ZA200600124B - Pyridazine derivatives and their use as therapeutic agents - Google Patents

Description

PYRIDAZINE DERIVATIVES AND THEIR USE AS THERAPEUTIC AGENTS

FIELD OF THE INVENTION

The present invention relates generally to the field of inhibitors of stearoyl-CoA desaturase, such as pyridazine derivatives, and uses for such compounds in treating and/or preventing various human diseases, including those mediated by stearoyl-CoA desaturase (SCD) enzymes, 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 de novo synthesis in the liver. Mammals synthesize at least three fatty acid desaturases of differing chain length specificity that catalyze the addition of double bonds at the delta-9, deita-6, and delta-5 positions.

Stearoyl-CoA desaturases (SCDs) introduce a double bond in the C9-C10 position of saturated fatty acids. The preferred substrates are palmitoyl-CoA (16:0) and stearoyl-

CoA (18:0), which are converted to paimitoleoyl-CoA (16:1) and oleoyl-CoA (1 8:1), respectively. The resulting mono-unsaturated 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 rat (SCD1, SCD2) and four SCD genes have been isolated from mouse (SCD1, 2, 3, and 4). While the basic biochemical role of SCD has : been known in rats and mice 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), it has only recently been directly implicated in human disease processes.

A single SCD gene, SCD1, has been characterized in humans. SCD1is described in Brownlie et al, PCT published patent application, WO 01/62954, the disclosure of which is hereby incorporated by reference in its entirety. A second human SCD isoform has recently been identified, and because it bears little sequence homology to altemate mouse or rat isoforms it has been named human SCD5 or hSCD5 (PCT published patent application, WO 02/26944, incorporated herein by reference in its entirety). .

To date, no small-molecule, drug-like compounds are known that specifically inhibit or modulate SCD activity. Certain long-chain hydrocarbons have been used historically to study SCD activity. Known examples include thia-fatty acids, cyclopropenoid fatty acids, and certain conjugated linoleic acid isomers. Specifically, cis-12, trans-10 conjugated linoleic acid is believed to inhibit SCD enzyme activity and reduce the abundance of SCD1 mRNA while cis-9, trans-11 conjugated linoleic acid does not. Cyclopropenoid fatty acids, such as those found in stercula and cotton seeds, are also known to inhibit SCD activity. For example, sterculic acid (8-(2- octylcyclopropenyi)octanoic acid) and malvalic acid (7<2-octylcyclopropenyl)heptanoic acid) are C18 and C16 derivatives of sterculoyl and malvaloyl fatty acids, respectively, having cyclopropene rings at their C9-C10 position. These agents are believed to inhibit SCD enzymatic activity by direct interaction with the enzyme, thus inhibiting delta-9 desaturation. Other agents that may inhibit SCD activity include thia-fatty acids, such as 9-thiastearic acid (also called 8-nonylthiooctanoic acid) and other fatty acids with a sulfoxy moiety.

These known modulators of delta-9 desaturase activity are not useful for treating the diseases and disorders linked to SCD1 biological activity. None of the known SCD inhibitor compounds are selective for SCD or delta-9 desaturases, as they also inhibit other desaturases and enzymes. The thia-fatty acids, conjugated linoleic acids and cyclopropene fatty acids (malvalic acid and sterculic acid) are neither useful at reasonable physiological doses, nor are they specific inhibitors of SCD1 biological activity, rather they demonstrate cross inhibition of other desaturases, in particular the delta-5 and delta-6 desaturases by the cyclopropene fatty acids.

The absence of small molecule inhibitors of SCD enzyme activity is a major scientific and medical disappointment because evidence is now compelling that SCD activity is directly implicated in common human disease processes: See e.g., Attie,

A.D. et al., "Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia®, J. Lipid Res. (2002), Vol. 43,

No. 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.

Natl. Acad. Sci. U S A. (2002), Vol. 99, No. 7, pp. 11482-6.

The present invention solves this problem by presenting new classes of compounds that are useful in modulating SCD activity and regulating lipid levels, especially plasma lipid levels, and which are useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, especially diseases related to elevated lipid levels, cardiovascular disease, diabetes,

obesity, metabolic syndrome and the like.

Related Literature

PCT Published Patent Applications, WO 03/075929, WO 03/076400 and

WO 03/076401 disclose compounds having histone deacetylase inhibiting enzymatic activity.

BRIEF SUMMARY OF THE INVENTION

The present invention provides pyridazine derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity - of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.

Accordingly, in one aspect, the invention provides methods of inhibiting human stearoyl-CoA desaturase (hSCD) activity comprising contacting a source of hSCD with a compound of formula (1):

R* RS = RS R’ ” ) . : dN N—V—R: (1)

Ne

R% 9 RS wherein: x and y are each independently 1, 2 or 3;

W is -O-, -C(0)O-, -N(R")-, -S(O)- (where tis 0, 1 or 2), -N(R")S(0).-, -OC(O)- or -C(O);

V is -C(O), -C(S)-, -C(O)N(R'}-, -C(0)O-, -S(0)z, -S(O)N(R")- or -C(R"")H-; each R' is independently selected from the group consisting of hydrogen,

C,-Cr2alkyl, C-Cizhydroxyalkyl, C4-Crzcycloalkylalkyl and C;-Ciearalkyl;

R? is selected from the group consisting of C,-Cyzalkyl, C»-Ci2alkenyl,

C,-Cizhydroxyalkyl, C,-Cyzhydroxyalkenyl, C,-Cszalkoxyalkyl, Cs-Cy cycloalkyl,

C4+C4zcycloalkylalkyl, aryl, C-Cyearalkyl, Cs-Cizheterocyclyl, C3-Cqzheterocyclylalkyl, C,-Cqzheteroaryl, and C;-Cyzheteroarylalkyl; or R? is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;

R? is selected from the group consisting of C-Czalkyl. Co-Cizalkenyl,

C,-Cyzhydroxyalkyi, C,-C1ohydroxyalkenyl, C»-Calkoxyalkyl, C,-Cocycloalkyl,

C.-Ciocycloalkylalkyl, aryl, C-Cigaralkyl, C3-Cyoheterocyciyt, C,-Cyzheterocyclylalkyl,

C4-Cyoheteroaryl and C,-Cizheteroarylalkyl; or R® is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;

R® and R® are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R¥)z;

RE R®, R’, R™ R®, R®, R® and R*™ are each independently selected from hydrogen or C,-Caalkyl; or R and R™® together, or R®and R™ together, or R°and R™ together, or R® and

R® together are an oxo group, provided that when V is -C(O)-, R’and R'™ together or

R8 and R™ together do not form an oxo group, while the remaining rR’, R™, R% R® R®,

R™ R®and R™ are each independently selected from hydrogen or Ci-Csalkyl; or one of RE, R®, R, and R™ together with one of R®, R®, R® and R® form an alkylene bridge, while the remaining R®, R®, R’, RR” R%, R® R? and R* are each independently selected from hydrogen or C-Caalkyl;

R" is hydrogen or C;-Caalkyl; and each R" is independently selected from hydrogen or C,~-Cealkyl; : a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

In another aspect, this invention provides methods of 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 formula (1) as set forth above.

In another aspect, this invention provides compounds of formula (lI) having the following formula (la)

R¢ R® “) A | ’ R72

X dN N—V—R® (la) = Rf y R82

R% R® RE wherein: x and y are each independently 1, 2 or 3;

W is -O-, -C(0)O-, -N(R")-, -S(O)r (where tis 0, 1 or 2), -N(R")S(0).-, -OC(O)- or -C(0O);

V is -C{O), -C(S)- -C(ON(R')-, -C(0)O-, -8(0)z-, -S(O)N(R")- or -C(R")H-; each R' is independently selected from the group consisting of hydrogen,

C1-Cizalkyl, C~-Cyohydroxyalkyl, C4Cizcycloalkylalkyl and Cr-Coearalkyl;

R? is selected from the group consisting of C4-Cqzalkyl, C,-Cyzalkenyl,

C,-Cq-hydroxyalkyl, C-Ci.hydroxyalkenyl, C-Cypalkoxyalkyl, Cs-Ciocycloalkyl, C4Cycycloalkylalkyl, aryl, C-Crearalkyl, C,-Cy heterocyclyl, Cs-Cizheterocyclylalkyl,

C,-Cyzheteroaryl, and C-Cioheteroarylalkyl, provided that, when W is -C(O)-, R? can not be C,-Cealkyl substituted by -S(OXR™ where R" is hydrogen, C-Cealkyl, Cr-

Cyzaralkyl, pyrazinyl, pyridinonyl, pyrrolidionyt or imidazolyi; or R? is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;

R3 is selected from the group consisting of C;-Cqzalkyi, Co-Croalkenyl,

C.-Cyohydroxyalkyl, CCy-hydroxyalkenyl, C-Cizalkoxyalkyl, Cs-Cizcycloalkyl,

C.-Ci.cycloalkylalkyl, aryl, Cr-Csgaralkyl, Cs-Cqzheterocyclyl, C,-Cyzheterocyclylalkyl,

C,-Cyheteroaryl and Ca-Cizheteroarylalkyl; or R® is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or.all of the rings may be fused to each other;

R* and R® are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R"),;

RS R® R’, R™ R®, R®, R® and R® are each independently selected from hydrogen or C4-Cjalkyl; or R” and R™ together, or R®and R™ together, or R%and R® together, or R® and

R® together are an oxo group, provided that when V is -C(O)., R’and R® together or

RPand R® together do not form an oxo group, while the remaining R’, R™, R®, R*, R®,

R® R® and R® are each independently selected from hydrogen or C;-Csalkyt; or one of R®, R®, R7, and R® together with one of R®, R®, R® and R* form an alkylene bridge, while the remaining R®, R®, R’, R™®, R®, R®, R®, and R™ are each independently selected from hydrogen or C,-Csalkyl;

R" is hydrogen or C-Csalkyl; and each R* is independently selected from hydrogen or C4-Cealkyl; a stereoisomer, enantiomer of tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

In another aspect, the invention provides methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, wherein the methods comprise administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention as set forth above. )

In another aspect, the invention provides compounds or pharmaceutical compositions useful in treating, preventing and/or diagnosing a disease or condition relating to SCD biological activity such as the diseases encompassed by cardiovascular disorders and/or metabolic syndrome (including dyslipidemia, insulin resistance and obesity). in another aspect, the invention provides methods of preventing or treating a disease or condition related to elevated lipid levels, such as plasma lipid levels, especially elevated triglyceride or cholesterol levels, in a patient afflicted with such elevated levels, comprising administering to said patient a therapeutically or : prophylactically effective amount of a composition as disclosed herein. The present invention also relates to novel compounds having 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 triglyceride level, or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient. In an embodiment of such composition, the patient has an elevated lipid level, such as elevated plasma triglycerides or cholesterol, before 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 for, or protecting a patient from developing, a disease or condition mediated by stearoyl-CoA desaturase (SCD), which methods comprise administering to a patient afflicted with such disease or condition, or at risk of developing such disease or condition, a therapeutically effective amount of a compound that inhibits activity of SCD in a patient when administered thereto.

In another aspect, the invention provides methods for treating a range of diseases involving lipid metabolism utilizing compounds identified by the methods disclosed herein. In accordance therewith, there is disclosed herein a range of compounds having said activity, based on a screening assay for identifying, from a library of test compounds, a therapeutic agent which modulates the biological activity of said SCD and is useful in treating a human disorder or condition relating to serum levels of lipids, such as triglycerides, VLDL, HDL, LDL, and/or total cholesterol.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Certain chemical groups named herein are preceded by a shorthand notation indicating the total number of carbon atoms that are to be found in the indicated chemical group. For example; C-Cq2alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms, and C,-Cq cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.

Accordingly, as used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated: "Methoxy" refers to the -OCH, radical. "Cyano" refers to the -CN radical. "Nitro" refers to the -NO, radical. *Trifluoromethyl” refers to the -CF; radical. "Oxo" refers to the =O substituent. "Thioxo" refers to the =S substituent. "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethy! (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyi (t-butyl), and the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, -OR™, -OC(O)-R", -N(R™),, -C(O)R™, -C(O)OR™, -C(O)N(R™),, -N(R™)C(O)OR'¢, -N(R")C(O)R",

-N(R™)(S(O}R'®) (where tis 110 2), -S(O)OR'® (where tis 110 2), -S(O)R'® (where tis 0 to 2), and -S(O)N(R™), (where tis 1 10 2) where each R'* is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl; and each R'is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,

heterocylylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted unless otherwise indicated.

"C,-Caalkyl" refers to an alkyl radical as defined above containing one to three carbon atoms.

The C;-Csalkyl radical may be optionally substituted as defined for an alkyi group.

"C,-Csalkyl" refers to an alkyl radical as defined above containing one to six carbon atoms.

The C,-Cgalkyl radical may be optionally substituted as defined for an alkyi group.

"C,-Cy,alkyl" refers to an alkyl radical as defined above containing one to twelve carbon atoms.

The C;-Cqzalkyl radical may be optionally substituted as defined for an alkyl group.

"C,-Cealky!" refers to an alkyl radical as defined above containing two to six carbon atoms.

The C,-Csalkyl radical may be optionally substituted as defined for an alkyl group.

"C,;-Csalkyl" refers to an alkyl radical as defined above containing three to six carbon atoms.

The Cs-Cealkyl radical may be optionally substituted as defined for an alkyl group.

"C,-Ci2alkyl" refers to an alkyl radical as defined above containing three to twelve carbon atoms.

The C3-Ci.alkyl radical may be optionally substituted as defined for an alkyl group.

"Ce-Cyalkyl” refers to an alkyl radical as defined above containing six to twelve carbon atoms.

The C4-Cy.alkyl radical may be optionally substituted as defined for an alkyl group.

"C,-Cq.alkyt" refers to an alkyl radical as defined above containing seven to twelve carbon atoms.

The C-Cy,alkyl radical may be optionally substituted as defined for an alkyl group.

- "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-1-

enyl, but-1-enyi, pent-1-enyl, penta-1,4-dienyl, and the like.

Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR™, -OC(O}R"™, N(R"), -C(O)R", -C(O)OR™, -C(OIN(R™), -N(R')C(O)OR™, N(R™)C(O)R™®, -N(R™)(S(O}R'®) (where tis 1 to 2), -S(O)OR'® (where tis 1 to 2), -S(O)R™ (where tis 0 to 2), and -S(OYN(R™), (where tis 1 to 2) where each R* is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl; and each R'is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyi, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted. "C,-Csalkenyl” refers to an alkenyl radical as defined above containing three to 12 carbon atoms.

The C3-Cizalkenyl radical may be optionally substituted as defined for an alkenyl group.

*C,-Cqoalkenyl” refers to an alkenyl radical as defined above containing two to 12 carbon atoms.

The C,-Cyalkenyl radical may be optionally substituted as defined above for an alkenyl group.

~Alkylene” and “alkylene chain” refer to a straight or branched divalent hydrocarbon chain, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons, e.g., methylene, ethylene, propylene, n-butylene, and the like.

The alkylene chain may be attached to the rest of the molecule and to the radical group through one carbon within the chain or through any two carbons within the chain.

"Alkenylene” and “alkenylene chain” refer to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like.

The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond.

The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.

»Alkylene bridge" refers to a straight or branched divalent hydrocarbon bridge,

linking two different carbons of the same ring structure, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons, e.g., methylene, ethylene, propylene, n-butylene, and the like.

The alkylene bridge may link any two carbons within the ring structure.

»Alkoxy” refers to a radical of the formula -OR, where R, is an alkyl radical as defined above.

The alkyl part of the alkoxy radical may be optionally substituted as defined above for an alkyl radical.

nC,-Cealkoxy” refers to an alkoxy radical as defined above containing one to six carbon atoms.

The alkyl part of the C,-Calkoxy radical may be optionally substituted as defined above for an alkyl group. ‘

"C,-Cs,alkoxy" refers to an alkoxy radical as defined above containing one to twelve carbon atoms.

The alkyl part of the C4-Cq.alkoxy radical may be optionally substituted as defined above for an alkyl group.

"C5-Cqalkoxy” refers to an alkoxy radical as defined above containing three to twelve carbon atoms.

The alkyl part of the C;-Croalkoxy radical may be optionally substituted as defined above for an alkyl group.

*Alkoxyalkyi" refers to a radical of the formula -R,-O-R. where each R, is independently an alkyl radical as defined above.

The oxygen atom may be bonded to any carbon in either alkyl radical.

Each alkyl part of the alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group.

"C,-C,alkoxyalkyl" refers to an alkoxyalkyl radical as defined above containing two to twelve carbon atoms.

Each alkyl part of the C-Ci.alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group.

"C,alkoxyalkyl” refers to an alkoxyalkyl radical as defined above containing three carbon atoms.

Each alkyl part of the C;alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group.

"C,-Cr.alkoxyalkyl" refers to an alkoxyalkyl radical as defined above containing three to twelve carbon atoms.

Each alkyl part of the Cs-Cyzalkoxyalkyl radical may be optionally substituted as defined above for an alkyl group. :

"Alkylsulfonyl” refers to a radical of the formula -S(O).R, where R, is an alkyl group as defined above.

The alkyl part of the alkylsuifonyl radical may be optionally substituted as defined above for an alkyt group. :

*C,-Cgalkylsulfonyl” refers to an alkyisulfonyl radical as defined above having one to six carbon atoms.

The C,-Cealkyisulfonyl group may be optionally substituted as defined above for an alkylsulfonyl group.

Aryl" refers to aromatic monocyclic or multicyclic hydrocarbon ring system "consisting only of hydrogen and carbon and containing from 6 to 19 carbon atoms, preferably 6 to 10 carbon atoms, where the ring system may be partially or fully saturated.

Aryl groups include, but are not limited to groups such as fluorenyl, phenyl and naphthyl.

Unless stated otherwise specifically in the specification, the term "aryl" orthe prefix "ar-" (such as in maralkyl") is meant to include aryl radicals optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclytalkyl, heteroaryl, heteroarylalkyl, -R'>-OR", -R®-OC(0)-R™, -R"-N(R™),, -R'S-C(O)R™, -R'"S-C(O)OR™, -R'S-C(O)N(R™),, -R'-N(R")C(O)OR", -R'*-N(R™C(O)R™®, RY-N(R™}S(O}R'®) (where tis 1 to 2), -R'-S(O)OR'® (where tis 1 to 2), -R'-S(O}R" (where tis 0 to 2), and -R'5-S(O}N(R™), (where t is 1 to 2) where each R" is independently hydrogen, alkyl, haloatkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R" is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R™ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted. "Aralky!" refers to a radical of the formula -RqR; where R, is an alkyl radical as defined above and R; is one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl and the like.

The aryl part of the aralkyl radical may be optionally substituted as described above for an aryl group.

The alkyi part of the aralkyl radical may be optionally substituted as defined above for an alkyl group. "C,-Cssaralkyl” refers to an aralkyl group as defined above containing seven to twelve carbon atoms.

The aryl part of the C~Cy.aralkyl radical may be optionally substituted as described above for an aryl group.

The alkyl part of the Cr-Csaralkyl radical may be optionally substituted as defined above for an alkyl group. "CCyearalkyl" refers to an aralkyl group as defined above containing seven to nineteen carbon atoms.

The aryl part of the C-Cq.aralkyl radical may be optionally . substituted as described above for an aryl group.

The alkyl part of the Cr-Cyoaralkyl radical may be optionally substituted as defined above for an alkyl group. "C,a-Cyparalkyl" refers to an aralkyl group as defined above containing thirteen to nineteen carbon atoms.

The aryl part of the Cy3-Cysaralkyl radical may be optionally substituted as described above for an aryl group.

The alkyl part of the Cy3-Csgaralkyl radical may be optionally substituted as defined above for an alkyl group.

"Aralkenyl” refers to a radical of the formula -R.R; where R; is an alkenyl radical as defined above and Rs is one or more aryl radicals as defined above, which may be optionally substituted as described above.

The aryi part of the aralkenyl radical may be optionally substituted as described above for an aryl group.

The alkenyl part of the aralkenyl radical may be optionally substituted as defined above for an alkenyl group.

“Aryloxy" refers to a radical of the formula -OR,, where R, is an aryl group as defined above.

The aryl part of the aryloxy radical may be optionally substituted as defined above.

"Aryl-C4-Cgalkyl” refers to a radical of the formula -Ry-R, where Ry is an unbranched alkyl radical having one to six carbons and R; is an aryl group attached to the terminal carbon of the alkyl radical.

"Cycloalkyl" refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, preferably having from three to twelve carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl and the like.

Unless otherwise stated specifically in the specification, the term *cycloalkyt” is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,

nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -RS-OR™, -R'®-OC(0)-R", -R">-N(R™), R'-C(O)R", -R™-C(O)YOR™,

} R'S-C(OIN(R™)z. -R'-N(R™)C(O)OR'®, -R'-N(R™)C(O)R", -R'-N(R™)(S(O)R'®) (where tis 1 to 2), -R'>-S(O)}OR'® (where tis 1 to 2), -R'S-S(O)R™ (where tis 0 to 2), and -R'-S(O)}N(R™), (where t is 1 to 2) where each R'is independently hydrogen,

alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R' is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R'is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclytalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted.

"C,-Cscycloalkyt” refers to a cycloalkyl radical as defined above having three to six carbon atoms.

The C;-Cscycloalkyl radical may be optionally substituted as defined above for a cycloalkyl group.

"C4-Cyocycloalkyt” refers to a cycloalkyl radical as defined above having three to twelve carbon atoms.

The C,-Cyocycloalkyl radical may be optionally substituted as defined above for a cycloalkyl group.

"Cycloalkylalkyi” refers to a radical of the formula -R,Rq where Rs is an alkyl radical as defined above and Rg is a cycloalkyl radical as defined above. The cycloalkyl part of the cycloalkyl radical may be optionally substituted as defined above for an cycloalkyl radical. The alkyl part of the cycloalkyl radical may be optionally substituted as defined above for an alkyl radical. "C+Cicycloalkylalkyl” refers to a cycloalkylalkyl radical as defined above having four to tweive carbon atoms. The C-Cicycloalkylalkyl radical may be optionally substituted as defined above for a cycloalkylalkyl group. "Halo" refers to bromo, chloro, fluoro or iodo. "Haloalky!" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, " trichloromethyl, 2,2,2-trfluoroethyl, 1-fiuoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group. "Haloalkenyl” refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 2-bromoethenyl, 3-bromoprop-1- enyl, and the like. The alkenyl part of the haloalkenyl radical may be optionally substituted as defined above for an alkyl group. : *Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the heterocyclyl radical may be partially or fully saturated.

Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindoiyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryi, trithianyl, tetrahydropyranyi, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyt, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyciyl” is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,

Claims (41)

WHAT IS CLAIMED IS

1. Use of a compound of formula (I): R* R® pte R® RT r7e Vk RZ—W / \ —v—=R® (1) - rs y Ro R% po RB wherein: x and y are each independently 1, 2 or 3; W is -O-, -C(0)O-, -N(R')-, -S(O)- (where tis 0, 1 or 2), -N(R")S(O)z-, -OC(O) or -C(O)-; V Is C(O}, -C(S})-, -C(O)N(R'})-, -C(0)O-, -S(O)z-, -S{O)N(R')- or C(R")H-; each R' is independently selected from the group consisting of hydrogen, C1-Ciz8lkyl, C2-Cizhydroxyalkyl, C.-CizCycloalkylaikyl and C,-Ciearalkyl; R? is selected from the group consisting of C(-C,zalkyl, C2-Cyzalkenyl, CCihydraxyalkyl, C.-Czhydroxyalkenyl, C2-Cyzalkoxyalkyl, Cs-Ci cycloalkyl, C+-Cizcycloalkylalkyl, aryl, C,~Ciearatkyl, C3-Cyzheterocyclyl, Cs-Cyzheterocyclylalkyl, C,-Cy heteroaryl, and C;-C,;heteroarylalkyl; or R? is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R? is selected from the group consisting of C-Cyzalkyl, C2-Ci2alkenyl, Cr-Ciohydroxyalkyl, C2-C1zhydroxyalkenyl, C.-C alkoxyalkyl, C5-Cicycloalkyl, Cq-Cizcydoalkylalkyl, aryl, Cr-Crgaralkyl, Cy-Cizheterocyclyl, C3-Cizheterocyclylalkyl, C,-Cyzheteroanyl and Cy-Cizheteroarylalkyi; or R® is a multi4ing structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R* and R® are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R™),; R%, R®, R’ R™ R% R™ R® and R* are each independently selected from hydrogen or C4-Calkyl; or R” and R™ together, or R%and R™ together, or R%and R* together, or R® and R™ together are an oxo group, provided that when V is -C(O)-, Rand R™ together or R and R* together do not form an oxo group, while the remaining R’, R™®, R%, R*, R', R®, R® and R* are each independently selected from hydrogen or C-Calkyl; or one of R®, R®, R’, and R* together with one of R®, R™, R® and R* form an alkylene bridge, while the remaining R®, R*, R’, R™, R®, R®, R?, and R* are each independently selected from hydrogen or C,-Csalkyl; R'is hydrogen or C,-Caalkyl; and each R" is independently selected from hydrogen or C,-Csalkyt; a sterecisomer, enantiomer or tautomer thereof, a pharmaceutically

. acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof in the manufacture of a medicament for inhibiting human stearoyl-CoA desaturase (hSCD) activity wherein the compound of formula (1) is contacted with a source of hSCD.

2. Use of a compound of formula (1): rR! R® R% R® R' Rr’? Mek dS —Vv—R® = Df R%® Re wherein: x and y are each independently 1, 2 or 3; Wis -O-, -C(O)O-, -N(R'})-, -S(O)- (Where tis 0, 1 or 2), -N(R")S(O).-, -OC(O})- or -C(O)-: V is -C(O)-, -C(S)-, -C(ON(R')-, -C{O)O~, -S(O)z-, -S(O)N(R')- or CR"; each R' is independently selected from the group consisting of hydrogen, C,-Cy28lkyl, C-C12hydroxyalkyl, C-Ci.Cycloalkylalikyl and C;-Ciearalkyl; R? is selected from the group consisting of C,-Cyalkyl, C,-Cy.alkenyl, Cz Crahydroxyalkyl, C2-C1zhydroxyalkenyl, C2-Crzalkoxyalkyl, C3-Ci.cycloalkyl,

C.-Cizcycloalkylalkyl, aryl, C-Chearalkyl, Cy-Cizheterocyclyl, C3-Cizheterocyclylalkyl, Ci-C heteroaryl, and C;-Cyzheteroarylalkyt; or R? is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R? is selected from the group consisting of C,-C1alkyl, C-Ci2alkenyl, CzCishydroxyalkyl, C,-Ci2trydroxyalkenyl, C2-Cizalkoxyalkyl, Cs-C cycloalkyl,

C.+-Cycycloalkytalkyl, aryl, Cr-Cisaralkyl, C3-Cizheterocyclyl, Cs-Cizheterocyclylalkyl, C1-Cizheteroaryl and Cy-Ci heteroarylalkyl; or R? is a multiring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyciyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R* and R® are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R").; R®, R® R’, R™, R®, R™, R’ and R™ are each independently selected from hydrogen or C,-Csalkyl; or R” and R’® together, or R®%and R™ together, or R%and R™ together, or R® and R™ together are an oxo group, pravided that when V is -C(O)-, R’and R™® together or R? and R™ together do not form an oxo group, while the remaining R’, R™, R® R®™, R?, R™, R® and R® are each independently selected from hydrogen or C-Csalkyl; or one of R®, R®, R’, and R™® together with one of R®, R*, R® and R™ form an alkylene bridge, while the remaining R®, R®, R’, R™, R®, R®, R®, and R™ are each independently selected from hydrogen or C,-Calkyl; R'is hydrogen or C-Caalkyl; and each R" is independently selected from hydrogen or C,-Cealky!; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof in the manufacture of a medicament for treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal.

3. The use of Claim 2 wherein the mammal is a human.

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

5. The use of Claim 4 wherein the disease or condition is Type Il diabetes.

6. The use of Claim 4 wherein the disease or condition is obesity.

7. The use of Claim 4 wherein the disease or condition is metabolic syndrome.

8. The use of Claim 4 wherein the disease or condition is fatty liver.

9. The use of Claim 4 wherein the disease or condition is non-alcoholic steatohepatitis.

10. A compound of formula (1a): 7 R¢ R® RSa R® R R7® Vek as N—V—R3 (la) — Wf R® Ro RE wherein: x and y are each independently 1, 2 or 3; Wis -O-, -C(0)O-, -N(R")-, S(O) (where tis 0, 1 or 2), -N(R")S(O)z, -OC{O}) or -C(O)-; Vis -C(O)-, -C(S)-, -C(ON(R")-, -C(0)O-, -S(O)z-, -S(O):N(R")- or CR"; each R' is independently selected from the group consisting of hydrogen, C,-Cszalkyt, C-Cyzhydroxyatkyl, C4-Cscycloalkylalkyl and C,-Cyearalkyi; R? is selected from the group consisting of C,-Cialkyl, C,-Cy.alkenyl, C2-Cizhydroxyalkyl, C,-Cishydroxyalkenyl, C-Cy alkoxyalkyl, Cs-CizCycioalkyl, C+Cycycloalkylalkyl, aryl, Cr-Cigaratkyl, Cs-Cyzheterocyciyl, Cy-Cosheterocyclylalkyl, C1-Cizheteroaryl, and Cs-Cyzheteroarylalkyl, provided that, when W is -C(O)-, R? can not be C,-Cealkyl substituted by -S(O)R* where R'* is hydrogen, Cy-Cealkyl,

C,-Cy.aralkyl, pyrazinyi, pyridinonyl, pyrrolidionyl or imidazolyl; or R? is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl! and where some or all of the rings may be fused to each other, Re is selected from the group consisting of Cs-Cizalkyl, C2-Cyzalkenyl, C,-Crohydroxyalkyl, C.-C1zhydroxyalkenyl, C,-C,.alkoxyalkyl, Ca-Ciocycloalkyl, C4-Cycycloalkylalkyl, aryl, C,-Cisaralkyl, Cy-Cizheterocyciyl, C4-Cy2heterocycliylatkyl, C,-Cqzheteroaryl and Cs-Ciheteroarylalkyl; or R® is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R* and R® are each independently selected from hydrogen, fluoro, chioro, methyl, methoxy, triflucromethyt, cyano, nitro or N(R"); RS R® R’, R™ R®, R¥, R® and R* are each independently selected from hydrogen or C-Caalkyl; or R” and R™ together, or R®and R™ together, or R°and R™ together, or RE and R® together are an oxo group, provided that when V is -C(O}-, R’and R™ together or R® and R* together do not form an oxo group, while the remaining R’, R™, : RE. R®, R?, R®, R® and R* are each independently selected from hydrogen or C,-Caalkyl; : or one of R®, R® R, and R™ together with one of R®, R®, R® and R® form an alkylene bridge, while the remaining R®, R®, R’, R”, R®, R®, R® and R* are each independently selected from hydrogen or C4-Caalkyl; R" is hydrogen or Cy-Csalkyl; and each R" is independently selected from hydrogen or C1-Cealkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

11. The compound of Claim 10 wherein: x and y are each 1; Wis -O-; Vis -C(O)- or -C(S)-; R? is selected from the group consisting of Cy-Crzalkyl, C,-C12alkenyl, C-C,zhydroxyalkyl, C~Cizhydroxyalkenyl, C,-Cizalkoxyalkyl, C3-Cyocycloalkyl, C4-Cyocycloalkylalkyl, aryl, Cr-Cisaralkyl, C,-Cyzhsterocyclyl, Cs-Cizheterocyclylalkyl,

C,-Cyzheteroaryl, and C;-Cyzheteroaryialkyl; R? is selected from the group consisting of Cs-Cazalkyl, CCyalkenyl, C2-Csohydroxyalkyl, C-Cizhydroxyalkenyl, Co-Cyalkoxyalkyl, Cs-CioCycloalkyl, C+Ca cycloalkylalkyl, aryl, Cr-Ciearalkyl, Cs-Cizheterocyclyl, Cs-Cizheterocyclylalkyi, C;-Cyzheteroaryl and Cs-Cioheteroarylalkyl; R?* and R® are each hydrogen; and RE, R® R’, R™ R® R%®, R? and R™ are each hydrogen.

12. The compound of Claim 11 wherein: Vis -C(O); R? is C;-C.aralkyl optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C,-Cgalkyl, C,-Cetrihaloalkyl and C4-Cetrihaloalkoxy; R®is phenyl! optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C,-Cealkyl, C;-Cetrihaloalkyl, C,-Cqtrihaloalkoxy, C-Cealkylsulfonyl, -N(R'2),, -OC(O)R", -C(O)OR™, -S(0),N(R"),, cycloalkyl, heterocyclyl, heteroaryl and heteroaryicycloalkyl; and each R'is independently selected from hydrogen, C;-Cealkyl, Cs-Cecycloalkyl, aryl or aralkyl.

13. The compound of Claim 12 wherein: R? is C;-Ci.aralkyl optionally substituted by one or more substituents selected from halo, C;-Csalkyl, C4-Cgtrihaloalkyl and C,-Cgtrihaloalkoxy; and R3is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C-Cetrihaloalkyl and C,-Cqtrihaloalkoxy.

14. The compound of Claim 13, namely, [4-(6-Phenethyloxy-pyridazin-3-yl}- piperazin-1-yl]-(2-trifluoromethyl-phenyl)}-methanone.

15. The compound of Claim 11 wherein: Vis -C(O); R?is C~Cyalkyl or C,-Cyoalkenyl; R3is phenyl! optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C;-Cealkyl, C;-Cetrihaloalkyl, C4-Cetrihaloalkoxy, C,-Cgalkyisulfonyl, -N(R'?),, -OC(O)R™, -C(O)YOR™, -S(O)},N(R'?);,

cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R'? is independently selected from hydrogen, Cs-Cgalkyl, Cs-Cscycloalkyl, aryl or aralkyl.

16. The compound of Claim 11 wherein: Vis -C(O); R? is C3-Ci,cycloalkyl or C4-Cyzcycloalkylalkyl; R3is phenyl optionally substituted by one or more substituents selected : from the group consisting of halo, cyano, nitro, hydroxy, Cs-Cealkyl, C4-Cetrihaloalkyl, Cs-Cetrihaloalkoxy, Cq-Cealkylsulfonyl, -N(R'),, -OC(O)R™, -C(O)OR™, -S(0),N(R"),, cycloalkyl, heterocyclyl, heteroaryl and heteroaryicycloalkyl; and each R'? is independently selected from hydrogen, C;-Csalkyl, Cs-Cecycloalkyl, aryl or aralkyl.

17. The compound of Claim 16 wherein: R2is C4-Cyzcycloalkylalkyl; and R3is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C-Cetrihaloalkyl and C,-Cetrihaloalkoxy.

18. The compound of Claim 17, namely, {4-[6-(2-Cyclopropyil-ethoxy)- pyridazin-3-yl]-piperazin-1-yi}-(2-trifluoromethyl-phenyl)-methanone.

19. The compound of Claim 10 wherein: x and y are each 1; W is -S(O)- (where tis 0, 1 or 2); Vis -C(O)- or -C(S}-; R? is selected from the group consisting of Cy-Cyaalkyl, C,-Cizalkenyl, C»-C1zhydroxyalkyl, C,-Cihydroxyalkenyl, Co-Ci.alkoxyalkyl, Cs-Cizcycloalkyl, C4-Cyocycloalkylalkyl, aryl, C-Cyzaralkyl, Cs-Cqoheterocyclyl, Ca-Cizheterocyclylalkyl, C,-Cyzheteroaryl, and C;-Cqoheteroarylalkyl; R? is selected from the group consisting of C-Cyzalkyl, C,-Cyzalkenyl, C,-Cizhydroxyalkyl, C,-Ci;hydroxyalkenyl, C-Cqzalkoxyalkyl, C;-Cq2cycloalkyl, C4-Cizcycloalkylalkyl, aryl, C,-Cqzaralkyl, Cs-Cioheterocyclyl, Cs-Cizheterocyclylalkyl, C4-Cqz2heteroaryt and C,-Cyzheteroarylalkyl; R* and R® are each hydrogen; and

R®, R®, R’, R™?, R®, R®, R® and R™ are each hydrogen.

20. The compound of Claim 19 wherein: Vis -C(O); R? is C;-C.aralky! optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C-Cealkyl, C4-Cetrihaloalkyl and C1-Cgtrihaloalkoxy; R3is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C-Cealkyl, Cs-Cetrihaloalkyl, C,-Cetrihaloalkoxy, Ci-Cgalkylsulfonyl, -N(R'2),, -OC(O)R™, -C(O)OR"Y, -S(0)N(R"), cycloalkyl, heterocyclyl, heteroaryl and heteroaryicycloalkyl; and each R'? is independently selected from hydrogen, C-Cgalkyl, Ci-Cecycloalkyl, aryl or aralkyi.

21. The compound of Claim 20 wherein: R? is C,-Cparalkyl optionally substituted by one or more substituents selected from halo, Cs-Cgalkyl, C;-Cetrihaloalkyl and C;-Cetrihaloalkoxy; and R3is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C;-Cstrihaloalkyl and C;-Cstrihaloalkoxy.

22. The compound of Claim 21 selected from the group consisting of the following: [4-(6-Phenethylsulfanyl-pyridazin-3-yl)-piperazin-1-yl}-{2-trifluoromethyl-phenyl)- methanone; . {4-[6-(2-Phenyi-ethanesulfinyl)-pyridazin-3-yi}-piperazin-1-yl}-(2-trifluoromethyi-phenyi)- methanone; and {4-[6-(2-Phenyl-ethanesulfonyl)-pyridazin-3-yi]-piperazin-1-yl}-(2-trifiioromethyl- phenyl)-methanone.

23. The compound of Claim 19 wherein: V is -C(O); R? is C;-Cyalkyl or C»Cyoalkenyl; R?is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C,-Cgalkyl, Cs-Cgtrihaloalkyl, C1-Cetrihaloalkoxy, C-Cealkylsulfonyl, -N(R'2),, -OC(O)R", -C(O)OR"?, -S(0),N(R"?),,

cycloalkyl, heterocyclyl, heteroaryl and heteroaryicycloalkyl; and each R" is independently selected from hydrogen, C;-Cealkyi, C;-Cgcycloalkyl, aryl or aralkyl. 24, The compound of Claim 23 wherein R®is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C,-Cgtrihaloalkyl and C4-Cetrihaloalkoxy.

25. The compound of Claim 24, namely, {4-[6-(3-Methyl-butylsulfanyl)- pyridazin-3-yl]-piperazin-1-yi}-(2-trifluoromethyl-phenyl}-methanone.

26. The compound of Claim 10 wherein: x and y are each 1; Wis -N(R}; V is -C(O}- or -C(S); R' is hydrogen or C,-Cgalkyl; R? is selected from the group consisting of C;-Cyalkyl, C-Cizalkenyl, C,-Cyshydroxyalkyl, C»-Cyzhydroxyaikenyl, C-Cizalkoxyalkyl, Cs-Cqcycloalkyl, C4-Ciocycloalkylalkyl, aryl, Cr-Cyaaralkyl, C3-Cizheterocyclyl, Cs-Cizheterocyclylalkyl, C,-Cqzheteroaryl, and C;-Cyzheteroarylalkyl; R3 is selected from the group consisting of C,-Cyaalkylt, C-Cyzalkenyl, C,-Cyzhydroxyalkyl, C-Ci,hydroxyalkenyl, C,-Cqzalkoxyalkyl, C;-Cs2cycloalkyl, C4-Ciacycloalkylalkyl, aryl, Cr-Cyaralkyl, Cs-Cioheterocyciyl, Cs-Cizheterocyclylalkyl, C4-Cyzheteroaryl and C;-Cyzheteroarylalkyl; R* and R® are each hydrogen; and RE, R% R’, R’® R® R®, R® and R*® are each hydrogen.

27. The compound of Claim 26 wherein: Vis -C(O); R! is hydrogen or C,-Cealkyt; R? is C;-Cssaralkyl optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, Cs-Cgalkyl, C-Cstrihaloalkyl and C4-Cgtrihaloalkoxy,; R3is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C,-Cealkyl, Cs-Cetrihaloalkyl,

C,-Cetrihaloalkoxy, Ci-Cealkyisulfonyl, N(R"), -OC(O)R™, -C(O)OR™, -S(OXN(R")z, cycloalkyl, heterocyclyl, heteroaryl and heteroaryicycloalkyl; and each R" is independently selected from hydrogen, C,-Cgalkyl, Cs-Cecycloalkyl, aryl or aralkyl.

28. The compound of Claim 27 wherein R3is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C4-Cetrihaloalkyl and C,-Cetrinaloalkoxy.

29. The compound of Claim 28 selected from the group consisting of the following: [4-(6-Phenethylamino-pyridazin-3-yl)-piperazin-1 ~yllH2-trifluoromethyi-phenyl)- methanone; and {4-[6-(Methyl-phenethyl-amino)-pyridazin-3-Yil-piperazin-1 -yi}-(2-trifluoromethyl- phenyl)}-methanone.

30. The compound of Claim 26 wherein: Vis C(O); R' is hydrogen or Cy-Cealkyl; R? is C;-Cy2alkyl, C-Cyoalkenyi, C1-Cocycloatkyl or C,4-Cyocycloalkylalkyl; } R?is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-Cealkyl, C;-Cgtrihaloatkyl, C,-Cgtrihaloalkoxy, C-Cealkylsutfonyl, -N(R'%),, -OC(O)R™, -C(O)OR", -S(0)XN(R?),, cycloalkyl, heterocyclyl, heteroaryl and heteroarylicycloalkyl; and each R"? is independently selected from hydrogen, C;-Cealkyt, Cs-Cscycloalkyl, aryl or aralkyl.

31. The compound of Claim 10 wherein: x and y are each 1; Wis -N(R")S(O)z; V is -C(O)- or -C(S)~; R' is hydrogen or Cy-Cealkyl; R? is selected from the group consisting of Cs-Ci2alkyl, C.-Cyalkenyl, C,-Cizhydroxyalkyl, Co~-Cqzhydroxyalkenyl, C,-Cyzalkoxyalkyl, Cs-Cizcycloalkyl,

Ca-Ciocycloalkylalkyl, aryl, C-Cizaralkyl, Cs-Cqsheterocyciyl, Cs-Cizheterocyciylalkyl, C4-Cyoheteroaryl, and C;-Cooheteroarylalkyl; R? is selected from the group consisting of C-Cialkyl, C,-Cy.alkenyl, C,-Cy hydroxyalkyl, C.-Ci,hydroxyalkenyl, C~Csqalkoxyalkyl, C;-Ciocycloalkyl, C4-Crocycloalkylalkyl, aryl, C~Cqoaralkyl, Cs-Cizheterocyclyl, Cs-Cizheterocyclylalkyd, C,-Cyzheteroaryl and Cs-Cyzheteroarylalkyl; R* and R® are each hydrogen; and R®, R® R’, R™, R® R®™, R® and R® are each hydrogen.

32. The compound of Claim 31 wherein: Vis -C(O); R' is hydrogen or Cs-Cealkyl; R? is C,-Cyzalkyl, C-Cyzalkenyl, Cs-Ciocycioalkyl or C4-Cqocycloalkylalkyl; ) Ris phenyl optionally substituted by one or more substituents selected . from the group consisting of halo, cyano, nitro, hydroxy, C,-Cealkyl, C,-Cetrihaloalkyi, C,-Cetrihaloalkoxy, C-Cealkylsulfonyl, -N(R?),, -OC(O)R'2, -C(O)OR'?, ~S(O)}:N(R'?),, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R'? is independently selected from hydrogen, C,-Cealky, Cs-Cecycloalkyl, aryl or aralkyl.

33. The compound of Claim 32 wherein: R? is C,-Cyalkyl; and R® is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C,-Cetrihaloalkyl and C,-Cgtrihaloalkoxy.

34. The compound of Claim 33, namely, Propane-1-sulfonic acid {6-[4-(2- triffluoromethyl-benzoyl)-piperazin-1-ylJ-pyridazin-3-yl}-amide.

35. The compound of Claim 31 wherein: Vis -C(O)-; R' is hydrogen or C,-Cgalkyi; R? is C,-Cy,aralkyl optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C,-Cealkyl, Ci-Cstrihaloalkyl and C-Cgtrihaloalkoxy;

Ris phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C,-Cealkyl, C,-Cetrihaloalkyt, C:-Cetrihaloalkoxy, C-Cealkytsutfonyl, -N(R'?)z, -OC(O)R'?, -C(O)OR™, -S(0)N(R"),, cycloalkyl, heterocyclyl, heteroaryl and heteroaryicycioalkyl; and each R' is independently selected from hydrogen, C-Cealkyt, Cy-Cacycloalkyt, aryl or aralkyl.

36. Use of a compound of Claim 10 in the manufacture of a medicament for treating a disease or condition mediated by stearoyl-CoA desaturase (SCD.

37. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Claim 10.

38. A compound of claim 10 for use in treating a disease or condition mediated by stearoyl-CoA desaturase(SCD).

39. Use of any of claims 1, 2 or 36, substantially as herein described and exemplified.

40. A compound of claim 10, substantially as herein described and exemplified.

41. A pharmaceutical composition of claim 37, substantially as herein described and exemplified.