ZA200600123B - Pyridyl derivatives and their use as therapeutic aPyridyl derivatives and their use as therapeutic agents gents - Google Patents

Description

PYRIDYL 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 pyridine derivatives, and uses for such compounds in treating andlor 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 deita-9, delta-6, and delta-5 positions.

Stearoyl-CoA desaturases (SCDs) introduce a double bond in the C8-C10 position of saturated fatty acids. The preferred substrates are paimitoyl-CoA (16:0) and stearoyl-

CoA (18:0), which are converted to palmitoleoyl-CoA (16:1) and oleoyl-CoA (18:1), : respectively. The resulting mono-unsaturated fatty acids are substrates for incorporation into phospholipids, triglycerides, and cholestery! esters.

A number of mammalian SCD genes have been cloned. For example, two genés 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. SCD1 is 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 alternate mouse or rat isoforms it has been named human SCD5 or hSCDS5 (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- octylcyclopropenyl)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 C3-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-nonytthiooctanoic 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 stearoyi-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 application WO 01/86327 discloses novel benzamide derivative compounds. 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 pyridine 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 (I): 4 5 10 7

R R R108 R™ R R78

Wt ie N—V—R? (1) pr y 9a 8a wherein: x and y are each independently 1, 2 or 3;

Wis -O-, N(R"), -C(R')-, C(O), -OC(O), S(O); (where tis 0, 1 or 2), -N(R")S(O)- (where tis 1 or 2), -S(O)N(R'}-, -C(OIN(R")-, -C(SIN(R'})-, -OS(O):N(R'}-, -OC(ON(R'), -OC(SIN(R'}, -N(R"YC(O)N(R')- or -N(R")C(S)N(R')-;

V is -C(O)-, -C(S)-, -C(O)N(R')-, -C(O)O-, -C(S)O-, -S(O)~(where tis 1 or 2), -S(OXN(R')- (where tis 1 or 2) or -C(R'")H,; each R' is independently selected from the group consisting of hydrogen,

C4-Cy2alkyl, C,-Cy hydroxyalkyl, C4-Cy cycloalkylalkyl and C,-C,garalkyl;

R? is selected from the group consisting of C-Cs.alkyl, C,-Cqzalkenyl,

CrCyzhydroxyalkyl, C,-Cyhydroxyalkenyl, C,-Cjqalkoxyalkyi, C3-Cqzcycloalkyl,

C+-Cyzcycloalkylalkyl, aryl, C,-Cygaralkyl, Cs-Cyzheterocyclyl, C;-Cyzheterocyclylalkyl,

C4-Cy heteroaryl, and C3-Cysheteroarylalkyt;

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;-Cqzalkyl, C-Ciaalkenyl, C,-Cizhydroxyalkyl, C-Cizhydroxyalkenyl, Co-Cyealkoxyalkyl, Cs-Ci2Cycloalkyl,

C.-Cycycloalkylalkyl, aryl, C,-Cisaralkyl, Cs-Cozheterocyclyl, Cs-Cizheterocyclytalkyl,

C,-Ci heteroaryl and C;-Cizheteroarylalkyt; or R? is a muiti-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*, R® and R® are each independently selected from hydrogen, bromo, 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, 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™, R®, R®, R®,

R%® R'’, and R'™ are each independently selected from hydrogen or C,-Csalkyt; 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,-Csalkyt; and each R" is independently selected from hydrogen or Ci-Cealkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

In another aspect, the 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 (I) as set forth above.

In another aspect, the invention provides compounds of formula (I) having the following formula (lla):

R4 R100 rR" R7 -

R' hk 0 \—? \ —{ (ita)

Sn Gan o R® Re hope RB wherein: x and y are each independently 1, 2 or 3;

R' is selected from the group consisting of hydrogen, C,-C12alkyl, C,-Cyhydroxyalkyl, C+Cicycioalkylalkyl and C,-Cigaralkyl;

RZis selected from the group consisting of Cr-Cy,alkyl, Cs-C+zalkenyi,

C-Cs2hydroxyalkyl, Co-Cioalkoxyatkyl, Cs-Ci2hydroxyalkenyl, C;-Cyocycloalkyl,

C.-Cy,cycioalkylalkyl, C1s-Cearalkyl, Ci-Cyzheteroaryl, Cs-Cozheterocyclylalkyl,

Cs-Cyzheterocyclyl, and Cs-Crzheteroarylalkyl, provided that R? is not pyrazinyl, pyridinonyl, pyrrolidinonyl 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 cycloalkyi, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;

Reis selected from the group consisting of C;-Cyzalkyl, C-Cy2alkenyi, C;-Cyohydroxyalkyl, Cs-Cyzhydroxyalkenyl, Cs-Cozalkoxy, Ca-Cizalkoxyalkyl,

C4-Ci2cycloalkyl, C-Cycycloalkylalkyl, aryl, Cr-Cisaralkyl, Cs-Cizheterocyciyl,

C,-Cqoheterocyclylalkyl, Ci-Cy, heteroaryl and Cs-Cizheteroarylaikyt; or R® is a muiti-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycioaliyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;

R* R® and R® are each independently selected from hydrogen, bromo, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R'3),;

R’, RR}, R¥® R?, R®™, R'® and R'® are each independently selected from hydrogen or C-Cjalkyl; or R%and R® together, or R'® and R'® together form an oxo group, while the remaining R’, R™, R®, R®, R®, R*®, R"°, and R'™ are each independently selected from . hydrogen or C,-Cjalkyi; or one of R7, 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 Cy-Csalkyl; and each R" is independently selected from hydrogen or Cs-Cealkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

In another aspect, the invention provides compounds of formula (1) having the following formula (lib):

RY R® 100 R10 R7 a

R’ Mk 0 \ 4 \ vd (lib) —( ==N rf R® 0 RS R® bogs R wherein: x and y are each independently 1, 2 or 3;

R! is selected from the group consisting of hydrogen, C,-Czalkyl, C,Cyhydroxyalkyl, Cs-Cy.cycloalkylalkyl and Cr-Crearalkyl;

R?is selected from the group consisting of Cy-Cyzalkyl, C-Czalkenyl,

C,-Cyzhydroxyalkyl, C,-Czhydroxyalkenyl, Ci-Cealkoxy, Cs-Cqzalkoxyalkyl,

C5-Ci,cycloalkyl, C4-Cyocycloalkylalkyl, Cr~Ciearalkyl, Cs-C2 heterocyclyl,

C.-Cioheterocyclylalkyl, C-Cheteroaryl and Cs-Cizheteroarytalkyl; 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, where some or all of the rings may be fused to each other;

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,-Cetrihaloalkoxy, C;-Csalkyisulfonyl, -N(R'2), -OC(O)R', -C(O)OR', -S(O)N(R"),, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl, provided that Ris not phenyl substituted with optionally substituted thienyl;

R* R® and R® are each independently selected from hydrogen, bromo, 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 form an oxo group, while the remaining R’, R™, R®, R®, R®, R%, R'’, and R'™ are each independently selected from hydrogen or C;-Cyalkyl;

or one of R7, 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-Caalkyl; and each R" is independently selected from hydrogen, C-Cealkyl, Cs-Cecycloalkyl, aryl or aralkyl; 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, the invention provides compounds of formula (1) having the following formula (lif): rR R100 R10 R7 - eld / \ N N—V,—R® (I)

A =N rf rR R koe RF wherein: x and y are each independently 1, 2 or 3;

V, is -C(O)-, -C(S)-, -C(OIN(R'}-, -C(S)N(R')-, -C(O)O-, -C(S)O-, -S(O)-(where tis 1 or 2) or -S(O}N(R')- (where tis 1 or 2); each R' is independently selected from the group consisting of hydrogen,

C,-Cyaalkyl, CCiohydroxyalkyl, C4-Cizcycloalkylalkyl and C;-Cygaralkyl;

R?is selected from the group consisting of C,-Cy.alkyl, C-Cizalkenyl,

C,-Cizhydroxyalkyl, C-Cszhydroxyalkenyl, C-Cealkoxy, Cs-Cszalkoxyalkyl,

Cs-Cycycloalkyl, C4-Cyacycloalkytalkyl, aryl, Cr-Cigaralkyl, C5-Cy2 heterocyclyl,

C3-Cy,heterocyciylalkyl, C4-Cyzheteroaryl and Cs-Cozheteroaryialkyl; 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, aryt and heteroaryl, where some or all of the rings may be fused to each other;

R3 is selected from the group consisting of C;-C.alkyl, C-C,zalkenyl,

C,-C;-hydroxyalkyl, C.-C hydroxyalkenyl, C,-Ci2alkoxyalkyl, Cs-Csacycloalkyt,

C4-Ciocycloalkylalkyl, aryl, C-Cyearalkyl, C;-Cyzheterocyciyl, Cs-Cizheterocyclylalkyt,

C;-Cyzheteroaryl and C,-Cy heteroarylalkyi; 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* R® and R® are each independently selected from hydrogen, bromo, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or NR");

R’, R™*, R%, R® R®, R® R™, and R' are each independently selected from hydrogen or C;-Csalkyt; or R” and R™ together, or R®and R® together, or R%nd R® together, or R" 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™, Ré, R®, R’,

R™ R', and R™ are each independently selected from hydrogen or C,-Csalky}; 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-Csalkyl; and each R" is independently selected from hydrogen or C,-Cealkyt; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof. in another aspect, the invention provides compounds of formula (1) having the following formula (IV):

RY R® 100 RY R7 re

R! W 4 \ N N—V,—R? (IV) = re

R? 0 R® R® Rope R wherein: x and y are each independently 1, 2 or 3;

Vi is C(O), -C(S)-, -C(OIN(R)-, -C(S)N(R)-, -C(O)O-, -C(S)O-, -S(O)(where tis 1 or 2) or -S(OXN(R")- (where tis 1 or 2); each R' is independently selected from the group consisting of hydrogen,

C4-Cqaalkyl, C-Cyhydroxyalkyl, C4-Cqocycloalkylalkyl and C,-Cygaralkyl;

R2is selected from the group consisting of C;-Cyzalkyl, C,-Cyzalkenyl,

C2-Cy hydroxyalkyl, C,-Cy2hydroxyalkenyl, Cs-Calkoxyalkyl, C3-CiaCycloaltkyl,

C4-Cracycloalkylalkyl, aryl, C;-Cyearalkyl, C3-Ci2 heterocyclyl, Cs-Cq heterocyclylalkyl,

C4-Cy heteroaryl 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, where some or all of the rings may be fused to each other;

R? is selected from the group consisting of C,-Cizalkyl, C-Cizalkenyl, C,-Cyzhydroxyatkyl, C-Ciohydroxyalkenyl, C.-Ci.alkoxyalkyl, Cs-CiCycloalkyl,

C.-Cy.cycloalkytalkyl, aryl, C~Cigaralkyl, Cs-Cyzheterocyciyl, C-Ci2heterocyclylalkyl,

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

R’ R™ RS R®, R®, R® R', and R'™ are each independently selected from hydrogen or C,-C,alkyl; 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

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; and each R"? is independently selected from hydrogen or Cs-Cgalkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

In another aspect, the invention provides compounds of formula (1) having the following formula (V):

Rr R100 R10 R7 7a

Oh

R%—W, 4 \ N N—V,—R® (V) —\ 0 i {

RC R* ko ge wherein: x and y are each independently 1, 2 or 3;

W, is -O-, -N(R')- or -S(O)- (where tis 0, 1 or 2);

Va is -C(O}, -C(S})-, -C(ON(R"), -C(S)N(R"}-, -C(0)O-, -C(S)O-, -S(O)(where tis 1 or 2) or -S(O}N(R')- (where tis 1 or 2); each R' is independently selected from the group consisting of hydrogen, C,-Cyaalkyl, C/Cyohydroxyalkyi, C,-CioCycloalkylalkyl and Cr-Cyearalkyl;

R2is selected from the group consisting of C,-Cy,alkyl, C-Cioalkenyl,

C,-Cy2hydroxyalkyl, Co-Cqzhydroxyalkeny, C3-Ci.alkoxyalkyl, Cs-CizCycloalkyl,

C.-Cycycloalkylalkyl, aryl, C;-Cygaralkyt, C3-Ci2 heterocyclyl, C;-Cizheterocyclylalkyl,

C,-Cyzheteroaryl and Cs-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, where some or all of the rings may be fused to each other;

R? is selected from the group consisting of Cy-Cqalkyl, C.-Cyzalkenyl,

C,-C12hydroxyalkyl, C~Cyohydroxyalkenyl, C-Cyalkoxyalkyl, Cs-Crocycloalkyl, CCu.cycloalkylalkyl, aryl, C,-Cisaralkyl, Cs-Cizheterocyciyl, Cs-Crzheterocyclytalkyl,

C4-Cyzheteroaryl and C,-Cioheteroarylalkyl; or R? is a multi-ring 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*, R® and R® are each independently selected from hydrogen, bromo, fiuoro, 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,-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

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,-Csatkyl; 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 Ci-Csalkyl; and each R™ is independently selected from hydrogen or C,-Csalkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

In another aspect, the invention provides compounds of formula (1) having the following formula (la):

0)

Ro Rw ROR, 0 x {

R2—w / \ N N—V—R? (la) —_ 0 - {

RS R®™ he Re rR wherein: x and y are each independently 1, 2 or 3;

W is -N(R")S(O)- (where tis 1 or 2);

Vis -C(O)-, -C(S)-, -C(O)N(R')-, -C(SIN(R'})-, -C(O)O~, -C(S)O~, -S(O)-(where t is 1 or 2), -S(OXN(R')- (where tis 1 or 2) or -C(R'")H; each R' is independently selected from the group consisting of hydrogen,

C,-Cyaalkyl, C.-C hydroxyalkyl, C+-Ci2Cycloalkylaikyl and C-Cearalkyf;

RZ is selected from the group consisting of C,-Czalkyl, C,-Cizalkenyl,

C2-Cizhydroxyalkyl, C-Cyshydroxyalkenyl, Co-Cszalkoxyalkyl, C3-Ci cycloalkyl,

Ca+-Cicycloalkylalkyl, aryl, Cr-Cioaralkyl, Cs-Cizheterocyciyl, Cy-Cizheterocyciylalkyl,

Cy-Cq2heteroaryl, and C3-Cizheteroarytalky; 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,-Cizalkyl, C-Cyoalkenyd,

CChydroxyalkyl, C-Cizhydroxyalkenyl, C2-Cizalkoxyalkyl, C1-CiCycloalkyl,

C+Cicycloalkylakyl, aryl, C7-Cisaralkyl, C;-Cizheterocyciyl, Cy-Cyoheterocyclylalkyl,

Ci-Cyzheteroaryt and C,-Cy 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*, R® and R® are each independently selected from hydrogen, brome, fluoro, chloro, methyl, methoxy, tritluoromethyl, cyano, nitro or =N(R').:

R’, R™, R%, R* R’ R™ R', and R'™ are each independently selected from hydrogen or C-Calkyl; or R” and R™ together, or R®%and R® together, or Rand R™ together, or R'® 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™®, R®, R®, R®,

R™, R", and R'™ are each independently selected from hydrogen or C,-Calkyt; 11

AlZNDID S77

Claims (42)

] v ' C WHAT IS CLAIMED IS

1. Use of a compound of formula (1): rR R® 10a RYO RT R79 N- seas N—V—R® (1) = rk RS R™ ko go R* wherein: x and y are each independently 1, 2 or 3. Wis -O-, N(R), -C(R"), -C(O})-, -OC(O)-, -S(O)-; (where tis 0, 1 or 2), -N(R")S(O)- (where tis 1 or 2), -S(O)2N(R')-, -C(OIN(R')-, -C(S)N(R"}-, -OS(O):N{R")-, -OC(ON(R'}-, -OC(S)N(R'}-, -N(R)C(O)N(R')- or -N(R'}C(SIN(R'}-; V is -C(O)-, -C(S)-, -C{O)N(R')-, -C(0)O-, -C(S)O~, -S(O)-(where t is 1 or 2), -S(OXN(R')- (where tis 1 or 2) or -C{R'")H; each R'is independently selected from the group consisting of hydrogen, C,-C,.alkyl, C,-Cy;hydroxyalkyl, C-C;,cycloalkylalkyl and C,~C,garalkyi; R? is selected from the group consisting of C,-Cyalkyl, C2-Cyzalkenyl, C,-Cizhydroxyalkyl, C-Cihydroxyalkenyl, C,-Cizalkaxyalkyl, Cy-Cy.cycloalkyl, CC cycloalkylalkyl, aryl, C-Cyearalkyl, C5-Ci heterocyclyl, Cy-Czheterocyclytalkyl, C,-Cyzheteroaryl, and C5-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, heterocyclyt, 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,-C alkyl, C-C.alkenyl, C2-Cizhydroxyalkyl, Co-Cihydroxyalkenyt, C,-C.alkoxyalkyl, C5-Cr.Cycloalkyl, C+-C, cycloalkylalkyl, aryl, C-Cparalkyl, C;-C1zheterocyclyl, C3-Cizheterocyclylalkyl, C,-Cyzheteroaryl and C,-Czheteroarylalkyl; or R® is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyciyl, aryl and heteroaryl and whera some or all of the rings may be fused to each other; R* R®and R® are each independently selected from hydrogen, bromo, fluoro, chioro, 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,-Cialkyt; or R” and R™ together, or R%nd 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 R®and R™ together do not form an oxo group, while the remaining R’, R’*, RY, 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 C,-Cjalkyl; R" is hydrogen or C,-Csalkyl; 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 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): RA R® 100 RO R? i. N- RZ—W at N—V—R? (I) —N pr RS R ko gs RK wherein: x and y are each independently 1, 2 or 3; Wis -O-, -N(R"}-, -C(R')-, C(O), -OC(O}-, -S(O)-; (where tis 0, 1 or 2), -N(R")S(O)- (where tis 1 or 2), -S(OXN(R')-, -C(OIN(R')-, -C(SIN(R')-, -OS(ORN(R'}, “OC(OIN(R')-, -OC(SIN(R')-, -N(R)C(OIN(R')- or -N(R')C(SIN(R'}-; V is -C(O}, <C(S), -C(OIN(R')-, -C(S)N(R'}-, -C(0)O-, -C(S)O-, -S(O)(where tis 1 or 2), -S(OWN(R')- (where tis 1 or 2) or -C(R'")H; each R' is independently selected from the group consisting of hydrogen, C,-Calkyl, C-Cs2hydroxyalkyl, C-Cicycloalkylalkyl and C,-Cyearalkyt;

R? is selected from the group consisting of Cy-Cyalkyl, C-Croalkenyl, @ C- Cyaan, C-Ciohydroxyalkenyl, C-Cyalkoxyalkyl, Ca-Ci2cycloalkyl,

C.-Cixcycloalkylalkyl, ary, Cr-Cisaralkyl, C;-Cizheterocyclyl, C;-Cizheterocyclylalkyl, Cy-Ci;heteroaryl, and C;-Cy;heteroarylaliyl; 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,-C,zalkyl, C-Cizatkenyl, C-C;hydroxyalkyl, C,-C,hydroxyalkenyl, C,-C.alkoxyalkyl, C3-Ci cycloalkyl, CC cycloalkylalkyl, aryl, Cr-Cigaralkyl, C3-C:heterocyciyl, Cs-Cizheterocyclylatkyl, C,-Ci2heteroaryl and C;-Ci 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*, R® and R® are each independently selected from hydrogen, bromo, 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,-Cjalkyf; 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 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 Ci-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 C,-Calkyl; R'is hydrogen or C,-Csalkyl; and each R" is independently selected from hydrogen or C,-Cgalky}; 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 ll diabetes, fatty liver, non-alcoholic steatohepatitis,

impaired glucose tolerance, insulin resistance, obesity, 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 (lia): 4 5 10 57 R R R108 R™ R RTs R! Mh 0 Nd NY N N N (a) *— re 9a R82 0 RS R™ RoR wherein: x and y are each independently 1, 2 or 3; R'is selected from the group consisting of hydrogen, C,-Cq.alkyl, C,-Cyzhydroxyalkyl, C4-C cycloalkylalkyl and Cr-Cigaralkyl; R?is selected from the group consisting of C-Cyzalkyl, Cs-Ci,alkenyt, CrCi2hydroxyalkyl, C-Cs.alkoxyalkyl, C3-Cihydroxyalkenyl, C5-C.Cycloalkyl,

C.-Cizcycloalkylalkyl, C13-Cearalkyl, C,-Cyzheteroaryl, C5-C,heterocyclylalkyt, C;-Cizheterocyciyl, and C,-Cy heteroarylalkyl, provided that R? is not pyrazinyl, pyridinonyl, pyrrolidinonyl or imidazolyt; or R? is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyctyl, aryl and heteroaryl, where some or all of the rings may be fused to each other, R%is selected from the group consisting of C3-Ci,alkyl, C5-Crzalkenyi, Cs-Ciohydroxyalkyl, Ca-Cyzhydroxyalkenyl, Ca-Cizalkoxyalkyl, Cs-Ciocycloalkyl, C4-Cqocycloalkylalkyl, aryl, Cr-Ciearalkyl, C3-Cyzheterocyclyl, Cs-Cizheterocyclylalkyl, C4-Cy heteroaryl and C;-Cy;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* R® and R® are each independently selected from hydrogen, bromo, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R'®),; R’, RR: RE R® R% Rand R' are each independently selected from hydrogen or C,-Csalkyl; or R%nd R together, or R'® and R'® together form an oxo group, while the remaining R7, R®, R®, R®, R®, R®, R', and R'™ are each independently selected from hydrogen or C4-Caalkyt; 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"®, R7, R™, R?, R®, R® and R* are each independently selected from hydrogen or Cy-Cjalkyl; 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.

11. The compound of Claim 10 wherein: x and y are each independently 1, 2 or 3; R'is selected from the group consisting of hydrogen, C,-Cyalkyl, C,-Cyohydroxyalkyl, C4-Cyscycloalkylalkyt and C,-Csgaralkyt; RZis selected from the group consisting of C~C;.alkyl, Cs-Cysalkeny, C;-Cqshydroxyalkyl, Co-Czalkoxyalkyl, Cs-Cizhydroxyalkenyt, Cs-Cyzcycloalkyl, C4+-Cqocycioalkylaikyl, Cqa-Cygaralkyl, C4-Cyzheteroaryl, Cs-Cozheterocyclylalkyl,

C.-Cqoheterocyclyl and Cs-Cyoheteroarylalkyl, provided that R? is not pyrazinyl, pyridinonyl, pyrrolidinonyl or imidazolyl; Reis selected from the group consisting of Cs-Csaalkyl, Cs-Cyalkenyl, C,-Cyshydroxyalkyl, Cs-Cyshydroxyalkenyl, Cs-Cyaalkoxyalkyl, Cs-Ciacycloalkyl, C4-Ciocycloalkylalkyl, aryl, C;-Cigaralkyl, C3-Cizheterocyclyl, Cs-Ciheterocyclylalkyl, C;-C2 heteroaryl and C;-C,zheteroarylalkyl;

R* R® and R® are each independently selected from hydrogen, bromo, 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-Csalkyl; and each R" is independently selected from hydrogen or C,-Cealkyl.

12. The compound of Claim 11 wherein: x and y are each 1; R! is selected from the group consisting of hydrogen or C-Ci2alkyl; R2is selected from the group consisting of C,-Cszalkyl, Cs-Ci2alkenyl, C,-Ciocycloalkyl, C,-Ciacycloalkylalkyl, C13-Cioaralkyl, C-Cizheteroaryl, Cs-C,-heterocyclylalkyl and C,-Cyzheteroarylalkyl; Ris selected from the group consisting of C3-Csaalkyl, Cs-Cs2cycloalkyi, C4-Cyocycioalkylalkyl, aryl, Cr-Cgaralkyl, Cs-Cysheterocyclyl, Cs-Cisheterocyclylalkyl, C4-C,, heteroaryl and C;-Cy;heteroarylalkyt; R* R® and R® are each independently selected from hydrogen, bromo, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or N(RB); R’, R™® R8, R®, R°, R®, R'® and R'* are each independently selected from hydrogen or C,-Csalkyl; and each R" is independently selected from hydrogen or C-Cealkyl.

13. The compound of Claim 12 wherein: R?is C3-C.cycloalkyl or C4-Ci cycloalkylalkyl; R3is selected from the group consisting of Cs-Cy,cycloalkyl or C,4-C4ocycloalkylalkyl; R* R® and R® are each hydrogen; and R’, R™®, R®, R®, R?, R®, R" and R'® are each hydrogen or C-Csalkyl.

14. The compound of Claim 13 wherein: R? is C;-Cy cycloalkyl; and R® is C3-Cyscycloalkyl.

15. The compound of Claim 14, namely, Cyclohexanecarboxylic acid [6-(4- cyclohexanecarbonyl-piperazin-1-yl}pyridin-3-ylJamide.

® 16. 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) in a mammal.

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

18. A compound of formula (lib): rR R® 108 RYO R? i R! Mek 0 wh v—{ (Nib) *—( = opr R® 0 rR R® hogs R* wherein: x and y are each independently 1, 2 or 3; R' is selected from the group consisting of hydrogen, C,-C1.alkyl, CCzhydroxyalkyl, C4-CizCycioalkylalkyl and C-Cearalkyl, R?is selacted from the group consisting of C,-C,,alkyl, C-Cizalkenyl, C2-C.zhydroxyalkyl, C,-Ci2hydroxyalkenyl, C4-Calkoxy, Cs-C alkoxyalkyl, Cs-Crcycloalkyl, C.-C cycloalkylalkyl, C-Cyoaralkyl, C;-C,; heterocycivi, Cs-Cizheterocydiytalikyl, C.-Cyzheteroaryl and Cs-Coaheteroarylalkyf, or R? is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyciyl, aryl and heteroaryl, where some or all of the rings may be fused to each other; R’is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, Cs-Cealkyl, C,-Cetrihaloalkyl, Ci-Cetrihaloalkoxy, Cy-Cealkytsutfonyl, N(R"), -OC(O)R™, -C(OJOR'", -S(O),N(R"%),, cycloalkyl, heterocyclyl, hetsroaryl and heteroaryicycioalkyl, provided that R® is not phenyl substituted with optionally substituted thienyt; R*, R® and R* are each independently selected from hydrogen, bromo, fluoro, chioro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R*); R’, R™ R®, R®™ R®, R™ R', and R*® are each independently selected 77 ELAZNDID ETT from hydrogen or C-Caalkyl; or R%nd R™ together, or R"® and R'* together form an oxo group, while the remaining R?, R”®, R®, R®, R®, R®, R'°, and R'™ are each independently selected from hydrogen or C4-Caalkyl; or one of R7, 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,-Cjalkyl; and each R'? is independently selected from hydrogen, Cs-Csalkyl, Cs-Cscycloalkyl, aryl or aralkyl; and each R'3 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.

19. The compound of Claim 18 wherein: x and y are each independently 1, 2 or 3; R'is selected from the group consisting of hydrogen, Cs-Cyzalkyi, C2-Ciohydroxyalkyl, C4-C,.cycloalkylalkyl and C-Cygaralkyl; Ris selected from the group consisting of C;-Cysalkyl, C,-Cizalkenyl, C,-Cq,hydroxyalkyl, Co-Cyshydroxyalkenyl, C4-Cealkoxy, C;-Cqzalkoxyalkyl, Ca-Cy,cycloalkyl, C4-Cqocycloalkylalkyl, C-Cigaralkyl, C5-Cy; heterocyclyl, Cs-Cysheterocyciylalkyl, C,-Cizheteroaryl and C;-Cizheteroarylalkyt; R3is phenyl! optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C,-Cgalkyl, C:-Cetrihaloalkyl, C1-Cetrihaloalkoxy, C-Cealkyisulfonyl, -N(R'2),, -OC(O)R'?, -C(OYOR™?, -S(O),N(R"?),, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl, provided that R? is not phenyl substituted with optionally substituted thienyl; R* R® and R® are each independently selected from hydrogen, bromo, 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;-Caalkyl, or R' and R'® together form an oxo group and the remaining R’, R”, R?, R%, R® and R™ are each hydrogen; each R'is independently selected from hydrogen, C,-Cealkyi, Cs-Cgcycloalkyl, aryl or aralkyl; and each R* is independently selected from hydrogen or C;-Cgalky!.

20. The compound of Claim 19 wherein: x and y are each 1; R' is hydrogen or C;-Cyzalkyl; R2is selected from the group consisting of Cs-Csaalkyl, C,-Cizalkenyl, C,Ci.hydroxyalkyl, C~Cszhydroxyalkenyl, C;-Cealkoxy, C;-Cioalkoxyalkyl, Cs-Cy.cycloalkyl, C4-Cq.cycloalkylalkyl, C-Ciearalkyl, Cs-Cs2 heterocyclyl, C,-C,-heterocyclylalkyl, C-Cioheteroaryl and C3-Cqzheteroarylalkyl, R3is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C-Cealkyl, C,-Cetrihaloatkyl, C,-Cetrihaloalkoxy, Cs-Csalkylsutfonyl, -N(R'2),, -OC(O)R", -C(OYOR'"?, -S(O),N(R"),, cycloalkyl, heterocyclyl, heteroaryl and heteroaryicycloalkyl, provided that R® is not pheny! substituted with optionally substituted thienyl; R* R® and R® are each hydrogen; R’, R™?, R®, R® R® R™ R'" and R' are each hydrogen; or R™ and R'™ together form an oxo group and the remaining R’, R”, R®, R® R® and R® are each hydrogen; and each R'? is independently selected from hydrogen, C-Cgalkyl, Cs-Cecycloalkyl, aryl or aralkyl.

21. The compound of Claim 20 wherein: R?is Cy-Cyzalkyl; and R® is phenyl optionally substituted by one or more substituents selected from halo, C,-Cealkyl, Cs-Cstrihaloaikyl and C,-Cetrihaloalkoxy.

22. The compound of Claim 21 selected from the group consisting of the following: 4-Methylpentanoic acid {6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridin-3- yl}amide; Hexanoic acid {6-[4-(2-trifluoromethylbenzoyi)piperazin-1-yl]pyridin-3-yl}amide; Heptanoic acid {6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridin-3-yl}amide; Heptanoic acid {6-[4~(2,5-dichlorobenzoyl)piperazin-1-yllpyridin-3-yl}lamide; and Hexanoic acid {6-[4-(2,5-dichlorobenzoyl)piperazin-1-yl]pyridin-3-yl}amide.

23. The compound of Claim 20 wherein:

R? is Cs-C cycloalkyl; and R? is phenyl optionally substituted by one or more substituents selected from halo, C,-Cealkyt, Ci-Cetrihaloalkyl and C,-Cetrihaloalkoxy.

24. The compound of Claim 23, namely, Cyciohexanecarboxytic acid {6-{4- (2-trifluoromethyibenzoyl)piperazin-1-yljpyridin-3-yl}amide.

25. The compound of Claim 20 wherein: R? is C;-Cqzarakyl optionally substituted by one or more substituents selected from halo, C,-Cealkyl, C-Cetrihaloalkyl and C,-Cetrihaloalkoxy; and R3 is phenyl optionally substituted by one or more substituents selected from halo, C,-Cealkyl, C,-Cetrihaloalkyl and C,-Cetrihaloatkoxy.

26. The compound of Claim 25 selected from the group consisting of the following: 3-Phenyl-N-{8-{4-{2-triflucromethyibenzoyl)piperazin- 1 -yi]-pyridin-3-yi}propionamide; 4-Phenyl-N-{6-[4<(2-trifluoromethyibenzoyl)piperazin- 1-yi}-pyridin-3-yi}butyramide; and N-{6{2-Ox0-4-(2-trifluoromethytbenzoyl)piperazin-1-yf}-pyrilin-3-y{}-4- phenylbutyramide.

27. Use of a compound of Claim 18 in the manufacture of a medicament for treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal.

28. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Claim 18.

29. The compound of formula (Ill):

rR? R® 100 RY R7 7a —N ( ° rR RY Lo oo wherein: x and y are each independently 1, 2 or 3; Vais -C(O), -C(S)-, -COIN(R), -C(S)N(R')-, -C(0)O-, -C(S)O-, -S(O)~«(where tis 1 or 2) or -S(O)N(R')- (where tis 1 or 2); each R'is independently selected from the group consisting of hydrogen, C;-Cizalkyl, C-Ci2hydroxyalkyl, C4-Ci cycloalkylalkyl and C-Cisaralkyl; R?is selected from the group consisting of C1-Cysalkyl, C-Cizalkenyi,

C.-C1.hydroxyalkyl, Co-Cyohydroxyalkenyl, C,-Cealkoxy, Cs-Cyoalkoxyalkyl, Cs-Cy.cycloalkyl, C4-Cy cycloalkylalkyl, aryl, Cr-Cearalkyl, Cs-Cy. heterocyclyl, C5-Cyzheterocyciylalkyl, C,-Cioheteroaryl and C3-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, where some or all of the rings may be fused to each other; R? is selected from the group consisting of C4-Cy,alkyl, C~Cizalkenyl, C»Cyshydroxyalkyl, C,-Cyshydroxyatkenyl, Co-Cioalkoxyalkyl, Cs-Ci2cycloalkyl, C+-Cy cycloalkylalkyl, aryl, Cr-Cigaralkyl, Cs-Ci2heterocyclyl, Cs-Cizheterocyclylalkyl, C:-Cyzheteroaryt and C;-Cq;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, aryt and heteroaryl and where some or all of the rings may be fused to each other; R* R® and R® are each independently selected from hydrogen, bromo, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R"),; R’, R™ R%, R®™ R® R™, RY, and R' are each independently selected from hydrogen or C,-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)-, 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,-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'%, R7, R™ R®, R®, R®, and R* are each independently selected from hydrogen or C,-Csalkyl; and each R" is independently selected from hydrogen or C;-Cealkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmacsutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

30. The compound of Claim 29 wherein: x and y are each independently 1, 2 or 3; V, is -C(O)- or -C(S)-; R' is selected from the group consisting of hydrogen, C;-Cq2alkyl, C,-Cyzhydroxyalkyl, C,-Cy cycloalkylalkyl and C-Cyqaralkyt; R?is selected from the group consisting of C,-C,,alkyt, C,-Cy.alkenyl, C-Cyzhydroxyalkyl, C»-C, hydroxyalkenyl, C.-Cealkoxy, Cs-C4zalkoxyalkyl, Cs-Cy2cycloalkyl, C,-Cycycloalkylalkyl, aryl, C-Cyearalkyl, C3-Cy, heterocyclyl, C3-Cyzheterocyclylalkyl, C,-C4;heteroaryl and C;-Cyoheteroaryialkyl; R? is selected from the group consisting of C4-Cqzalkyl, C-Cy,alkenyl, C-Czhydroxyalkyl, C.-C hydroxyalkenyl, C-Cyzalkoxyalkyl, C;-Cq2cycioatkyl, C4+-Cyocycloalkylalkyl, aryl, C-Cysaralkyl, C3-Cyoheterocyclyl, Cs-Cyoheterocyclylalkyl, C,-Cizheteroaryl and C;-Cizheteroarylalkyi; R* R® and R® are each independently selected from hydrogen, bromo, fluoro, chloro, methyl, methoxy, trifluoromethyi, cyano, nitro or -N(R'®),; R’, R™, RE, R®, R® R*®, R', and R'™ are each independently selected from hydrogen or C,-Caalkyl; and each R" is independently selected from hydrogen or C,-Csalkyl.

31. The compound of Claim 30 wherein; x and y are each 1; Va is -C(O); R'is hydrogen or C;-Cy.alkyl; R?is selected from the group consisting of C,-Csaalkyl, C>-Cialkenyl, C2-Cizhydroxyalkyt, C,~Cy hydroxyalkenyl, C4-Cealkoxy, C,-Cyaalkoxyalkyt, C5-Cyzcycloalkyl, Cs-Ciacycloalkylalkyl, aryl, Cr-Ciearalkyl, Cs-Cs, heterocycivi, Cs-Cyzheterocyclylalkyl, Cy-Cisheteroaryl and C;-Cosheteroaryialky; Ris naphthyl or phenyl, each optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-Csalkyl, C,-Cetrihaloalkyl, Cs-Ctrihaloalkoxy, Cs-Cealkylsulfonyl, -N(R'?),, -OC(O)R", -C(O)OR"2, -S(0)N(R"™),, cycloalkyl, heterocyclyl, heteroaryl and heteroaryicycloalkyl; R* R® and R® are each hydrogen; R’, R™, R8, R® R® R® R'°, and R'® are each hydrogen; and each R'? is independently selected from hydrogen, C;-Cealkyl, C,-Cecycloalky!, aryl or aralkyl.

32. The compound of Claim 31 wherein: R?is C4-Cy2alkyl or C;-Cyzaralkyl optionally substituted by one or more substituents selected from the group consisting of halo, C4-Csalkyl, C4-Cetrihaloalkyl and C,-Cetrihaloalkoxy; R? is naphthyl or phenyl, each optionally substituted by one or more substituents selected from the group consisting of halo, C;-Cealkyl, Cy-Cetrihaloalkyl and C,-Cgtrihaloalkoxy.

33. The compound of Claim 32 selected from the group consisting of the following: Pentane-1-sulfonic acid {6-[4~2-trifluoromethylbenzoyl}-piperazin-1-ylpyridin-3- yl}amide; Butane-1-sulfonic acid {6-[4-(2-trifluoromethylbenzoyl}-piperazin-1-yl]pyridin-3- yl}amide; Hexane-1-sulfonic acid {8-[4~(2-triflucromethylbenzoyl)-piperazin-1-yflpyridin-3- yl}amide; Pentane-1-sulfonic acid {6-]4-(2-bromobenzoyl)piperazin-1-yi]pyridin-3-yl}amide; Hexane-1-sulfonic acid {6-[4-(2,5-dichlorobenzoyl}-piperazin-1-yl]pyridin-3-ylyamide; Pentane-1-sulfonic acid {6-{4-(2,5-dichlorobenzoyi)-piperazin-1-yi]pyridin-3-yi}amide; Hexane-1-sulfonic acid {6-[4-(naphthalene-1-carbonyl)-piperazin-1-yi]pyridin-3- yl}amide; Pentane-1-sulfonic acid {6-[4-(naphthalene-1-carbonyl}-piperazin-1-yl]pyridin-3- yilamide; and 3-Phenylpropane-1-sulfonic acid {6-{4~(2-trifluoromethyl-benzoyl)piperazin-1-yllpyridin- 3-yl}amide.

® 34. The compound of Claim 31 wherein: R? is C4-Cizcycioalkytalkyl, Cr-Cysaralkyl, C5-Cisheterocyclylalkyl or Cy-Crheteroarylaliyt; R® is naphthyl or phenyl, each optionally substituted by one or more substituents selected from the group consisting of halo, C,-Caalkyl, C,-Cetrihaloalkyl and Cy-Cetrihaloalkoxy.

35. Use of a compound of Claim 29 in the manufacture of a medicament for treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal.

36. A phamaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Claim

29.

37. The compound of formula (IV): rR R® 100 R'C RY ra R! ik R' 4 \ N N—V,—R® (V} 2 or Rb R® ko go RK wherein: x and y are each independently 1, 2 or 3; Va Is -C(O}, -C(S})-, -C(OIN(R)-, -C(SIN(R')-, -C(0)O-, -C(S)O-, -S(O)~where tis 1 or 2) or -S(OMN(R')- (where t is 1 or 2); each R' is independently selected from the group consisting of hydrogen, C-C,zalkyl, Cz-Cy;hydroxyalkyt, C.-C, Cycioalkylakyl and Cr-Ciearalkyt; R?is selected from the group consisting of C,-C1zalkyl, C,-Czalkenyl, Cz-C1zhydroxyalkyl, Cz-Cr2hydroxyalkenyl, Cs-Csaalkoxyalkyl, C5-CizCycloalkyl, Ca-CrzCycloalkylalkyl, aryl, C,-Csaralkyl, C3-Cy; heterocyciyl, C;-Cizheterocyclylalkyl, Cy-Cizheteroaryl and C3-Cizheteroarylalkyt; or R? is a multi-ring structure having 2 to 4 rings wherein the rings are 84 ATNBID eT independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryt, where some or all of the rings may be fused to each other; R? is selected from the group consisting of C1-Cialkyl, C~Cyoalkenyl, C,-Cizhydroxyalkyl, Co-Cyhydroxyalkenyl, C2-Cqoalkoxyalkyl, C3-Ciocycloalkyi,

C.+-Cyzcycloalkylalkyl, aryl, C-Cigaralkyl, Cs-Czheterocyclyl, Cs-Cyzheterocyclylalkyl, C,-Cy2heteroaryl and C3-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* R® and R® are each independently selected from hydrogen, bromo, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R")5; R’, R™ R8, 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 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,-Cjalkyl; and each R" is independently selected from hydrogen or Cs-Cealkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

38. The compound of Claim 37 wherein: x and y are each independently 1, 2 or 3; V, is -C(O), -C(S)-, -C{OIN(R'}, -C(S)N(R')-, -C(O)O-, -S(O)~(where t is 1 or 2) or -S(OXN(R')- (where t is 1 or 2); each R' is independently selected from the group consisting of hydrogen, C;-C1zalkyl, C,-Ci2hydroxyalkyl, C4-Cy.cycloalkylalkyl and Cr-Ciearalkyl; Ris selected from the group consisting of C4-Cyaalkyl, C-Cizalkenyl,

C.-C hydroxyalkyl, C~Cyshydroxyalkenyl, Cs-Cyzalkoxyalkyl, Cs-Cizcycloalkyi, C+ Cy2cycloalkylalkyl, aryl, C;-Cearalkyl, Cs-Ci, heterocyclyl, Cs-Cizheterocyclylatkyl, C,-Cyoheteroaryl and C;-Cyzheteroarylalkyl;

R? is selected from the group consisting of C4-C.alkyl, C2-Ciaalkenyl, CC2hydroxyalkyl, C-Cszhydroxyalkeny, C>-C1,alkoxyalkyl, C3-Ci.Cycloalkyl,

C.-Cy,cycloalkylalkyl, aryl, Cr-Cearalkyl, C5-Cszheterocyclyl, Cs-C1zheterocyclylalkyl, C,-Cy,heteroaryl and Cs-Cszheteroarylalkyl; R*, R® and R® are each independently selected from hydrogen, bromo, 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;-Cjalkyl; and each R" is independently selected from hydrogen or C-Cealkyl.

39. The compound of Claim 38 wherein: x and y are each 1; Va is -C(O); each R' is independently hydrogen or C,-Cealkyl; R?is selected from the group consisting of C4-Cy.8lkyl, C,-Cszalkenyl, C-Cyzhydroxyalkyl, Co-Cizhydroxyalkenyl, Cs-Cyzalkoxyalkyl, Cs-Ci.cycloalkyl, C4-Cizcycloalkylalkyl, aryl, Cr-Cyearalkyl, Cs-Cy2 heterocyclyl, C;-Cyzheterocyclylalkyl, C,-Cq-heteroaryl and C,-Cyoheteroarylalkyi; R?is selected from the group consisting of C3-C2alkyl, C+-Cqzalkenyl, C;-Cs.hydroxyalkyl, Cs-Cqohydroxyalkenyl, C3-Csalkoxyalkyl, Cs-Cixcycloalkyl, C4Cyo0ycloalkylalkyl, aryl, Cr-Cygaralkyl, Cs-Cizheterocyclyl, Cs-Cyzheterocyclylalkyt, C4-C1. heteroaryl and Cs-Cyzheteroarylalkyl; R* R°® and R® are each hydrogen; R’, R™®, R8, R®, R®, R®, R'’, and R'™ are each hydrogen; and each R'is independently selected from hydrogen, C,-Cgalkyl, Cs-Cgcycloalkyl, aryl or aralkyl.

40. The compound of Claim 39 wherein: R? is C,-Cy.alkyl or C-Cy,aralkyl optionally substituted by one or more substituents selected from the group consisting of halo, Cs-Cgalkyl, Cs-Cetrihaloalkyl and C,-Cetrihaloalkoxy; and R? is selected from the group consisting of Cy-C,cycloalkyl, aryl, C;-Cyzheterocyclyl or C;-C,, heteroaryl.

41. The compound of Claim 40 wherein R? is C5-Cy,cycloalkyl.

®

42. The compound of Claim 41 selected from the group consisting of the following: 1-{6-(4-Cyclohexanecarbonyipiperazin-1-yl)pyridin-3-yi}-3-pentylurea; and 1-[6-{4-Cyclopentanecarbonyipiperazin-1-yl)pyridin-3-yi}-3-pentylurea.

43. The compound of Claim 40 wherein R® is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C,-Cealkyl, C-Cetrihaloalkyl and Cy-Cgtrihaloalkoxy.

44. The compound of Claim 43 selected from the group consisting of the following: 1-Pentyl-3-{6-{4-(2-trifluoromethyibenzoyi)piperazin- 1-yi]-pyridin-3-yijurea; 1-Butyl-3-{6-{4-(2-trifluoromethyibenzoyl)piperazin- 1 -yl}-pyridin-3-yljurea; 1-Phenethyt-3-{6-{4-(2-triffluoromethyibenzoyl)piperazin- 1 -yijpyridin-3-yijurea; 1-Benzyl-3-{6-{4-(2-triffuoromethylbenzoyl)piperazin-1-yi}-pyridin-3-yljurea; and 1-{4-Fiuorobenzyl)-3-{6-[4-{2-trifluoromethylbenzoyl)-piperazin-1-yljpyridin-3-yljurea.

45. The compound of Claim 40 wherein R® is piperidinyl optionally substituted by C-Cealkyl or C~C.z2ralkyl, wherein the Cr-Cizaralkyl group is optionally substituted by one or more substituents selected from the group consisting of halo, Cy-Cealkyl, C,-Cetrihaloalkyt and Cs-Cgtrihaloalkoxy.

48. The compound of Claim 45, namely, 1-{6{4-(1-Benzylpiperidine-4- carbonyl)piperazin-1-yi}-pyridin-3-y/}-3-pentyturea.

47. The compound of Claim 40 wherein R® is pyridinyl optionally substituted by one or more substituents selected from the group consisting of halo or C-Cealkyl.

48. The compound of Claim 47 selected from the group consisting of the following: 1-Pentyl-3-{6-{4-(pyridine-2-carbonyl)piperazin-1-yl}-pyridin-3-yijurea; and 1-Pentyl-3-{6-{4-(pyridine-4-carbonyl)piperazin-1-yf}-pyridin-3-yljurea.

49. Use of a compound of Claim 37 in the manufacture of a medicament for 87 AlLLTNOID Sm

® treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal.

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

37.

51. The compound of formula (V): o7 rR Rite ROR Je Ot R2—wW, / \ N—V,—R® (V) { RE RY R? RS R wherein: x and y are each independently 1, 2 or 3; W, is -O-, -N(R')- or -S(O)- (where tis 0, 1 or 2); Vy is -C(O)-, -C(S}, -C(ON(R')-, -C(SIN(R"}-, -C(0)O-, -C(S)O-, -S(O)-(where tis 1 or 2) or -S(O)N(R')- (where t is 1 or 2); each R' is independently selected from the group consisting of hydrogen, C4-Cszalkyl, C-Ci2hydroxyalkyl, C4-C2cycloalkylalkyl and C,-Ciearalkyt. Ris selected from the group consisting of C,-C1zalkyl, C2-C.alkenyl, C2-Ci2hydroxyalkyl, C.-C ohydroxyalkenyl, Cy-Cyzalkoxyalkyl, C3-Cy cycloalkyl,

C.+-Cicycloalkytalkyl, aryl, C,-Cigaralkyl, C3-Ci2 heterocyclyl, C5-Cizheterocyciylalkyl, C-Cizheteroaryl 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, where some or all of the rings may be fused to each other; R'is selected from the group consisting of C,-Cralkyl, C-C,,alkenyl, C2-Cizhydroxyalkyl, C2-Cihydroxyalkenyl, C,-Ci.alkoxyalkyl, Cx-Cicycloalkyl, C+-Crzcycloalkytalkyl, aryl, Cr-Cysaralkyl, C3-Cyzheterocyclyl, Cs-Cy heterocyclytalkyl, Ci-Cizheteroaryl and C;-Cyzheteroarylalkyl; or R* is a multi-ring structure having 2 to 4 rings wherein the rings are 88 AMINDIDS TT 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; RY, R® and R® are each independently selected from hydrogen, bromo, fluoro, chioro, 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, 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™, R®, R% R® R® R' and R'® are each independently selected from hydrogen or C1-Cialkyl; or one of RY, 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-Csalkyl; and each R" is independently selected from hydrogen or Cy-Cealkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.

52. The compound of Claim 51 wherein: x and y are each independently 1, 2 or 3; W, is -O-, -N(R")- or -S(O)r (where tis 0, 1 or 2); Va is -C(O), -C(S) -C(O)N(R")-, -C(S)N(R'}-, -C(O)O-, -S(O)-(where t is 1 or 2) or -S(OYN(R')- (where tis 1 or 2); each R' is independently selected from the group consisting of hydrogen, C,-Cizalkyl, C-Ciohydroxyalkyl, C4-Cqcycloalkylalkyl and C-Cygaralkyt; R?is selected from the group consisting of C-Cy.alkyl, C~C4 alkenyl, C,-C,;hydroxyalkyl, C~Cyohydroxyalkenyl, Cs-Cq.alkoxyalkyl, Cs-Cs2cycloalkyt, C+-Cy cycloalkylalkyl, aryl, C-Cygaralkyl, C3-C4, heterocyclyl, C;-Cizheterocyclylalkyl, C,-Cyzheteroaryl and C,;-Cysheteroarylalkyl; Ris selected from the group consisting of C4-Cyzalkyl, Co-Cyzalkenyl, C,-Cyshydroxyalkyl, C-Cyohydroxyalkenyl, C,-Cyzalkoxyalkyl, Cs-Cizcycloalkyl,

C.-Ci.cycloalkylalkyl, aryl, C;-Ciearalkyl, C3-Cszheterocyclyl, C,-Cyzheterocyclylalkyi, C1-Csheteroaryl and C;-Cy heteroarylalkyi; RY, R® and R® are each independently selected from hydrogen, bromo, 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; and each R" is independently selected from hydrogen or Cy-Cealkyl.

53. The compound of Claim 52 wherein: x and y are each 1; WwW, is -O-; V, is -C(O}- or -C(S); R?is selected from the group consisting of C-Cy,alkyl, C-Ci.alkenyl, C,-Cyzhydroxyalkyl, Co-Cyzhydroxyalkenyl, Cs-Cioalkoxyalkyl, Cs-Cizcycloalkyl, C4-Ci.cycloalkylalkyl, aryl, Cr-Cysaralkyl, C3-Cy, heterocyclyl, Cs-Cizheterocyclylalkyl, C;-Cyzheteroaryl and C;-Cy heteroarylalkyl; R®is selected from the group consisting of C;-Cszalkyl, C;-Cioalkenyl, Cs-C1ohydroxyalkyl, Cs-Cyzhydroxyalkenyl, C3-Cszalkoxy, Cs-Cszalkoxyalkyl, C,-Crcycloalkyl, C4~Crcycloalkylalkyl, aryl, Cr-Cyearalkyl, Cs-Cizheterocyclyl, C+-Cheterocyclylalkyl, C4-Cy, heteroaryl and Cs-Croheteroarylalkyl; R* R® and R® are each hydrogen; and R’, R™ R® R®™ R® R% R™, and R'™ are each hydrogen.

54. The compound of Claim 53 wherein: V, is -C(O); R?is selected from the group consisting of C-Cszalkyl, C5-Cyocycloalkyl, C4+-Cy.cycloalkylalkyl, aryl, C-Cyearalkyl, C:-C1, heterocyclyl, C;-Cizheterocyclylalkyl,

C,.-Cyzheteroaryl and C;-Cyheteroarylalkyl; and Ris selected from the group consisting of C;-Cy,cycloalkyl, C4-Ciocycloalkylalkyl, aryl, C~Ciearalkyl, Cs-Cszheterocyciyl, Cs-Cyzheterocyclylalkyl, C;-C,, heteroaryl and C;-Ci heteroarylalkyl.

55. The compound of Claim 52 wherein: xand y are each 1; W, is -N(R")-; V, is -G(O)- or -C(S}; R' is hydrogen or C;-Csalkyl; R?is selected from the group consisting of C;-Cy,alkyl, C,-Cizalkeny, C,-Cyzhydroxyalkyt, C2-Cyshydroxyalkenyl, Cs-Cizalkoxyalkyl, Cs-Cyacycloalkyl,

C.~Crzcycloalkylaliyl, aryl, C,-Crearalkyl, C5-C,; heterocyclyl, Cs-Crzheterocyclylalkyl, C,-Cy;heteroaryt and Cs-Cysheteroarylalkyl; Reis selected from the group consisting of Cs-Ci2alkyl, Cs-Cyzalkenyl, Cs-Cyzhydroxyalkyl, Cs-Cyshydroxyalkenyl, Cs-Cizalkoxy, Cs-Croalkoxyalkyl, C;-Ciacycloalkyl, Cs-Cyzcycloalkylalkyl, aryl, C,Cyearalkyl, Cs-Cy heterocyclyl, C5-Cyzheterocyclylalkyl, Ci-Cyz heteroaryl and Cs-Cysheteroarylalkyl; R* R% and R® are each hydrogen; and R’ R™ R® R® R® R%™, R', and R'™ are each hydrogen.

56. The compound of Claim 55 wherein: V, is -C(O); R2is selected from the group consisting of C4-Cszalkyl, C3-Cq2Cycloalkyl, C4-Cyocycloalkylalkyl, aryl, C-Crearalkyl, C5-Cy. heterocyclyl, Cs-Cizheterocyclylalkyl, C,-Cq heteroaryl and C,-Cyheteroarylalkyi; and R’is selected from the group consisting of C3-Cy,cycloalkyl, C4+-Ci cycloalkylalkyl, aryl, C-Cyearalkyl, C3-Cizheterocyclyl, Cs-Cizheterocyclytalkyl, C,-C;y; heteroaryl and C3-Cyyheteroarylalkyi.

57. The compound of Claim 52 wherein: x and y are each 1; W, is -S(O)- (where tis 0, 1 or 2); V, is -C(O)- or -C(S}; Ris selected from the group consisting of C4-Cy.alkyl, C,-Cqalkenyl, C,-Cyzhydroxyalkyl, C,-Cyhydroxyalkenyl, C,-Cyaalkoxyalkyl, Cs-Cyocycloalkyl,

C.-Cicycloalkylalkyl, aryl, Cr-Cyearalkyl, C5-Ci2 heterocyclyl, Cs-Cozheterocyclylalkyi, C;-Cyoheteroaryl and C;-Cysheteroarylalkyl; R3is selected from the group consisting of C5-Cy.alkyl, C5-Cy alkenyl, C,-Cyohydroxyalkyl, Cs-Ciohydroxyalkenyl, C;-Cyqalkoxy, Cs-Cialkoxyalkyl, C;-Cyocycloalkyl, C4-Ciacycloalkylalkyl, aryl, C,-Cygaralkyl, Cs-Cqzheterocyclyi, Ci-Cqzheterocyclylalkyl, C4-C,, heteroaryl and C3-Ci.heteroarylalkyl; R*, R® and R® are each hydrogen; and R’, R™, R%, R® R® R™ R™, and R'™ are each hydrogen.

58. The compound of Claim 57 wherein: Va is -C(O};

® R?is selected from the group consisting of C1-Czalkyl, Cs-Cszcycloalkyl, CC cycloalkylalkyl, aryl, CrChsaralkyl, Cs-Cy2 heterocyclyl, Cs-Cyzheterocyclytalkyl, Ci-Cizheteroaryl and C3-Cizheteroarylalkyl; and R’is selected from the group consisting of Cs-C1,Cycloalkyt, C+-Cicycloalkylalkyl, aryl, Cr-Cioaraliyt, Ci-Cizheterocyclyi, C3-Ci2heterocyclylalkyl, C,-C2 heteroaryl and Cy-C,heteroarylalkyl.

59. Use of a compound of Claim 51 in the manufacture of a medicament for treating a disease or condition mediated by stearoyi-CoA desaturase (SCD) in a mammal.

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

51.

81. A compound of formula (la): 4 5 10 7 R R R108 R™ R RT Oh RZ—W / \ N N—v—R3 (la) ( Sa rb R \ 0 I) Re wherein: x and y are each independently 1, 2 or 3; W is -N(R")S(O)- (where t is 1 or 2); Vis C(O}, -C(S)-, -C(O)N(R')-, -C(S)N(R"}-, -C(0)O-, -C(S)O-, -S{O)-(where tis 1 or 2}, -S(OXN(R’)- (where tis 1 or 2) or -C(R"")H; each R' is independently selected from the group consisting of hydrogen, C,-Craalkyl, C-Cyzhydroxyalkyl, C-Ci2cycloalkylalkyl and Cr-Cioaralkyl; R? is selected from the group consisting of C,-Calkyl, C2-Cy.alkenyt, CC hydroxyalkyl, Co-Cizhydroxyalkenyl, C,-Cizalkoxyalkyl, C5-Cizcycloalkyl, C«-Cricycloalkylatkyl, aryl, Cr-Cisaralkyl, Cs-Cozheterocyciyl, C3-Ci heterocyclylalkyl, Cy-Cizheteroaryl, and C;-C, heteroarylatkyl; or R? is a muiti-ring structure having 2 to 4 rings wherein the rings are 92 AVTNDID ST 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;-Cyalkyi, Co-Cyzalkenyl, C,-Cqohydroxyalkyl, C-Cohydroxyalkenyl, C,-Cizalkoxyalkyl, C;-CizCycloalkyl, C4-Cyocycloalkyialkyl, aryl, Cr-Cygaralkyl, C5-Cizheterocyclyl, Cs-Cizheterocyclylalkyl, C;-Cyoheteroaryl 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 heteroary! and where some or all of the rings may be fused to each other; R* R’ and R® are each independently selected from hydrogen, bromo, 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®%nd 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 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 Cy-Caalkyt; 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;-Csalkyt; R'" is hydrogen or C;-Csalkyl; 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.

62. The compound of Claim 61 wherein: x and y are each independently 1, 2 or 3; Vis -C(O})- or -C(S)~; R'is hydrogen, C;-Cy.alkyl, C-Cszhydroxyalkyl, C4-Cy2cycloalkylalkyl and Cr-Ciearalkyl; R? is selected from the group consisting of C,-Cy,alkyl, C-Cizalkkenyl, CrCizhydroxyalkyl, C,-Ci.hydroxyalkenyl, C,-Cszalkoxyalkyl, C;-Cs cycloalkyl, C4-Cy2cycloalkylalkyl, aryl, C,-Cygaralkyl, C,-Cyoheterocyciyl, Cs-Cyzheterocyclylalkyl, C,-Cqzheteroaryl, and C;-Cizheteroarylalkyl;

R® is selected from the group consisting of C1-Cjzalkyl, C-C,.alkenyl,

C.-Cyohydroxyalkyl, Co-Cishydroxyalkenyl, Ci-Cyalkoxy, C2-Ciaalkoxyalkyl, C5-Cicycloalkyl, C4-CyaCycloalkylatkyl, aryl, Cr-Cyearalkyl, C5-Cizheterocyclyi, C5-Cheterocyclylalkyl, Ci-Cioheteroaryt and Cs-Cizheteroarylalkyt; R* R® and R® are each independently selected from hydrogen, bromo, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R'3),; R’, R™ R® R® R° R*™ R'C, and R'® are each independently selected from hydrogen or C,-Caalkyl; and each R" is independently selected from hydrogen or C1-Cealkyl.

63. The compound of Claim 62 wherein: x and y are each 1; Vis -C(O); R'is hydrogen, C-Cizalkyl or C4-Cs.cycloalkytalkyt; R?is selected from the group consisting of C,-C;.alkyl, C,-Cyzalkenyl, Cs-Cqocycloalkyl, Ci-Cacycloalkylalkyl, Cr-Chearalkyl, Cs-Cysheterocyclylalkyl and C,-Cysheteroarylalkyl; R? is aryl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C;-Csalkyl, C,-Cgtrihaloalkyi, Cs-Cgtrihaloalkoxy, C,-Cealkylsulfonyl, -N(R?),, -OC(O)R', -C(O)YOR™?, -S(O),N(R"?),, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalky; R* R® and R® are each independently selected from hydrogen, bromo, 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-Csalkyl; and each R" is independently selected from hydrogen or C,-Cgalkyl.

64. The compound of Claim 63 wherein: x and y are each 1; Vis -C(O); R' is hydrogen, C;-Cszalkyl or C,-C;.cycloalkylalkyi; R? is C,-Csaalkyl or C-Crlatkenyt; R® is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C;-Csalkyl, C,-Cgtrihaloalkyl, C+-Cetrihaloalkoxy, C4-Calkylsulfonyl, -N(R'?),, -OC(O)R™, -C(O)OR* and

-S(OXN(R")z; R*, R® and R® are each independently selected from hydrogen, bromo, fluoro or chloro; and R7, R™ RE, R®, R?, R%, R' and R'® are each hydrogen.

65. The compoundof Claim 63 wherein: x and y are each 1; Vis -C(O)-: R'is hydrogen, C4-Ci2alkyl or C4 Cacycloalkylalkyl, R2 is C5-Cq.cycloalkyl or C4-Crocycloalkylalkyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C:-Cealkyl, C4-Cetrihaloalky, C,-Cetrihaloalkoxy, Cs-Cealkylsutfonyl, -N(R™),, -OC(O)R", -C(O)OR" and -S(ORNR™)z; R* R® and R® are each independently selected from hydrogen, bromo, fluoro or chloro; and R’, R’*, RS, R®, R®, R®, R' and R" are each hydrogen.

66. The compound of Claim 65 wherein: R?is C4Cyacycloalkylalkyl; R? is phenyl optionally substituted by one or more substituents selected from halo, C4-Cgalkyl, C4-Cetrihaloalkyl and C,-Cgtrihaloalkoxy; R* and R® are both hydrogen: and RS is hydrogen or bromo.

67. The compound of Claim 66 selected from the group consisting of the following: 5-Bromo-6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1 -yl]-pyridine-3-sulfonic acid (2-cyclopropylethyl)amide; and 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yipyridine-3-sulfonic acid (2- cyclopropylethyl)amide.

68. The compound of Claim 63 wherein: x and y are each 1; Vis -C(O)-;

R' is hydrogen, C,-C1zalkyl or C.-C. cycloalkylalkyl; R? is C-Ciearalkyl, Cs-Croheterocyciylalkyl or C3-Cyoheteroarylalkyl; R} is pheny! optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C.-Ceatkyl, C,-Cetrihaloalkyl, Ci-Cetrihaloalkoxy, Ci-Cealkyisuifonyl, -N(R'?),, -OC(O)R™, -C(O)OR™ and -S(ORN(R); R*, R® and RS" are each independently selected from hydrogen, bromo, fluoro or chioro; and R’,R™ R® R® R® R™ R'", and R'™ are each hydrogen.

69. Use of a compound of Claim 61 in the manufacture of a medicament for treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal.

70. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Claim 61.

71. Use of any one of claims 1, 2, 16, 27, 35, 49, 59 and 69, substantially as herein described and exemplified.

72. A compound of any one of claims 10, 18, 29, 37, 51 and 61, substantially as herein described and exemplified.

73. A pharmaceutical composition of any one of claims 17, 28, 36, 50, 60 and 70, substantially as herein described and exemplified. 96 ALTNDIN 0 me