyzed through capillary column gas chromatography (GC) or Thin Layer Chromatography (TLC). Those skilled in the art are aware of a variety of modifications to this assay that may be useful in measuring the inhibition of stearoyl-CoA desaturase activity in microsomes through the test compounds. Representative compounds of the invention showed activity as SCD inhibitors when tested in this assay. The activity was defined in terms of percent SCD enzyme activity remaining at the desired concentration of the test compound. All patents of E.U.A. publications of U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referred to 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 the specific embodiments of the invention have been described herein 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 (91)

1. A method for inhibiting human stearoyl-CoA (hSCD) desaturase activity comprising contacting a source of hSCD with a compound of formula (I): wherein: x and y are each independently 1, 2 or 3; W is -C (0) N (R1) -; -C (0) N [C (0) R1a] -, -N (R1) C (0) N (R1) - or -N (R1) C (0) -; V is -C (O) -, -C (S) -, or -C (R10) H; each R1 is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxyl; R1a is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl; 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, alkoxy of 1 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 12 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 from 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and wherein some or all of the rings may be fused with one another; R3 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, alkoxy of 1 to 12 carbon atoms. carbon, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkyl or ylkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms carbon, 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 from 2 to 4 rings, wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and some or all of the rings may be fused to one another; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N (R12) 2; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together with an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not forming an oxo group, while the rest of R6, R6a, R7, R7a, R8, R8a, R9, and R9a each is independently selected from hydrogen, or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a each it is independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; R10 is hydrogen or alkyl of 1 to 3 carbon atoms; each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable composition thereof or a prodrug thereof.

2. A method for treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of the formula (I): wherein: x and y are each independently 1, 2 or 3; W is -C (0) N (R1) -; -C (0) N [C (0) R1a] -, -N (R1) C (0) N (R1) - or -N (R1) C (0) -; V is -C (O) -, -C (S) -, or -C (R10) H; each R1 is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxyl; R1a is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl; 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, alkoxy of 1 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 12 carbon atoms, heterocyclic 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 from 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and wherein some or all of the rings may be fused with one another; R3 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, alkoxy of 1 to 12 carbon 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 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl from 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 from 2 to 4 rings, wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and some or all of the rings may be fused to one another; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N (R12) 2; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together with an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not form an oxo group; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge; R10 is hydrogen or alkyl of 1 to 3 carbon atoms; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable composition thereof or a prodrug thereof.

3. The method according to claim 2, wherein the mammal is a human being.

The method according to claim 3, wherein the disease or condition is selected from the group consisting of Type II diabetes, impaired glucose tolerance, insulin resistance, obesity, fatty liver, non-alcoholic steatohepatitis, dyslipidemia and syndrome metabolic and any combination of these.

5. The method according to claim 4, wherein the disease or condition is Type II diabetes.

6. The method according to claim 4, wherein the disease or condition is obesity.

The method according to claim 4, wherein the disease or condition is metabolic syndrome.

The method according to claim 4, wherein the disease or condition is fatty liver.

The method according to claim 4, wherein the disease or condition is non-alcoholic steatohepatitis.

10. A compound of the formula (II): wherein: x and y are each independently 1, 2 or 3; W is -C (0) N (R1) - and -N (R1) C (0) -; each R1 is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxy; R2 is selected from the group consisting of alkyl of 7 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 7 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 atoms carbon, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aralkyl of 13 to 19 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, and heteroarylalkyl of 3 to 12 carbon atoms; or R2 is a multi-ring structure having from 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclic, aryl and heteroaryl and wherein some or all of the rings may be fused with one another; R3 is selected from the group consisting of alkyl of 3 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 3 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 carbon atoms, alkoxy of 3 to 12 carbon atoms. carbon, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl from 3 to 12 carbon atoms, heteroaryl of 5 to 12 carbon atoms and heteroarylalkyl of 3 to 12 carbon atoms; or R3 is a multi-ring structure having from 2 to 4 rings, wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl ,. aryl and heteroaryl and some or all of the rings may be fused with one another; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together are an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not forming an oxo group, while the rest of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen, or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are selected each independently of hydrogen, or alkyl of 1 to 3 carbon atoms; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable composition thereof or a prodrug thereof.

11. The compound according to claim 10 wherein: X and y are each 1; W is selected from -C (0) N (R1) - and -N (R1) C (0) -; each R1 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; R2 is selected from the group consisting of alkyl of 7 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 7 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 atoms carbon, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aralkyl of 13 to 19 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, and heteroarylalkyl of 3 to 12 carbon atoms; each R2 is optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) OR11, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; R3 is selected from the group consisting of alkyl of 3 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 3 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 carbon atoms, alkoxy of 3 to 12 atoms of carbon, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aralkyl of 7 to 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, heteroaryl of 5 to 12 carbon atoms and heteroarylalkyl of 3 to 12 carbon atoms; each R3 is optionally substituted by one or more substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms carbon, alkylsufonyl of 1 to 6 carbon atoms, halogen, cyano, nitro, hydroxy, -N (R12) 2, -C (0) OR11, -S (0) 2N (R12) 2, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl and heteroarylcycloalkyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8a, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl or aralkyl; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

12. The compound according to claim 11 wherein: W is -N (R1) C (0) -; R1 is hydrogen; R2 is cycloalkylalkyl of 4 to 12 carbon atoms; R3 is alkyl of 3 to 12 carbon atoms or alkenyl of 3 to 12 carbon atoms, each optionally substituted with one or more halogen groups; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8a, R8a, R9, and R9a are each hydrogen.

The compound according to claim 12 selected from the group consisting of the following: 6- [4- (2-Ethylbutyryl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyl-ethyl) amide; 6- [4- (3,3,3-Trifluoro-2-methyl-2-trifluoromethylpropionyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide; 6- [4- (2,2-Dimethylpropionyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; (2- cyclopropylethyl) amide of 6- [4- (2,2-Dimethyl-butyryl) piperazin-1-yl] pyridazine-3-carboxylic acid; 6- (4- (2,2-Dimethyl-pentazinyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropllethyl) amide; 6- [4- (4,4,4-Trifluorobut-2-enoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; and 6- (4- (4,4,4-Trifluoro-3-trifluoromethylbut-2-eneyl) -piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyl-ethyl) -amide.

14. The compound according to claim 11 wherein: W is -N (R1) C (0) -; R1 is hydrogen; R2 is cycloalkylalkyl of 4 to 12 carbon atoms; R3 is cycloalkyl of 3 to 12 carbon atoms optionally substituted with one or more substituents selected from hydroxy, trihaloalkyl of 1 to 6 carbon atoms or aralkyl of 1 to 6 carbon atoms; R4 and R are each hydrogen; and R6, R6a, R7 R7a, R8, R8a, R9, and R9a are each hydrogen.

15. The compound according to claim 14 selected from the group consisting of the following: 6- [4- (1-hydroxycyclopropanecarbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; n. 6- (4-Cyclobutanecarbonylpiperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- (4- (2-tri-fluoro-methylcloclopropanedcarbonyl) piperazin-1-yl] -pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- (4-Cyclohexanecarbonylpiperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (2-Methylcyclohexanecarbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (3-Methylcyclohexanecarbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (4-Methylcyclohexanecarbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (2-Methylcyclopropancarbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; and 6- (4- (2, 2,3,3-tetramethylcyclopropancarbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide.

16. The compound according to claim 11 wherein: W is -N (R1) C (0) -; R2 is cycloalkylalkyl of 4 to 12 carbon atoms and R3 is hydroxyalkyl of 3 to 12 carbon atoms optionally substituted with one or more halogen groups; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8a, R8a, R9, and R9a are each hydrogen.

The compound according to claim 16 selected from the following: 6- [4- (4,4,4-trifluoro-3-hydroxy-3-trifluoromethylbutyryl) plperazin-1-yl (2-cyclopropylethyl) -amide ] pyridazine-3-carboxylic acid; 6- [4- (4,4,4-Trifluoro-3-hydroxy-3-methylbutyryl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; and 6- (4- (3,3,3-trifluoro-2-hydroxy-2-methylpropionyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyloethyl) amide.

18. The compound according to claim 11 wherein: W is -N (R1) C (0) -; R1 is hydrogen; R2 is cycloalkylalkyl of 4 to 12 carbon atoms; R3 is alkoxy of 3 to 12 carbon atoms; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8a, R8a, R9, and R9a are each hydrogen.

19. The compound according to claim 18 selected from the group consisting of the following: 4- [6- (3-methylbutylcarbamoyl) pyridazin-3-yl] piperazine-1-carboxylic acid tert-butyl ester; and 4- [6- (2-Cyclopropylethylcarbamoyl) -pyridazin-3-yl] piperazine-1-carboxylic acid tert-butyl ester.

20. The compound according to claim 11 wherein: W is -N (R1) C (0) -; R1 is hydrogen; R2 is cycloalkylalkyl of 4 to 12 carbon atoms; R3 is aralkyl of 7 to 12 carbon atoms optionally substituted with one or more substituents independently selected from halogen or trihaloalkyl of 1 to 6 carbon atoms; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8a, R8a, R9, and R9a are each hydrogen.

21. The compound according to claim 20, especially, 6- (2-cyclopropylethyl) -amide. { 4- [2- (2-trifluoromethylphenyl) acetyl] piperazin-1-I} pyridazin-3-carboxylic acid.

22. The compound according to claim 11 wherein: W is -N (R1) C (0) -; R1 is hydrogen; R2 is cycloalkylalkyl of 4 to 12 carbon atoms; R3 is heterocyclyl of 3 to 12 carbon atoms or heteroaryl of 5 to 12 carbon atoms, each optionally substituted with one or more substituents independently selected from halogen, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms or aralkyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R3a, R8a, R9, and R9a are each hydrogen.

23. The compound according to claim 22 selected from the group consisting of the following: 6- [4- (pyridine-2-carbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) -amide.; 6- [4- (2-Trifluoromethyl-furan-3-carbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (2-Chloro-4-trifluoromethylpyrimidin-5-carbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (5-Methyl-2-trifluoromethyl-furan-3-carbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (2-Chloropyridine-3-carbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (2-Methyl-5-trifluoromethyloxazole-4-carbonyl) piperazin-1-yl] -pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- (4- (2,6-Dichloropyridine-3-carbonyl) piperazi- n-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide; 6- [4- (Pyrrolidin-1-carbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (1-Methyl-1 H -pyrrol-2-carbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; and 6- (4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide.

24. A method for treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 10.

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to claim 10.

26. A compound of the formula (III): wherein: x and y are each independently 1,2 or 3; A is oxygen or sulfur; W is selected from C (0) N (R1) - and -N (R1) C (0) -; each R1 is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxy; 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, alkoxy of 1 to 6 atoms carbon, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 12 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 from 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein some or all of the rings may be fused to one another; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylphosphonium of 1 to 6 carbon atoms, -N (R11) 2, -OC (0) R11, -C (0) OR1 \ -S (0) 2N (R11) 2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl, provided that R3 is not phenyl substituted with optionally substituted thienyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; R6, R6a, R7, R7a, R8a, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together are an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not form an oxo group, while the rest of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, R6a, R7, R7a, R, R, R, and R are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; and each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

27. The compound according to claim 26 wherein: x and y are each 1; A is oxygen or sulfur; W is selected from -C (0) N (R1) - and -N (R1) C (0) -; each R is independently selected from hydrogen or alkyl of 1 to 6 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, alkoxy of 1 to 6 atoms carbon, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms carbon, heterocyclylalkyl of 3 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms and heteroarylalkyl of 3 to 12 carbon atoms; each R2 is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) R1, -OC (0) R11, -C (0) OR 11, -C (0) N (R 12) 2, -N (R 12) 2, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, N (R1); -OC (O) R 11 -C (0) OR 11 S (0) 2N (R? A cycloalkyl, heterocyclyl and heteroarylcycloalkyl; R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms: Rd, R6a, R7, R7a, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms, or R6 and R6a together or R9 and R9a together are an oxo group, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms, each R11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl; R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms

28. The compound according to claim 1 n 27 where: x and y are each 1; A is oxygen or sulfur; W is -N (R1) C (0) -; R1 is hydrogen, methyl or ethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms.

29. The compound according to claim 28 wherein: R2 is cycloalkylalkyl of 4 to 12 carbon atoms optionally substituted by one or more substituents selected from the group consisting of -OR11, alkyl of 1 to 3 carbon atoms or aryl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R11, -C (0) OR11, -S (0) 2N (R12) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl, and each R 12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

30. The compound according to claim 29 selected from the group consisting of the following: 6- (4-benzoyl-piperazin-1-yl) -pyridazine-3-carboxylic acid (2-cyclopropylethyl) -amide; 6- [4- (2-Chloro-5-fluorobenzoyl) piperazin-1-yl] pyridazin-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (5-Chloro-2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropllethyl) amide; 6- [4- (2,6-Difluorobenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- (4- (2,5-bis-trifluoromethylbenzoyl) piperazin-1-yl (2-cyclopropyl ethyl) amide} pyridazin-3-carboxylic acid; 6- [4- (2,4-Bis-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- (4- (2,5-difluorobenzoyl) piperazi- n-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- (4- (5-Fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide; 6- [4- (2-Fluorobenzoyl) piperazin-1-yl] pyridazin-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (3-Fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (4-Fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-methylcyclopropylmethyl) -iiaiide; 6- [4- (5-Fluoro-2-methoxybenzoyl) plperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (2-Dimethylaminobenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (2-Chloro-5-dimethylaminobenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- (4- (2,5-dimethyl-benzoyl) piperazi- n-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- (4- (2,5-Dichlorobenzoyl) pi perazi n-1 -i I] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) pip'erazin-1-yl] pyridazine-3-carboxylic acid cyclobutyl methyl amide; Ester 2-4- [6- (2-cyclopropylethylcarbamoyl) -pyridazin-3-yl] piperazine-1-carbonyl} phenylacetic acid; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl-pyridazine-3-carboxylic acid (2-phenylcyclopropylmethyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide; 6- [4- (2-Cyanobenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; (2-cyclopropylethyl) acid amide 6-. { 4- [2- (2-trifluoro methyl n-nyl) acetyl] piperazin-1-yl} pyridazine-3-carboxylic acid; 6- [4- (4-fIuoro-2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- (4- (5-Chloro-2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide; 6- (3,5-Dimethyl-4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; Methyl ester of acid 2-. { 4- [6- (2-Cyclopropylethylcarbamoyl) pyridazin-3-yl] piperazine-1-carbonyl} benzoic; 6- [4- (2-Trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (2-cyclobutyl-ethyl) -amide; 2- acid. { 4- [6- (2-Cyclopropyl-ethylcarbamoyl) -pyridazin-3-yl] -piperazine-1-carbonyl} -benzoic; (2- (4- (5-Chloro-2-trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (2-cyclobutyl-ethyl) -amide; 6- [4- (5-Fluoro-2-trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (2-cyclobutyl-ethyl) -amide; 3- (4- (2-Trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (3-cyclobutyl-propyl) -amide; 6- [4- (5-Fluoro-2-trifluoromethyl-benzoyl) - [1,4] diazepan-1-yl] -pyridazine-3-carboxylic acid (2-cyclopropyl-ethyl) -amide; 6- (4- (2-trifluoromethyl-thiobenzoyl) -p i -petran-1-yl] -pyr-dazin-3-carboxylic acid (2-cyclopropyl-ethyl) -amide; 6- [4- (2-Trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (4-cyclopropyl-butyl) -amide; and 6- (4- (2-trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (2,2-dimethyl-cyclopropylmethyl) -amide.

31. The compound according to claim 28 wherein: A is oxygen; R2 is alkyl of 1 to 12 carbon atoms or alkenyl of 2 to 12 carbon atoms, each optionally substituted by one or more substituents selected from the group consisting of halogen, aryloxy, -C (0) R11, -OC (0) R11 or -C (0) OR11; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R11, -C (0) OR11, -S (0) 2N (R12) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

32. The compound according to claim 31 selected from the group consisting of the following: 6- (4- (2-nitrobenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methylbutyl) amide; 6- [4- (2-Chlorobenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methylbutyl) -amide; 6- [4- (2,4-Dichlorobenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methylbutyl) -amide; 6- [4- (2-Aminobenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methylbutyl) -amide; [2- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazoline-3-carboxylic acid [2- (4-cycloophenoxy) ethyl] amide; [2- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid [2- (4-fluorophenoxy) ethyl] amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3,3-dimethylbutyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carboxylic acid phenylamide; Ethyl 4- (. {6- [4- (2-trifluoromethylbenzoyl) p-perazin-1-yl] pyridazin-3-carbonyl) amino) butyric acid ethyl ester; 6- [4- (5-Fluoro-2-trifluoromethylbenzoyl) piperazi n-1-yl] pyridazine-3-carboxylic acid phenylamide; 6- (4- (2-trifluoromethylbenzoyl) p i perazi n-1 -i I] pyridazine-3-carboxylic acid (4-methylpentyl) -amide; 6- [4- (2-Fluoro-6-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methylbutyl) -amide; 6- [4- (2,6-difluorobenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methylbutyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-oxo-2-phenylethyl) -amide; 1, 1-Dimethyl-3- (. {6- [4 - (2-tri-fluoro-ethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carbonyl} -amino) -propyl acetic acid ester; (2- (4- (2-trifluoromethylbenzoll) piperazin-1-yl] pyridazine-3-carboxylic acid (2-phenoxyethyl) -amide; 6- [4 ~ (2-Trifluoromethylbenzoyl) piperazi n-1-yl] pyridazine-3-carboxylic acid hexyl amide; (4- methylpentyl) 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid amide; 6- (4- (5-Fluoro-2-trifluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-methylpentyl) -amide; 6- [2,5-dimethyl-4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid pentilamide; 6- [4- (2-trifluoromethyl-1-benzoyl) -piperazin-1-yl] -pyridi-3-carboxylic acid heptylamide; 6- [4- (2-Sulfamoyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (3-methyl-butyl) -amide; 6- [4- (5-Chloro-2-trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid hexylamide; 6- [4- (2-Trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (2-cyclopropyl-2-oxo-ethyl) -amide; 4-Trifluoromethyl-6- [4- (2-trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (3-methyI-butyl) -amide; and 6- [4- (5-Fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid pentyl-4-enylamide.

33. The compound according to claim 28 wherein: A is oxygen; R2 is hydroxyalkyl of 2 to 12 carbon atoms, hydroxyalkenyl of 2 to 12 carbon atoms, each optionally substituted by one or more halogen groups; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R11, -C (0) OR11, -S (0) 2N (R 2) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

34. The compound according to claim 33 selected from the group consisting of the following: 6- [4- (2-trifluoromethylbenzoyl) piperazi- n-1-yl] pyridazine-3-carboxylic acid (4-hydroxybutyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-hydroxy-4,4-dimethyIpentyl) acid amide; 6- [4- (2-Trifluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-hydroxy-3-methylbutyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl) -amide; and 6- (4- (5-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl) -amide.

35. The compound according to claim 28 wherein: A is oxygen; R2 is aralkyl of 7 to 12 carbon atoms, wherein the aryl part of the aralkyl of 7 to 12 carbon atoms group is optionally substituted by one or more substituents independently selected from halogen, alkyl of 1 to 3 carbon atoms, -OR11 , -C (0) OR11, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl and aryl, and the alkyl part of the aralkyl group of 7 to 12 carbon atoms group is optionally substituted by one or more substituents independently selected from halogen, -OR11 and -OC (0) R11; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R 12) 2, -OC (0) R 11, -C (0) OR 11, -S (0) 2 N (R 2) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

36. The compound according to claim 35 selected from the group consisting of the following: 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] 2- (2,4-fluorophenyl) ethyl] amide] pyridazine-3-carboxylic acid; [2- (2-trifluoromethylbenzoyl) pi perazin-1-yl] pyridazine-3-carboxylic acid [2- (2-fluorophenyl) ethyl] amide.; [6- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid [2- (4-chlorophenyl) ethyl] amide; [2- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid [2- (3-cyclophenyl) ethyl] amide]; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-phenylpropyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-biphenyl-4-ylethyl) -amide; (R) -6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) -amide; (S) -6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) -amide; 1-Phenyl-2- (. {6- [4- (2-trifluoromethyl-benzoyl) -piperazin-1-yl] pyridazine-3-carbonyl} -amino) ethyl ester of acetic acid; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid [3- (4-fluorophenyl) propyl] -amide; 6- [4- (2-Trifluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,2-difluoro-2-phenylethyl) -amide; and 6- [4- (2-trifluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid [2- (3-fluorophenyl) -2-hydroxyethyl] -amide.

37. The compound according to claim 28 wherein: A is oxygen; R 2 is akoxy of 1 to 6 carbon atoms or alkoxyalkyl of 3 to 12 carbon atoms, each optionally substituted with one or more substituents independently selected from halogen or cycloalkyl of 3 to 6 carbon atoms; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -0C (0) R1? (0) OR11, -S (0) 2N (R12) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

38. The compound according to claim 37 selected from the group consisting of the following: 6- [4- (2-trifluoromethylbenzoyl) pi perazi n-1-yl] pyridazine-3-carboxylic acid (2-ethoxyethyl) amide.; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-methoxy-3,3-dimethylbutyl) -amide; and 2- (2-Cyclopropyl-ethoxy) -N-. { 6- [4- (2-trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazin-3-yl} -acetamide.

39. The compound according to claim 28 wherein: A is oxygen; R2 is aryl optionally substituted with one or more substituents independently selected from halogen, cyano, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) R11, -OC (O) R11, -C (0) OR11, -C (0) N (R12) 2, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; R3 is phenyl optionally substituted by trihaloalkyl of 1 to 6 carbon atoms or trihaloalkoxy of 1 to 6 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

40. The compound according to claim 39 selected from the group consisting of the following: 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-chloro-phenyl) -amide; 6- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-carbamoyl-phenyl) amide; 6- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-carbamoyl-phenyl) amide; 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid m-tolylamide; 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid p-tolylamide; 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid o-tolylamide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-propylphenyl) amide; 6- (4- (2-trifluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-propylphenyl) amide; 6- (4- (2-t-fluoro-met-l-benzoyl) -piperazin-1-yl] -pyridinyl-3-carboxylic acid (4-isopropylphenyl) amide, 6- (4-isopropylphenyl) -amide - (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid; (2- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-chloro-phenyl) acid; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyano-3-fluorophenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,4-dimethyl-phenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,5-dimethyl-phenyl) -amide; (2,6-Dimethyl-phenyl) -amide of 6- [4- (2-trifluoromethyl-benzoyl) -pyridin-1-pyridazine-3-carboxylic acid; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,3-dimethyl-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3,5-dimethyl-phenyl) amide; 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3,4-dimethyl-phenyl) amide; (4-ethylene glycol) amide of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid; (2- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-ethyl-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-fluoro-2-methylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carboxylic acid (2-fluoro-4-methylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-fluoro-2-methylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-fluoro-5-methylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-fluoro-5-methylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-fluoro-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-f! Uoro-phenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-fluoro-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,4-difluoro-phenyl) -amide; 6- (4- (2-trifluoromethylbenzoyl) pipe razin-1-yl] pyridyl-3-carboxylic acid (2,5-difluoro-phenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3,4-difluoro-phenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,3-difluoro-phenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,6-difluoro-phenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-cyano-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyano-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-cyano-phenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-chloro-phenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-chloro-2-methylphenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-chloro-3-methylphenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,5-dichlorophenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-chloro-5-methylphenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-chloro-6-methylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-chloro-2-methylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-chloro-3-methylphenyl) -amide; (3- Chloro-4-methylphenyl) amide of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid; (2- (4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-c) -olamyl-4-methylphenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carboxylic acid (2-chloro-5-fluorophenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-chloro-2-fluorophenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,5-difluorophenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,6-dichlorophenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-trifluoromethylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-trifluoromethylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-trifluoromethylphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid phenylamine; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-chloro-2-methoxyphenyl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2,5-dimethoxyphenyl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-chloro-4-methoxyphenyl) -amide; 6- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-methoxy-phenyl) -amide.; (2-methoxy-phenyl) -6- [4- (2-trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methoxyphenyl) amide; 4- (. {6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carbonyl} -amino) -benzoic acid methyl ester; 4- (. {6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carbonyl} amino) -benzoic acid; 2- (. {6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carbonylamino) -benzoic acid methyl ester; 2- (. {6- [4- (2-Trifluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carbonyl} amino) -benzoic acid; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3,4-dichlorophenyl) amide.

41. The compound according to claim 28 wherein:. A is oxygen; R2 is heteroaryl of 1 to 12 carbon atoms optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) R11, -OC (0) R11, -C (0) OR11, -C (0) N (R12) 2 and trihaloalkyl of 1 to 6 carbon atoms; R3 is phenyl optionally substituted by trihaloalkyl of 1 to 6 carbon atoms or trihaloalkoxy of 1 to 6 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R 2 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

42. The compound according to claim 41, wherein heteroaryl of 1 to 12 carbon atoms is selected from the group consisting of pyridinyl, purinyl, pyrazinyl, indolyl, indazolyl, benzoimidazolyl, imidazolyl, tetrazolyl, triazolyl, isoxazolyl, pyrazolyl, pyrimidinyl, thiadiazolyl, thiazolyl and pyridazinyl.

43. The compound according to claim 42 selected from the group consisting of the following: 6- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin (5-chloro-pyridin-2-yl) -amide) -3-carboxylic acid; (5- trifluoromethylpyridin-2-yl) 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carboxylic acid amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (7H-purin-6-yl) -amide; 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid pyrazin-2-ylamide; 6- [4- (2-Trifluoromethyl enzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (1H-tetrazol-5-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2H- [1,2,4] triazol-3-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methyl-isoxazol-5-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-methyl-isoxazol-3-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (1 H-pyrazol-3-yl) amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-methyl-1 H -pyrazol-3-yl) -amide; pyrimidin-2-ylamide of 6- [4- (2-trifluoromethyl-benzoyl) -piperazin-1-yl] pyridaz-n-3-carboxylic acid; 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carboxylic acid pyrazin-2-ylamide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-methyl-pyrimidin-2-yl) -amide; 6- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-oxo-2,3-dihydro-pyrimidin-4-yl) (6-oxo-1,6) 6- [4- (2-trifluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid dihydro-pyrimidin-2-yl) amide; [1, 3,4] thiadiazol-2-ylamide 6- [4- (2-trifluoromethyl] -benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid; thiazol-2-ylamide of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid; 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl] pyridazine-3-carboxylic acid pyridin-2-ylamide 6- [4- (2-trifluoromethyl-benzoyl) -piperazine-1-pyridin-3-ylamide -yl] pyridazine-3-carboxylic acid; 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl] pyridazine-3-carboxylic acid pyridin-3-ylamide; 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl] pyridazine-3-carboxylic acid pyridin-4-ylamide; 6 - [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (6-oxo-1,6-dihydro- [1, 3, 5] triazin-2-yl) acid amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-fluoro-pyridin-2-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-cyano-pyridin-2-yl) -amide; 6- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4,6-dimethyl-pyrimidin-2-yl) -amide, (2-chloro-pyridin-4-yl) ) - 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid amide; (1- H -indol-6-yl) -amide of 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl] pyridazine-3-carboxylic acid; (1- H -indol-4-yl) -amide of 6- [4- (2-trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid; (1- H -indazol-5-yl) -amino acid 6- [4- (2-t-trifluoromethylbenzoyl) -piperazin-1-yl] pyridazine-3-carboxylic acid; (1 H-indazol-6-yl) -amide of 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl] pyridazine-3-carboxylic acid; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (4-methyl-thiazol-2-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (5-methyl-thiazoI-2-yl) -amide; (5-thioxo-4,5-dihydro-1 H- [1, 2,4] triazol-3-yl) -amide of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine- 3- carboxylic; (1- H- benzoimidazol-2-yl) -amide of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid; 6- [4- (2-Trifluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (6-methy1-pyridazin-3-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (6-methoxypyridazin-3-yl) -amide; and 6- (4- (2-trifluoromethylbenzoii) piperazin-1-yl] pyridazine-3-carboxylic acid (6-chloro-pyridazin-3-yl) -amide.

44. The compound according to claim 28 wherein: A is oxygen; R 2 is heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms or heteroarylalkyl of 3 to 12 carbon atoms, each optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) R11, -OC (0) R11, -C (0) OR11, -C (0) N (R12) 2 and trihaloalkyl of 1 to 6 carbon atoms; R3 is phenyl optionally substituted by halogen, trihaloalkyl of 1 to 6 carbon atoms or trihaloalkoxy of 1 to 6 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

45. The compound according to claim 44 selected from the group consisting of the following: 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] -pyridazine-3-carboxylic acid indan-1-ylamide; (2-oxo-1,3-diaza-bicyclo [3.1.0] hex-3-en-4-yl) 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] -pyridazine 3-carboxylic; (5- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] -pyridazine-3-carboxylic acid (5-oxo-4, 5-d-hydrohydro-1 H-pyrazol-3-yl) -amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] -pyridazine-3-carboxylic acid indan-5-ylamide; . { 6- [4- (2-trifluoromethylbenzoyl) -1-i!] - pyridazin-3-yl} - 5- [1,2] difiolan-3-yl-pentanoic acid amide; 6- [4- (2-Trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (2-thiophen-2-yl-ethyl) -amide; (2- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-benzo [1,3] dioxol-5-yl-ethyl) -amide; 6- (4- (2-trifluoromethy-I-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (2,2-difluoro-2-pyridin-2-ylethyl) -amide; 6- (4- (2-Trifluoromethyl-benzoyl) -piperazin-1-yl] -pyridazine-3-carboxylic acid (2-pyridin-2-ylethyl) -amide; and (pyridin-2-yl-methyl-1-methylamide) - [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid.

46. The compound according to claim 27 wherein: x and y are each 1; A is oxygen; W is -C (0) N (R1) -; R1 is hydrogen, methyl or ethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms.

47. The compound according to claim 46 wherein: R2 is cycloalkyl of 3 to 12 carbon atoms or cycloalkylalkyl of 4 to 12 carbon atoms, each optionally substituted by one or more substituents selected from the group consisting of -OR11, alkyl of 1 to 3 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms or aryl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms and trihaloalkoxy of 1 to 6 carbon atoms; and each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl.

48. The compound according to claim 47 selected from the group consisting of the following: 4-Cyclohexyl-N-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} Butyramide; . { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} 2,2,3,3-tetramethylcyclopropylcarboxylic acid amide; . { 6- [4- (2-trifluoromethyl-benzoyl) piperazin-1-yl] pyridazin-3-yl} cyclopropanecarboxylic acid amide; . { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} 1-trifluoromethylcyclopropanecarboxylic acid amide; Y . { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} 2-phenylcyclopropanecarboxylic acid amide.

49. The compound according to claim 46 wherein: R2 is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkoxy of 1 to 6 carbon atoms or alkoxyalkyl of 3 to 12 carbon atoms , each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR, -C (0) R11, -OC ( 0) R11, -C (0) OR11, -C (0) N (R12) 2, -N (R12) 2, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl and aryl; R3 is phenyl optionally substituted by halogen, trihaloalkyl of 1 to 6 carbon atoms or trihaloalkoxy of 1 to 6 carbon atoms; each R 1 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R 2 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

50. The compound according to claim 49 selected from the group consisting of the following: 2-Benzyloxy-N-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} acetamide; 2-Ethoxy-N-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} acetamide; 2-Cyclopropylmethoxy-N-. { 6- [4- (2-tri-fluoro-methylbenzoyl) -piperazin-1-yl] -pyridazin-3-yl} acetamide; 2- (2-Methoxyethoxy) -N-. { 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl] pyrid azin-3-i 1.}. acetamide; N-. { 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} -2- (3,3,3-trifluoropropoxy) acetamide; 3-Methoxy-N-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} propionamide; 3-Phenoxy-N-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] -pyridazin-3-yl} propionamide; 2-Butoxy-N-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} acetamide; 2-Methyl-1-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-ylcarbamoyl} propylamine; 2-Phenoxy-N-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] -pyridazin-3-yl} acetamide; Acid butyl ester. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} carbamic Propyl ester of acid. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} carbamic Isobutyl ester of acid. { 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl] pyridazin-3-yl} carbamic Ethyl ester of acid. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} carbamic . { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] -pyridazin-3-yl} hexanoic acid amide; 4-Fluoro-N-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] -pyridazin-3-yl} benzamide; Ester d imetilbutí! ico of acid. { 6- [4- (2-tpfluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} carbamic and Cyclopropylethyl ester of acid. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} carbamic

51. The compound according to claim 46 wherein: R2 is aralkyl of 7 to 12 carbon atoms optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) R11, -OC (0) R11, -C (0) OR11, -C (0) N (R12) 2, -N (R12) 2, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl and aryl; R3 is phenyl optionally substituted by halogen, trihaloalkyl of 1 to 6 carbon atoms or trihaloalkoxy of 1 to 6 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl or aryl (optionally substituted with one or more halogen groups); and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

52. The compound according to claim 51 selected from the group consisting of the following: 4- (4-Methoxyphenyl) -N-. { 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl] pyridazin-3-yl} Butyramide; and 3 - (4- Fluorofenyl) -N-. { 6- [4- (2-trif luoromethyl benzoyl) -piperazin-1-yl] -pyridazin-3-yl} propionamide

53. The compound according to claim 29 wherein: x and y are each 1; A is oxygen; W is -N (R1) C (0) -; R1 is hydrogen, methyl or ethyl; R2 is cyclopropylethyl or cyclopropylmethyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloride and trifluoromethyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen.

54. The compound according to claim 53 selected from the group consisting of the following: 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-carboxylic acid (2-cyclopropylethyl) -amide.; 6- [4- (5-Fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; and Cyclopropylmethylamide of 6- [4- (2-trifluoromethylbenzoyl) pipe razin-1-yl] pyridazin-3-carboxylic acid.

55. The compound according to claim 31 wherein: x and y are each 1; A is oxygen; W is -N (R1) C (0) -; R1 is hydrogen, methyl or ethyl; R2 is alkyl of 1 to 6 carbon atoms optionally substituted by -C (0) OR11; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; R4 and R5 are each hydrogen; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen; and R 1 is hydrogen, methyl, ethyl or 1,1-dimethylethyl.

56. The compound according to claim 55 selected from the group consisting of the following: methyl ester of 4-methyl-2- (. {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] - pyridazine-3-carbonyl.} amino) pentanoic; 6- [4- (2-Trifluoromethylbenzoyl) pipe razin-1-yl] pyridazine-3-carboxylic acid (3-methylbutyl) -amide; 6- [4- (5-Fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methylbutyl) -amide; 6- [4- (4-Fluoro-2-trifluoromethyl-benzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-methylbutyl) -amide; and 4-Methyl-2- (. {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carbonyl} amino) pentanoic acid.

57. The compound according to claim 35 wherein: x and y are each 1; A is oxygen; W is -N (R1) C (0) -; R1 is hydrogen, methyl or ethyl; R2 is 2-phenylethyl or 3-phenyl Ipropi wherein the phenyl group is optionally substituted by one or more substituents independently selected from chloro, fluoro or -OR11; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloride and trifluoromethyl; R4 and R5 are each hydrogen; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen; and R 1 is hydrogen, methyl, ethyl or 1,1-dimethylethyl.

58. The compound according to claim 57 selected from the group consisting of the following: 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid phenethylamide; [2- (4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid [2- (4-methoxyphenyl) ethyl] amide; 6- [4- (2-Trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid [2- (3-fluorophenyl) ethyl] amide; 6- [4- (2-Trifluoromethylbenzoyl) -piperazin-1-yl] pyridazine-3-carboxylic acid (3-phenylpropyl) amide; and 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazine-3-carboxylic acid [2- (4-fluorophenyl) ethyl] amide.

59. The compound according to claim 47 wherein: x and y are each 1; A is oxygen; W is -C (0) N (R1) -; R1 is hydrogen, methyl or ethyl; R2 is cyclopropylethyl, cyclopropylmethyl or cyclopentylethyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloride and trifluoromethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen.

60. The compound according to claim 59, in particular, 3-Cyclopentyl-N-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} propionamide

61. The compound according to claim 49 wherein: x and y are each 1; A is oxygen; W is -C (0) N (R1) -; R is hydrogen, methyl or ethyl; R2 is alkyl of 1 to 6 carbon atoms; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloride and trifluoromethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen.

62. The compound according to claim 61, mainly. { 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl] pyridazin-3-yl] amide 4-methylpentanoic acid.

63. The compound according to claim 51 wherein: x and y are each 1; A is oxygen; W is -C (0) N (R1) -; R1 is hydrogen, methyl or ethyl; R2 is 3-phenylpropl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloride and trifluoromethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen

64. The compound according to claim 63, mainly 4-phenyl-N-. { 6- [4- (2-trifluoromethyl benzoyl) piperazi n-1 -yl] -pyridazin-3-yl} Butyramide

65. A method for treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 26.

66. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to claim 26.

67. A compound of the formula (IV): wherein: x and y are each independently 1, 2 or 3; each R1 is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxy; 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, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, aryl, aralkyl of 7 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 from 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and wherein some or all of the rings may be fused to one another; R3 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, alkoxy of 1 to 12 carbon 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 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl from 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 from 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and wherein some or all of the rings may be fused with each other; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together are an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not they form an oxo group, while the rest of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each one independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

68. The compound according to claim 67 wherein: x and y are each 1; each R1 is hydrogen or alkyl of 1 to 6 carbon atoms; R2 is selected from the group consisting of alkyl of 3 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 3 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 carbon atoms, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl of 3 to 12 carbon atoms, aryl, aralkyl of 7 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms, and heteroarylalkyl of 3 to 12 carbon atoms; each R2 is optionally substituted by one or more substituents selected from the group consisting of halogen, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) OR11, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; R3 is selected from the group consisting of alkyl of 3 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, hydroxyalkyl of 3 to 12 carbon atoms, hydroxyalkenyl of 3 to 12 carbon atoms, alkoxy of 3 to 12 atoms carbon, alkoxyalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aralkyl of 7 to 12 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; wherein each of the above R3 groups is optionally substituted by one or more substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, trihaloalkyl of 3 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, halogen, cyano, nitro, hydroxy, -N (R12) 2, -C (0) OR11, -S (0) 2N (R12) 2 , cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together or R7 and R7a together are an oxo group while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each one independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms,

69. The compound according to claim 68 wherein: R2 is cycloalkyl of 3 to 12 carbon atoms or cycloalkylalkyl of 4 to 12 carbon atoms , each optionally substituted by one or more substituents selected from the group consisting of -OR11, alkyl of 1 to 3 carbon atoms or aryl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms and trihaloalkoxy of 1 to 6 carbon atoms; and each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl.

70. The compound according to claim 69 selected from the group consisting of the following: 1- (2-phenylcyclopropyl) -3-. { 6- [4- (2-trifluoromethyl] benzoyl) p i pera z in-l-yl] pyridazin-3-yl} urea; 1-Cyclopentyl-3-. { 6- [4- (2-trif luoromethyl benzoyl) piperazi n-1 -i I] -pyridazin-3-yl} urea; 1- (3-Cyclopropylpropyl) -3-. { 6- [4- (2-trifluoromethyl benzoyl) piperazin-1-yl] pyridazin-3-yl} urea; 1-Cyclopropylmethyl-3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} urea; 1- (2-Cyclopropylethyl) -3-. { 6- [4- (2-trifluoromethyl-benzoyl) piperazin-1-yl} pyridazin-3-il} urea; 1- (2-Cyclopropylethyl) -3-. { 6- [4- (2-Fluoro-6-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} urea; 1- (2-Cyclopropylethyl) -3-. { 6- [4- (5-Fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} urea; 1-Cyclohexyl-3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} urea; 1- (2-Cyclopropylethyl) -3-. { 6- [4- (2,6-difluorobenzoyl) piperazin-1-yl] pyridazin-3-yl} urea; and 1- (3-Cyclopropylpropi) -3-. { 6- [4- (5-Fluoro-2-trifluoromethyl-benzoyl) piperazin-1-yl] pyridazin-3-yl} urea.

71. The compound according to claim 68 wherein: R2 is aralkyl of 7 to 12 carbon atoms optionally substituted by one or more substituents selected from the group consisting of halogen, -OR11 or alkyl of 1 to 3 carbon atoms; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms and trihaloalkoxy of 1 to 6 carbon atoms; and each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl.

72. The compound according to claim 71 selected from the group consisting of the following: 1- [1-4 (-Fluorophen i I) eti I] 3-. { 6- [4- (2-trif luoromethyl benzoyl) -piperazin-1-yl] pyridazin-3-yl} urea; 1- [1- (4-Fluorophenyl) ethyl] -3-. { 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl] pyridazin-3-yl) urea; 1- (3- (4- Fluorophenyl) propyl] -3-. {6- [4- (2-trifluoro-methyl-benzoyl) -piperazin-1-yl] -pyridazin-3-yl} -urea; -Fenethyl-3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] -pyridazin-3-yl} urea; 1- (4-Fluorobenzyl) -3-. {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl.} Urea; and 1- (3,4-dichlorobenzyl) -3-. {6- [4- (2-trifluoromethylbenzoyl)] piperazin-1-yl] pyridazin-3-yl.} urea

73. The compound according to claim 68 wherein: R2 is aryl optionally substituted by one or more substituents selected from the group consisting of halogen, -OR11 or alkyl of 1 to 3 carbon atoms: R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms and trihaloalkoxy of 1 to 6 carbon atoms, and each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralk ilo

74. The compound according to claim 73 selected from the group consisting of the following: 1- (4-Fluorophenyl) -3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] -pyridazin-3-yl} urea; and 1- (2-FIuoprophenyl) -3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} urea.

75. The compound according to claim 68 wherein: R2 is alkyl of 3 to 12 carbon atoms, hydroxyalkyl of 3 to 12 carbon atoms or alkoxyalkyl of 3 to 12 carbon atoms, each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR11 or -C (O) OR11; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms and trihaloalkoxy of 1 to 6 carbon atoms; and each R1 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl.

76. The compound according to claim 75 selected from the group consisting of the following: 3- (3. {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] -pyridazine ethyl ester 3-yl.} Ureido) propionic; 1-Butyl-3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} urea; 1- (2-chloroethyl) -3-. { 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl] pyridazin-3-yl} urea; 1 -. { 6- [4- (2,6-D-fluorobenzoyl) piperazi n-1-il] p iri dazin-3-l} -3- (3-methylbutyl) urea; 1 - (3, 3-D i put I but i I) -3-. { 6- [4- (2-trif luoromethyl benzo I) piperazi n-1-1] pyridazin-3-yl} urea; 1- (2-lsopropoxyethyl) -3-. { 6- [4- (2-trifluoromethyl-benzoyl) -piperazin-1-yl] pyridazin-3-yl} urea; 1- (3-Hydroxy-4,4-dimethylpentyl) -3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} urea; 1-Hexyl-3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} urea; 1-Heptyl-3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3? } urea; and 1- (4-Methylpentyl) -3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} urea.

77. The compound according to claim 71 wherein: x and y are each 1; each R1 is hydrogen, methyl or ethyl; R2 is benzyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen.

78. The compound according to claim 77, mainly 1-Benzyl-3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl] pyridazin-3-yl} urea.

79. The compound according to claim 75 wherein: x and y are each 1; each R1 is hydrogen, methyl or ethyl; R2 is pentyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each hydrogen.

80. The compound according to claim 79, mainly 1-Pentyl-3-. { 6- [4- (2-trifluoromethylbenzoyl) piperazine-1-i I] p i r i d a z i n - 3 - i I} u r e a.

81. A method for treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 67.

82. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to claim 67.

83. A compound of the formula (Va): wherein: x and y are each independently 1, 2 or 3; W is -C (0) N (R1) -; -N (R1) C (0) N (R1) - or- N (R1) C (0) -; each RR is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxy; 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, alkoxy of 1 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, aralkyl of 13 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; R3 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, alkoxy of 1 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 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl from 3 to 12 carbon atoms, heteroaryl of 1 to 12 carbon atoms and heteroarylalkyl of 3 to 12 carbon atoms; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N (R12) 2; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together are an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not they form an oxo group, while the rest of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remainder of R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each one independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; R10 is hydrogen or alkyl of 1 to 3 carbon atoms; and each R12 is independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; provided, however, that R2 can not be pyrazinyl, pyridinonyl, pyrrolidinonyl or imidazolyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition or a prodrug thereof.

84. The compound according to claim 83 wherein: wherein: x and y are each independently 1; W is N (R1) C (0) -; each R1 is hydrogen or alkyl of 1 to 6 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, alkoxy of 1 to 12 atoms of carbon, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aralkyl of 13 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; each R2 is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, thioxo, alkyl of 1 to 3 carbon atoms, -OR11, -C (0) R11, -OC (0) R11, -C (0) OR11, -C (0) N (R12) 2, -N (R12) 2, trihaloalkyl of 1 to 6 carbon atoms, cycloalkyl, heterocyclyl, aryl, heteroaryl, and heteroarylcycloalkyl; R3 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, alkoxy of 1 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 12 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; each R3 is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R1? (0) OR11, -S (0) 2N (R12) 2, cycloalkyl, heterocyclyl and heteroarylcycloalkyl; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N (R12) 2; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; R10 is hydrogen or alkyl of 1 to 3 carbon atoms; and each R 11 is independently selected from hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

85. The compound according to claim 84 wherein: R 2 is cycloalkyl of 3 to 12 carbon atoms or cycloalkylalkyl of 4 to 12 carbon atoms, each optionally substituted by one or more substituents selected from the group consisting of halogen, trihaloalkyl of 1 to 6 carbon atoms, -OR, alkyl of 1 to 3 carbon atoms or aryl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, trihaloalkyl of 1 to 6 carbon atoms, trihaloalkoxy of 1 to 6 carbon atoms , alkylsulfonyl of 1 to 6 carbon atoms, -N (R12) 2, -OC (0) R11, -C (0) OR11, -S (0) 2N (R12) 2 and cycloalkyl; each R 11 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or aralkyl; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms.

86. The compound according to claim 85 selected from the group consisting of the following: 6- [4- (2-trifluoromethylbenzyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; (2-cyclopropylethi) 6- [4- (5-fluoro-2-trifluoromethylbenzyl) piperazin-1-yl] pyridazine-3-carboxylic acid amide; 6- [4- (4-Fluoro-2-trifluoromethylbenzyl) -piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (5-Chloro-2-trifluoromethylbenzyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- [4- (2-Chloro-4-fluorobenzyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; 6- (4- (2,5-Dichlorobenzyl) piperazi- n-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide; (2- (4- (2,4-Dichlorobenzyl) piperazin-1-yl] pyridazine-3-carboxylic acid (2-cyclopropylethyl) -amide; 6- [4- (5-fIuoro-2-trifluoromethylbenzyl) piperazin-1-yl] pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide; and 6- (2-cyclopropylethyl) -amide. { 4- [1- (2-trifluoromethylphenyl) ethyl] piperazin-1-yl} -pyridazine-3-carboxylic acid.

87. A method for treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 83.

88. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to claim 83.

89. A compound of the formula (Vb): wherein: x and y are each independently 1,2 or 3; W is -C (0) N (R1) -; -N (R1) C (0) N (R ') - O -N (R1) C (0) -; each R1 is independently selected from the group consisting of hydrogen; alkyl of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, methyl or trifluoromethyl; and alkyl of 2 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxy; 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, alkoxy of 1 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 12 carbon atoms, heterocyclyl of 3 to 12 carbon atoms, heterocyclylalkyl from 3 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 alkyl of 7 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, alkoxy of 1 to 12 atoms carbon or alkoxyalkyl of 1 to 12 carbon atoms; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N (R12) 2; R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or R6 and R6a together, or R7 and R7a together, or R8 and R8a together, or R9 and R9a together are an oxo group, provided that when V is -C (O) -, R7 and R7a together or R8 and R8a together do not they form an oxo group, while the rest of R6, R6a, R7, R7a, R8, R3a, R9, and R9a are each independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the rest of R6, R6a R7 R7a, R8, R8a, R9a and R9a is independently selected from hydrogen or alkyl of 1 to 3 carbon atoms; R10 is hydrogen or alkyl of 1 to 3 carbon atoms; and each R12 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; as a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition or a prodrug thereof.

90. A method for treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 89.

91. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to claim 89.