ZA200404395B - N-aryl-N'-arylcycloalkyl-urea derivatives as MCH antagonists for the treatment of obesity. - Google Patents

Description

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N- ARYL-N’-ARYLCYCLOALKYL-UREA DERIVATIVES AS MCH ANTAGONISTS FOR THE - 5 TREATMENT OF OBESITY :

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Applications 60/337,262 filed on

December 4, 2001 and 60/399,853 filed on July 31, 2002.

FIELD OF THE INVENTION

This invention relates to antagonists for melanin-concentrating hormone (MCH) and their use in the treatment of metabolic and eating disorders, novel compounds having MCH receptor modulatory activity, pharmaceutical compositions containing one or more such modulators, methods of preparing such modulators and methods of using such modulators to treat obesity, diabetes and related disorders.

BACKGROUND OF THE INVENTION

MCH, a cyclic peptide, was first identified over a decade ago in teleost fish where it appears to regulate color change. More recently, MCH has been the subject : of investigation for its possible role as a regulator of eating behavior in mammals. As reported by Shimada et al., Nature, Vol. 396 (17 Dec. 1998), pp. 670-673, MCH- deficient mice have reduced body weight and leanness due to hypophagia (reduced feeding). In view of their findings, it was suggested that antagonists of MCH may be effective for the treatment of obesity. U.S. Patent No. 5,908,830 discloses a combination therapy for the treatment of diabetes or obesity involving the - administration of a metabolic rate increasing agent and a feeding behavior modifying ’ agent, an example of the latter being an MCH antagonist. Further, MCH receptor } 30 antagonists may also be useful in the treatment of depression and/or anxiety.

Borowksy et al., Nature Medicine, 8, pp. 825 — 830 (01 Aug 2002).

“2. ®

SUMMARY OF THE INVENTION

In one embodiment, this invention provides novel compounds having MCH antagonist activity. These compounds are represented by structural formula i:

AR NR

Ar £

Ar’ formula or a pharmaceutically acceptable salt or solvate of said compound, isomer or racemic mixture wherein

Ar'is aryl, heteroaryl, (R7),-substituted aryi or (R7),-substituted heieroaryi, wherein p is a number from 1 to 3 and when p is more than 1, each R’ can be the same or different and is independently selected from the group consisting of alkyl, cycloalkyl, halo, -CN, alkoxy, -CF3, -OCF3, -C(OIN(R®),, -N(R®),, (C+-Ce)alkylene-

N(R%)2 -S-atkyl, -S{C}-alky!, -S{Ca)-alkyl, -S{Q2)N(R),, -N(RECIOIRS, (C;-

Ce)N(RBC(O)R®, NO,, -C(O)aikyi, C(02)R, C(R)L,ORE, C=nNOR® and 2 cyclic muoisiy selected from the group consisting of p— O : we) a RE) § 0) . N . a BL a a

CN NzN > © NN NT Yo NTO wherein said cyclic moiety, together with Ar’, can optionally form a fused aromatic moiety such as indole, indolone, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, or benztriazole; and further wherein if two R’ groups are adjacent, said adjacent R” moieties can optionally be joined together to form a methylenedioxy or ethylenedioxy moiety, = Ar is-aryl, heteroaryl, (R7);-substituted aryl or (R”),-substituted heteroaryl, wherein p is 2 number from 1 to 3 and when p is more than 1, each R’ can be the same or different and is independently selected from the group consisting of alkyi,

i v ® nN cycloalkyl, halo, -CN, alkoxy, -CF3, -OCF3, -C(O)N(R®),, -N(R®),, (C1-Ce)alkylene-

N(R®); -S-alkyl, -S(O)-alkyl, -S(Oz)-alkyl, -S(O2)N(R®),, -N(R®)C(O)RS, (C:- : Cs)N(R®)C(O)R®, NO, -C(O)alkyl, C(O2)R®, C(R®),OR®, C=NOR?® and a cyclic moiety ] selected from the group consisting of : ) __ a — __ —0

Ee re SERS Ska 0} ay SEN EN aS a a

NN NN» NAN Sv Yo N~ SO wherein said cyclic moiety, together with Ar’, can optionally form a fused aromatic moiety such as indole, indolone, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, or benztriazole; and further wherein if two R’ groups are adjacent, said adjacent R” moieties can optionally be joined together to form a methylenedioxy or ethylenedioxy moiety;

Xis O, S or N-(CN); Co

Y is a single bond or alkylene group;

Z is a C4-Cg cycloalkylene or C4-Cg heterocycloalkylene wherein each of said

C4-Cg cycloalkylene or C4-Cg heterocycloalkylene group optionally containing one or two double bonds inside the cyclic ring and optionally substituted with 1 to 4 R® groups on the ring wherein each R® is independently selected from the group consisting of alkyl, cycloalkyl, -OH, -N(R®),, -NR®COalkyl, alkoxy and -OC(O)-alkyl, with the proviso that when R® is OH or -N(R%),, R® is not attached to a carbon adjacent to a nitrogen and when two R® groups are -OH, neither R® is on the same carbon on Z and further that two R® groups can be optionally joined together so that Z and said two R® groups together form a bicycloalkylene or bicycloheteroalkylene . group containing from 5 to 12 atoms;

HY

/

R'is Ne , aryl, heteroaryl,

R3 (CHizle—n~ RY .

Ps Na a * (CHa)q where s and q independently number 0 to 6, the sum of s and q is 2 to 6 and r numbers 0 to 3; 3 N ory oR J ’ , N.p3 > N % N N [Y N > g 3 G “R® R3 Ls

Sng? 2 oN NS 2M CoN 1 . y

R

3 4

NR SOR

OH N | i se ow 8 SS ° ; 9 0, NOR NR ! LE . oo IN NG , ST o 0] OR OR? NO. ,

IIE ORNS

Ry

Rs 3-N . $-N $-N NH -N + 3-N , AN , . O Oe O- JR § S § SE. § OH . I) Rs Re

Ss lo] - LOY , §-N J -N -N _ : 2 3 SN Ry 4 SN ’ 4 \, ’ % NN or ’ 0 alkyl iN J R FN ned, . Nw ’ -N Re . $N R ’ — _ _ Da 0257Rs HN—( HN-SO0, 0 o} ~~ ~ ha ha \ © 3-N ,

J 3 3

FN NR EN NRPLEN N-RLEN NRUEN[ NR —/ _/ n/ —

ON

R' . Rr? A >

Ad Phe NNR \—/

R* ' orR'is -N(R®),, -N(H)C(O)alkyleneN(R>),, -C(O)N(H)alkyleneN(R®),, -C(O)N(alkyl)alkyleneN(R®),, -alkyleneC(H)(OH)alkyleneN(R®),, -N(alkylalkyleneN(R®),, -N(H)alkyleneC(O)R®, -N(alkyl)alkyleneN(alky!)S(O2)R® or —N(alkyl)alkyleneC(O)N(R®),;

R?is hydrogen or alkyt; each R? is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkylene-, aryl, aralkyl, heteroaryl, heterocyclyl, heteroaralkyl, -S(O,)alkyl, -S(02)aryl,-S(O2)N(H)alkyl, -S(O2)N(alkyl)z, -S(O2)alkyl, -S(O2)heterocycloalkyt, -C(O)alkyl, -C(O)aryl, -C(O)heteroaryl, -C(O)heterocycloalkyl, -C(O)N(H)alkyl, -C(O)N(alkyl)z, -C(O)N(H)aryl, -C(O)Oalkyl, -C(O)Oary! or alkylene-C(O)Oalkyl, wherein each of said alkyl, alkylene, alkoxy, aralkyl, aryl, heteroaryl, heteroaralkyl or cycloalkyl group can independently be nonsubstituted, halosubstituted or . 15 hydroxysubstituted; ’ R* is R?, alkoxy or -N(R?),, with the proviso that when R* is attached to a sulfur ; atom then R* is not hydrogen;

R® is hydrogen, -N(R3),, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaralkyl, alkoxy or alkoxyalkylene-, wherein each of said alkyl, alkylene, alkoxy,

aralkyl, aryl, heteroaralkyi or cycioalkyi group can independently be nonsubstiiuted, halosubstituted or hydroxysubstituted;

R® is hydrogen, alkyl or cycloalkyl;

R? is hydrogen, -C(O)alkyl or —S(O.)alkyl.

R'is RS or halogen; with the following provisos: that each R® of -N(R%), can be same or different and is independently selected; that each R® and R® of -C(O)N(R®),, -N(R®), and -S(O2)N(R®), can be the same or different and is independently selected; and that in the above chemical formulas, each R® and R* can be the same or different and is independently selected.

This invention is also directed to pharmaceutical compositions for the treatment of metabolic disorders such as obesity, and eating disorders such as hyperphagia. In one aspect, this invention is also directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of a compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

The present invention relates to compounds that are represented by structural formula |, or a pharmaceutically acceptable sait or solvate, wherein the various moieties are as described above.

The compounds of formula | can be administered as racemic mixtures or enantiomerically pure compounds. :

A preferred group of compounds are compounds of formula | wherein

Ar is aryl, heteroaryl, (R7),-substituted aryl or (R7),-substituted heteroaryl, wherein p is a number from 1 to 3 and when p is more than 1, each R’ can be the same or different and is independently selected from the group consisting of alkyl, cycloalkyl, halo, -CN, alkoxy, -CF3, -OCF3, -C(O)N(R®),, -N(R%),, (C1-Ce)alkylene-

N(R), -S-alkyl, -S(O)-alkyl, -S(Oz)-alkyl, -S(02)N(R?),, -N(R}C(O)R?, (C:-

Ce)N(R®)C(O)R®, NO,, -C(O)alkyl, C(02)R®, C(R®),0R®, C=NOR? and a cyclic moiety selected from the group consisting of

@® . prem Oo

El EE rE) i : 0)

V8 t= ET a : AN NaN NN N~ TO N~ YO wherein said cyclic moiety, together with Ar', can optionally form a fused aromatic moiety such as indole, indolone, benzimidazole, benzoxazole, benzthiazole, : benzisoxazole, or benztriazole; and further wherein if two R” groups are adjacent, said adjacent R” moieties can optionally be joined together to form a methylenedioxy or ethylenedioxy moiety,

AF? is aryl, heteroaryl, (R7),-substituted aryl or (R”),-substituted heteroaryl, wherein p is a number from 1 to 3 and when p is more than 1, each R’ can be the same or different and is independently selected from the group consisting of alkyl, cycloalkyl, halo, -CN, alkoxy, -CF3, -OCF3, -C(O)N(R®),, -N(R%),, (C1-Cg)alkylene-

N(R®), -S-alkyl, -S(O)-alkyl, -S(02)-alkyl, -S(02)N(R®),, -N(R®)C(O)R?, (C+-

Cs)N(R®)C(O)R?®, NO,, -C(O)alkyl, C(02)R®, C(R®),0R8, C=NOR? and a cyclic moiety selected from the group consisting of — — — — 9

SEL Tah TR rE 0)

TF flo ET Phy

LN NN ° NN No No wherein said cyclic moiety, together with Ar’, can optionally form a fused aromatic moiety such as indole, indolone, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, or benztriazole; and further wherein if two R groups are adjacent, } said adjacent R” moieties can optionally be joined together to form a methylenedioxy or ethylenedioxy moiety;

T20 Xis O;

Y is a single bond or -(C4-C4)alkylene- group; .

Lon : Rm

Zis ha , or a C4-Cg cycloalkylene or C4-Cs heterocycloalkylene wherein each of said C4-Cs cycloalkylene or C4-Cs heterocycloalkylene group optionally containing one or two double bonds inside the cyclic ring and optionally substituted with 1 to 4 R® groups on the ring wherein each R® is independently selected from the group consisting of alkyl, cycloalkyl, -OH, alkoxy and -OC(O)-alkyl, with the proviso that when R® is -OH, R® is not attached to a carbon adjacent to a nitrogen and when two R® groups are -OH, neither R® is on the same carbon on Z and further that two R® groups can be optionally joined together so that Z and said two R® groups together form a bicycloalkylene or bicycloheteroalkylene group containing from 5 to 12 atoms;

R'is -NHC(0)(C-Ca)alkyleneN(R),, -C(O)NH(C,-Ca)alkyleneN(R?),, -C(O)N(CH;)(C-Cs)alkyleneN(R3),, -alkyleneC(H)(OH)(C1-Cz)alkyleneN(R%),, -N(CH3)(C-Cs)alkyleneN(R?),, -N(H)(C,-Ca)alkyleneC(O)R?, -N{CH3}(Co-

Ca)aikylencN(CH3)S{02)R® or - N(CH3)(C2-Cs)alkyleneC{OIN(R®),, whersin each R® can be the same or different and is independentiy selected;

RZis hydrogen or -(C1-Cg)alkyl; each R¥is independently hydrogen, alkyl, cycloalkyl, cycloalkyialkyl, alkoxyalkylene-, aryl, aralkyl, heteroaryl, heterocyclyl, heteroaraikyl, -S(O,)alkyi, -3(02)aryl,-S(0O2)N(H)alkyl, -S(O2)N(alkyl),, -S(O,)alkyl, -S(O»)heterocycloalkyl, -C(O)alkyl, -C(O)aryl, -C(O)heteroaryl, -C(O)heterocycloalkyl, -C(O)N(H)alkyl, -C(O)N(alkyl)z, -C(O)N(H)aryl, -C(O)Oalkyl, -C(O)Oaryt or alkylene-C(O)Oalkyl, } wherein each of said alkyl, alkylene, alkoxy, aralkyl, aryl, heteroaryl, heteroaralkyl or cycloalkyl group can independently be nonsubstituted, halosubstituted or hydroxysubstituted;

R* is R, (C1-Cg)alkoxy or -N(R>),, with the proviso that when R* is attached to a sulfur atom then R* is not hydrogen; © R®is hydrogen, “N(R%),, -(C1-Cs)alkyl, -(C+-C7)cycloalkyl, (Ca-Crlcycloalkyl(Cy-

Ce)alkyl, aryl, aralkyl, heteroaraikyl, (C1-Cs)aikoxy or (C-Cs)alkoxy(C1-Csjaikyiere-,

_ nN wherein each of said alkyl, alkylene, alkoxy, aralkyl, aryl, heteroaralkyi or cycloalkyl group can independently be nonsubstituted, halosubstituted or hydroxysubstituted; . R® is -(C1-Cs)alkyl, (C3-Cs)cycloalkyl, -OH, -O-(C4-Cg)alkyl, -OC(0)-(C+-Cs alkyl), with the proviso that when RE is -OH, R® is not attached to a carbon adjacent to ~ 5 a nitrogen, and when mis 2 and both R® are -OH, neither R® is on the same carbon onZ;

R® is hydrogen, -(C4-Cg)alkyl or -(C3-C7)cycloalkyl; with the following provisos that each R® of -N(R®), can be same or different and is independently selected; that each R® and R® of -C(O)N(R®), -N(R®), and -S(02)N(R®), can be the same or different and is independently selected; and that in the above chemical formulas, each R® and R? can be the same or different and is independently selected. “A further preferred group of compounds of formula | are those in which

Ar! and A? are the same or different and are independently selected from : phenyl, pyridyl, (R7),-substituted aryl or (R"),-substituted heteroaryl, wherein p is a . number from 1 to 3 and when pis more than 1, each R” can be the same or different and is independently selected from the group consisting of alkyl, cycloalkyl, halo, -CN, alkoxy, -CF3, -OCFa, -C(O)N(R®)z, -N(R%)2, (C+-Cs)alkylene-N(R®), -S-alkyl, -S(O)- alkyl, -S(O2)-alkyl, -S(02)N(R®)2, -N(R®)C(O)R®, (C1-Cs)N(R®)C(O)R?, NO,, -C(O)alky!,

C(02)R®, C(R®),0OR® or C=NOR?,

Xis O;

Y is a single bond or —CHa-, -CH;CHz-, -CH,CH,CH,- or -CH,CH,CH;CH-;

Son .

R'is ; . R? is hydrogen; ' and X . R? is hydrogen, -(C+-Cg)alkyl, -(C3-Cr)cycloalkylmethyl, (C4-Cg)alkoxy(Cs-

Ce)alkylene- or SOqalkyl.

Another group of preferred compounds are compounds of formula | wherein

Ar! and Ar? are the same or different and are independently selected from phenyl, pyridyl; (R7),-substituted aryl or (R"),-substituted heteroaryl, wherein p is a number from 1 to 3 and when p is more than 1, each R” can be the same or difforont and is independently selected from the group consisting of alkyl, cycioalkyl, halo, -CN, s alkoxy, -CF3, -OCF3, -C(O)N(R®), -N(R®),, (C+-Cs)alkylene-N(R®), -S-aikyi, -S(0)- alkyl, -S(O2)-alkyl, -S(O2)N(R®),, -N(R®)C(O)R?, (C1-Cs)N(R®)C(O)R?, NO,, -C(O)alkyl,

C(02)R®, C(R®),0R® or C=NOR?,

Xis O;

Y is -CH,CHa~, -CH;CH,CH2- or =CH,CH,CH;CH,-;

R'is -N(R?), or -C(O)NH(C2-C3)alkyleneN(R3),; and

R3 is hydrogen, -(C;-Cg)alkyl, -ar(C-Cs)alkyl, heterocyclyl, heteroaryl, heteroarylalkyl, halo- substituted -(C+-Ce)alkyl, hydroxy-substituted -(C,-Cs)alkyl, -(C3-

Cr)cycloalkyl, wherein each R® can be same or different and is independently selected. ~ Another group of preferred compounds are compounds of formuia i wherein

Ar' and Ar? are independently phenyl, pyridyl, R™-substituted phenyi or R'- substituted pyridyl, wherein said Ar’ and Ar? are the same or different and is independently selected, and R” numbers 1 to 3 which can be the same or different, each being independently selected from the group consisting of alky!, cycloalkyl, halo, -CN, alkoxy, -CF3, -OCF3, -C(O)N(R®)2, -N(R®),, -S-alkyl, -S(O)-alkyl, -3(O2)-alkyl, -S(02)N(R®),, -N(R®)C(O)R?®, -NO, — ———— [—— pn —

ES! Ch TR ee J eh 0 )

EE ap ER = J EE DY

Nn NN ’ NN N 0 nN 0) wherein each R® and R® can be the same or different and is independently selected, or two adjacent R’ groups can be joined together to form a methylenedioxy or ~..... ethyelenedioxygrowp;_ . ....... oo ~

® -11-

Xis O;

Y is -CH,CH2-, -CH,CH2CH2- or —CH,CH2CH,CH,-; : R'is

A 9 : Nor :

NT oo. Jj

BN or ¢N N R

R3 is hydrogen, -(C1-Cs)alkyl, -(C3-C7)cycloalkyl, -(C3-C7)cycloalkyl(Cs-Ce)alkyl, (C4-Cs)alkoxy(C4-Ce)alkylene-, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl, wherein each of said alkyl, alkylene, alkoxy, aralkyl, aryl, heteroaryl, heteroaralkyl or cycloalkyl group can independently be nonsubstituted, halosubstituted or hydroxysubstituted,

R*is R?, (C;-Ce)alkoxy or -N(R®), wherein each R® can be same or different and is independently selected, with the proviso that when R* is attached to a sulfur atom then R* is not hydrogen;

RS is hydrogen, -(C1-Gg)alkyl, -(C3-C7)cycloalkyl, -(C3-C7)cycloalkyl(C1-Ce)alkyl, aryl, aralkyl, heteroaralkyl, (C1-Ceg)alkoxy or (C4-Cs)alkoxy(C,-Ce)alkylene-, wherein : each of said alkyl, alkylene, alkoxy, aralkyl, aryl, heteroaralkyl or cycloalkyl group can independently be nonsubstituted, halosubstituted or hydroxysubstituted; and

R® is hydrogen, -(C1-Cs)alkyl or -(C3s-C7)cycloalkyl.

Another group of preferred compounds are compounds of formula | wherein wherein Ar' is R7-substituted phenyl and said R’ is one group positioned at the 3- - position of said substituted pheny! with respect to the linking point to Z. 7 Another group of preferred compounds are compounds of formula | wherein R’ ’ is -CN, -OCF3, chloro, -C(O)N(R®)2, -N(R®)2, or -N(R®)C(O)R®.

Another group of preferred compounds are compounds of formula | wherein wherein Ar'is pyridyl and Ar? is halo-substituted phenyl or (CF3)-substituted phenyl.

-i2-

Another group of preferred compounds are compounds of formula | wherein wherein Ar'is pyridyl and Ar? is halo-substituted pyridyl or -CF3-substituted pyridyl.

A set of preferred compounds are listed below in Tables 1, 1a and 1h.

Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardiess of whether a term is used by itself or in combination with other terms. Hence the definition of “alkyl” applies to “alkyl” as well as to the “alkyl” portions of “alkoxy”, “alkylamino” etc.

As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings: "Patient" includes both human and other animals. “Mammal” means humans and other mammalian animals. "Alkyl" means an aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyi groups such as methyl, ethyl or propyl, are attached ic a linear alkyl chain. "Lower alkyl” means an alkyl group having about 1 tc about 8 : carbon atoms in the chain, which may be straight or branched. The term "substituted alkyl” means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alxyithio, amino, -NH(alky!), -NH(cycloalkyl), -N(alkyl),, carboxy and - C{O)O-alky!.

Non-iimiting exampies of suitabie aikyi groups inciude imethyi, ethyi, n-propyl, isopropyl, n-butyl, and t-butyl. "Alkenyl” means an aliphatic hydrocarbon group comprising at least one . carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl! groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as ....30 methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl” means an alkenyl group having about 2 to about 6 carbon atoms in the chain, which may be straight or branched. The term "substituted alkenyl” means that the alkenyl group may be substituted by one or more substituents which may be the same or different, each

® -13- substituent being independently selected from the group consisting of halo, alkyl, aryl, -cycloalkyl, cyano, and alkoxy. Non-limiting examples of suitable alkenyl groups : include ethenyl, propenyl, n-butenyl, and 3-methylbut-2-enyl. "Alkynyl" means an aliphatic hydrocarbon group comprising at least one - 5 carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means an alkynyl group having about 2 to about 6 carbon atoms in the chain, which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyt, propynyl and 2-butynyl. The term "substituted alkynyl” means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and -cycloalkyl. . “Alkylene” means an alkanediyl group commonly having free valencies on two carbon atoms. Non-limiting examples include methylene, ethylene, propylene and the - like. The term "substituted alkylene” means that the alkylene group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, -cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -

N(alkyt),, carboxy and —-C(O)O-alkyl. "Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be unsubstituted or substituted on the ring with one or more . substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, -OCF;, -OCOalkyl , -OCOary, -CF3, i heteroaryl, aralkyl, alkylaryl, heteroaralkyl, alkylheteroaryl, hydroxy, hydroxyalkyl, . alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, haloalkyl, haloalkoxy, nitro, cyano, : 30 carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsuifonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, -cycloalkyl and heterocyclyl. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. The “aryl” group can

Co 14- .. also be substituted by linking two adjacent carbons on its aromatic ring via a combination of one or more carbon atoms and one or more oxygen atoms such as, for example, methylenedioxy, ethylenedioxy, and the like.

“Arylene” means a bivalent group derived from an aromatic hydrocarbon by removal of a hydrogen atom from two ring carbon atoms.

Non-limiting examples include phenylene and the like.

“Alkylenedioxy” means a combination of one or more carbon atoms and one or more oxygen atoms such as the following non-limiting examples that include methylenedioxy, ethylenedioxy, and the like.

"Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.

Preferred heteroaryls contain about 5 to about 6 ring atoms.

The "heteroaryl" can be optionally substituted on the

1s ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyi, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, araikoxy, acyi, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyi,

alkylsuifonyl, arylsulfonyl, heteroarylsulfonyl, alkyisuifinyl, aryisulfinyl, heteroarylisulfinyl, alkylthio, arylthio, heteroaryithio, aralkyithio, heteroaralkyithio, -gycloalkyl, cycloalkenyl and heterocyclyl.

The prefix aza, oxa or thia before the neteroaryi root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.

A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.

Non-limiting examples of suitable :

~~ heteroaryls include pyridyl, pyrazinyl, furanyi, thienyl, pyrimidinyi, isoxazolyl!, isothiazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, and the like. “Heteroarylene™ means a bivalent group derived from a heterocyclic aromatic compound by removal of a hydrogen atom from two ring carbon atoms such as, for example, the bivalent group derived from pyridine, pyrrole and the like. "Aralkyl” means an aryl-alkyi- group in which the aryl and alkyl are as - previously described.

Preferred aralkyls comprise a lower alkyl group.

Non-iimiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and a

® -15- naphthienylmethyl. The bond to the parent moiety is through the alkyl. The term "substituted aralkyl" means that the aralkyl group may be substituted by one or more : substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, -cycloalkyl,

E 5 cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)z, carboxy and —C(O)O-alkyl. "Alkylaryl" means an alkyi-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl groups is tolyl. The bond to the parent moiety is through the aryl. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms.

Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, - 1 hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, . alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylisulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkyithio, heteroaralkyithio, cycloalkyl, cycloalkenyl and heterocyclyl.

Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like. "Halo" means fluoro, chloro, bromo or iodo groups. Preferred are fluoro, chloro - or bromo, and more preferred are fluoro and chloro. “Halogen” means fluorine, chlorine, bromine or iodine. Preferred are fluorine,

A chlorine or bromine, and more preferred are fluorine and chlorine. . “Haloalkyl” means an alkyl as defined above wherein one or more hydrogen . 30 atoms on the alkyl is replaced by a halo group defined above. "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl

LL ® rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryi, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalky!, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyti, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkyithio, heteroaralkylthio, cycloalkyl, cycloalkenyl and heterocyclyl. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbomylenyl. "Heterocyclyl” or “heterocycloalkyl” means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, .alone or in combination. There are no adjacent oxygen and/or suifur atoms present in the ring system. Preferred heterocyclyis contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl can be optionally substituted on the ring by replacing an available hydrcgen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, ary!, hetercaryi, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, . alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsuifonyl, aryisulfonyi, heteroarylsulfonyl, alkylsulfinyl, aryisulfinyl, heteroarylisulfinyi, alkylthio, aryithio, heteroarylthio, aralkyithio, heteroaralkylthio, cycloalkyl, cycloatkenyl and heterocyclyl.

The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, pyranyi, EE tetrahydrothiophenyl, morpholinyl and the like.

® -17 - "Aralkenyl” means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting : examples of suitable aralkenyl groups include 2-phenethenyl and 2-naphthylethenyl.

The bond to the parent moiety is through the alkenyl. k 5 "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. -

Non-limiting examples of suitable aralkyl groups include pyridyimethyl, 2-(furan-3- yl)ethyl and quinolin-3-yimethyl. The bond to the parent moiety is through the alkyl.

The "heteroaralky!" can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyisulfonyl, aryisulfonyi, heteroarylisulfonyl, alkylsulfinyl, arylsulfinyl, heteroaryisuifinyl, alkylthio, arylthio, : heteroarylthio, aralkylthio, heteroaralkylthio, -cycloalkyl, cycloalkenyl and heterocyclyl. "Heteroaralkeny!” means an heteroaryl-alkenyl- group in which the heteroaryl : and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower .. - alkenyl group. Non-limiting examples of suitable heteroaralkenyl groups include 2- (pyrid-3-yl)ethenyl and 2-(quinolin-3-yl)etheny. The bond to the parent moiety is through the alkenyl. : “Alkoxyalkyl” means an alkoxy-alkyl- group in which alkyl and alkoxy are as previously defined. Non-limiting examples of suitable alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxyethyi. "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. -

Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. } "Acyl" means an H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)-, cycloalkyl- . C(O}, cycloalkenyl-C(O)-, or cycloalkynyl-C(O)- group in which the various groups : 30 are as previously described. The bond to the parent moiety is through the carbonyl.

Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, and cyclohexanoyl.

-18- d “Aroyl” means an aryi-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- and 2-naphthoyl. "Alkoxy” means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy. The alkyl group is linked to an adjacent moiety through the ether oxygen. The term "substituted alkoxy" means that the alkyl portion of the alkoxy group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, -cycloalkyl, cyano, hydroxy, alkoxy, alkyithio, amino, -NH(alkyl), -

NH(cycloalkyl), -N(alkyl),, carboxy and —C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl. "Aryloxy” means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen. "Alkyiamino” means an -Ni i; or -NHa" group in which one or more of the hydrogen atoms on the nitrogen is replaced by an alky! group as defined above. 2

Cn "Alkylthio” means an alkyl-S- group in which the aikyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methyithio, ethylthio, i-propyithio and heptylthio. The bond to the parent moiety is through the sulfur. "Aryithio” means an aryl-S- group in which the ary! group is as previously described. Non-limiting exampies of suitabie aryithio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur. “Aralkyithio” means an aralkyl-S- group in which the aralkyl group is as - previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. “Alkoxycarbonyl” means an alkoxy group defined earlier linked to an adjacent moiety through a carbonyl. Non-limiting examples of alkoxycarbonyl groups include 130. -C(0)-CHjs, -C(O)-CH,CHj and the like. "Aralkoxycarbonyl” means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

® -19 - "Alkylsulfonyl” means an alkyl-S(O2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the : sulfonyl. "Alkylsulfinyl" means an alkyl-S(O)- group. Preferred groups are those in which - 5 the alkyl group is lower alkyl. The bond to the parent moiety is through the suifinyl. "Arylsulfonyl” means an aryl-S(O,)- group. The bond to the parent moiety is through the sulfonyl. "Arylsulfinyl" means an aryl-S(O)- group. The bond to the parent moiety is through the sulfinyl.

The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the 15 . specified amounts. ; : : Solvates of the compounds of the invention are also contemplated herein. "Solvate” means a physical association of a compound of this invention with one or . more solvent molecules. This physical association involves varying degrees of ionic. : and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H,0. "Effective amount” or "therapeutically effective amount” is meant to describe an - amount of compound of the present invention effective to treat a mammal (e.g., human) having a disease or condition mediated by MCH, and thus producing the

A desired therapeutic effect. . The compound of formula | forms salts which are also within the scope of this : 30 invention. Reference to a compound of formula I, herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound

Co. ® of formula | contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptabie) salts are preferred, although cther salts are also useful. Salts of the compound of the formula | may be formed, for example, by reacting a compound of formula | with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition saits include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulforiates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulifonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesuifonates, 2- naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persuifates, 3- phenyipropionates, phosphates, picrates, pivalates, propicnates, salicylates, . succinates, sulfates, sulfonates (such as those mentioned herein), tartaraies, . thiocyanates, toluenesulfonates (aiso known as tosylates,) undecanoaies, and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19;

P. Could, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The

Practice of Medicinal Chemistry {1998), Academic Press, Now York; and in The

Orange Book (Food & Drug Administration, Washington, D.C. on their website).

These disclosures are incorporated herein by reference thereto. .

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N- ) “30 bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyi-D- glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and N the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and

® -21- iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), . aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceutically k 5s acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Compounds of formula |, and salts and solvates thereof, may exist in their tautomeric form (for example, as an amide or imino ether). Ali such tautomeric forms are contemplated herein as part of the present invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts and solvates of the compounds), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, : ‘or may be admixed, for example, as racemates or with all other, or other selected, -. stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate" and the like, is intended to equally apply to the salt and solvate of enantiomers, stereoisomers, rotamers, tautomers or racemates of the inventive compounds.

When any variable (e.g., aryl, heterocycle, R?, etc.) occurs more than one time in any constituent or in formula |, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

A Compounds of formula | can be highly selective, high affinity Melanin ] Concentrating Hormone (MCH) receptor antagonists useful for the treatment of : 30 obesity.

Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition mediated by MCH by administering a -

®. therapeutically effective amount of at least one compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound to the mammal.

A preferred dosage is about 0.001 to 100 mg/kg of body weight/day of the compound of formula I. An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound.

Another aspect of this invention is directed to a method of treating obesity comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound.

Another aspect of this invention is directed to a method for treating eating and metabolic disorders such as bulimia and anorexia comprising administering to a : mammal a therapeutically effective amount of at least one compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound.

Another aspect of this invention is directed to a method for treating hyperlipidemia comprising administering to a mammal a therapeutically effactive amount of at least one compound of formula |, or a pharmaceuiicaiiy accepiabie sait or solvate of said compound.

Another aspect of this invention is directed to a method for treating cellulite and fat accumulation comprising administering to a mammal a therapeutically effective amount of at least one compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound.

Another aspect of this invention is directed to a method for treating type I diabetes comprising administering to a mammal a therapeutically effective amount of atleast one compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound.

In addition to the “direct” effect of the compounds of this invention on the MCH subtype, there are diseases and conditions that will benefit from the weight loss such as insulin resistance, impaired glucose tolerance, Type Il Diabetes, hypertension, hyperlipidemia, cardiovascular disease, gall stones, certain cancers, and sleep apnea.

Another aspect of this invention is directed toa method for treating mental } disorders such as major depression, manic depression, anxiety, schizophrenia and sleep disorders, comprising administering to a mammal a therapeutically effective

® -23- amount of at least one compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound. : This invention is also directed to pharmaceutical compositions which comprise at least one compound of formula I, or a pharmaceutically acceptable salt or solvate k s of said compound and at least one pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.

Compounds of formula I, can be produced by processes known to those skilled in the art using either solution phase or solid phase synthesis as shown in the following reaction schemes, in the preparations and examples below.

Compounds of this invention of type 1a and 1b can be prepared as shown below in Scheme 1. 1s Scheme 1

-24- | :

Br \

Ar” aol 0 Oo. 0 Acetone 1. n-Buli, -100 °C Pac TsOH, reflux 2. a 2 0 Za O~ <,

Zb 4 3

Y—R? : EE —_— A

NO Theewem, AS ————

OH Oo

Art Art H 6

Ar2_ AH

NH

A A _Y—R! 0) N—Y—R' Oo” 'N

Ps TFA/CH,CI 2 2b Cl es

Za —

Art

OH

Ar! 1b 1a

An aryl bromide 2 is treated with an organolithium reagent such as n- butyliithium in a solvent such as THF or ether at a temperature from -100°Ct0 0°C followed by reaction with a dione monoketal 3, where Za and Zb together with the 5 carbons to which they are attached form a cycloalkyl group Z as previously defined.

The ketal of the resulting diol 4 is removed under acidic conditions and the ketone is subjected to reductive amination followed by urea formation to give compounds of type 1a. These can be converted to compounds of type 1b by treatment with strong

ET EE ER

Compounds of type 1c can be prepared as shown in Scheme 2:

a5.

Scheme 2 0 0 ’ Lz

Za LL. SE J puch, a___ —_— ". OH

Ar Ar! 7

AP

1 —~y—R 0 Oo" °N

J J Same as scheme 1 74 >

Ar! Ar’ 8 1c

Intermediate 5 from Scheme 2 is treated with strong acid to give olefin 7. This 5° is reduced using hydrogen and a suitable catalyst such as platinum on carbon to give , compound 8. Using conditions analogous to those shown for compound 5 in Scheme 1, compound 8 is transformed to compounds of type 1c.

Compounds of type 1d can be prepared as shown in Scheme 3:

_26- oo

Scheme 3 0 Oo ) Zb 1 [Ya Ya N] CH MSL TAM -— 7 Zb

Za PP -avUCnG 2A, ISU Za 2. CHol,, ZnEt,, TFA

Ar! 3. Excess TFA | Ar! 7 9 1. MsCI/Et3N

No 2. CHyl,, ZnEt,, TFA 3. Acid

O—L—z7b

Za A

HO Ar! ArH 4

EN

Za

Ar! 1d

I Intermediate 7 from Scheme 2 is protected as its ketal under standard . conditions. The resulting olefin is cyclopropanated under known conditions, such as by treatment with methylene diiodide and diethylzinc in the presence of acid such as

TFA. After work-up, the crude product is treated with a strong acid such as TFA to give ketone 9. Alternatively, intermediate 4 from Scheme 1 can dehydrated, such as with methanestuifonyl chloride in the presence of triethylamine, and then converted to ketone 8 in a manner similar to 7. The ketone is converted to products of type 1d using the methods outlined in Scheme 1. .

Compounds of this invention of type 1b can also be prepared as shown below in Scheme 4:

® .

Scheme 4

Oo a) Ye a) Buli, -80 °C Jz HN” TR! - Ar'Br — a, —_— 5) fo) b) NaB(OAc)3H . 1 Za gp Ar! : 10 ow 11 -80-0°C c) acid

NHAr2

SYR! o=<( iy 1 \ a ArNCO 2, R!

Ar! = 12 1b

An aryl bromide 1 is treated with an organolithium reagent suchas n- butyllithium in a solvent such as THF or diethyl ether at —80 °C followed by reaction with an enone 10, where Za and Zb with the carbons to which they are attached g constitute a Z group as previously defined and W is any alkyl group. Quenching with - a solution of acid such as hydrochloric acid provides enone 11. Reductive amination : and treatment with an isocyanate under standard conditions provides compounds of type 1b. The starting aryl bromide 1 and enone 10 are either commercially available or are prepared by well-known procedures.

Compounds of this invention of type 1d can can also be prepared as shown below in Scheme 5:

Scheme 5 ja

Zb NaBH, OH Et,Zn, OH Dess’ za? 1 ole J Martin

Y CeCl3 ge pi CHlp J—zn Jatin

Ar! NY “A

Ar! : Ar! 11 13 14

NHAr? o Y=R! o=

Jem a pry N=,

A HoN Rr! Za Zb ArZNCO 2

Ar? b) NaBH, x / . ) /

Ar! 15 16 1d

Enone 11 is reduced to the allylic alcohol 13 with a reducing agent such as sodium borohydride. Cyclopropanation of 13 occurs upon treatment with Et,Zn and

CHql; to afford cyclopropyl alcohol 14. Oxidation proceeds under standard conditions, such as by treatment with Dess-Martin periodinane to give ketone 15. Reductive amination and treatment with an isocyanate under standard conditions provides Co compounds of type 1d.

Still another method of preparation of compounds of type 1d proceeds according to Scheme 6. :

® -29-

Scheme 6 0 ” act oy ’s Jz a) HN" OH 2a, 1) BOC,0 2a” N\,, - a b) NaBH,4 XN 2) Ph3P, CBry x 15 17 \ 18a

Boc., /'"S0 1) BOC,0 7a a 2) Dess-Martin reagent )

Ar 18b 18a R! ~~ | 0"

Boc, sR’ N—y i. Rr! 7a A 1) TFA ’a —F

Na(OAc);BH Xf 2) ANCO x 19 1d

Ketone 15 undergoes reductive amination to provide amino-alcohol 17. The basic nitrogen of 17 is protected using standard methods, such as carbamate formation. The hydroxyl group of 17 can be activated using a variety of methods, such conversion to a bromide 18a or by oxidation to aldehyde or ketone 18b. Treatment of 18a with an amine (herein defined as R') or 18b with an amine in the presence of a reducing agent such as sodium triacetoxyborohydride gives 19. Deprotection, such as by acid removal of the carbamate, and treatment of the resultant amine with an } isocyanate provides compounds of type 1d.

Compounds of type 1e are prepared according to Scheme 7:

Scheme 7

TH ee 260” Wel S280" pase AHO Pd(PhyP), 20 21 22

PAN

J 0 PPTs Zc oP, ld X J — nd =o _— ar—{ pa 2d O fy 2d NaBH, pd Y—R! 2 24 25

A?NCO zc me 2d Y-R 1e

A ketone 20, where Zc and Zd together with attached carbons and the C=O group : form a ring which constitute a Z group as previously defined,is treated with an base such as sodamide in a solvent such as THF, followed by reaction with an alkyl halide such as methyl iodide. The resultant ketone 21 is then treated with a base and a sulfonic anhydride, and the enol triflate 22 is coupled to an aryl boronic acid with a catalyst such as Pd(Ph,P), to give 23. The ketal is removed under acidic conditions and the resultant ketone is subjected to reductive amination followed by urea formation as described earlier to provide compounds of type 1e.

A method of preparation of compounds of type 1f proceeds according to Scheme 8:

Scheme 8 jo) NaBH OH

Zc 0 PhsP, Bry, Zc CeCly 2c , . P P Ar'B(OH); = EtaN -— _—

HO Br Br Pd(dppf)Cl2 ° 27 28 26 - 0) on En on pe 7

Ze 22 Ze Periodinane % —_— a

Ar! Art 29 31 30 ai a) Yo _Y. 0}

CHNTOR'Y PNT Anco NY - —_— Zc R b) NaBH, J {

Ar! 1 32 Ar 1

Enol ether 26, where Zc is as previously defined, is brominated to provide vinyl - bromide 27. Enone 27 is reduced to the allylic alcohol 28 with a reducing agent such as sodium borohydride. Cross-coupling of 28 with a boronic acid provides arylated enol 29. Cyclopropanation of 29 occurs upon treatment with Et,Zn and CH,l» to afford cyclopropyl! alcohol 30. Oxidation proceeds under standard conditions, such as by treatment with Dess-Martin periodinane to give ketone 31. Reductive amination and treatment with an isocyanate under standard conditions provides compounds of type 1f. : . Still another method of preparation of compounds of type 1d proceeds according to

Scheme 9.

Scheme 9

NHAr2 o=<( o . OH Ne, rd Yo (gl) ee \

LA a) HaN" "OH 2, 1) APNCO 2, CHO d b) NaBH, x 2) Dess-Martin Xf

Ar Periodinane Af 15 17 33

NHAr2 o=(

N~

R!

R? _— 2

NaB(OAc)zH Xr

Ar! 1d

Ketone 15, where Za and Zb are as previously defined, undergoes reductive amination to provide amino-alcohol 17. Treatment of the resultant amine with an isocyanate followed by oxidation of the hydroxyl with a suitable oxidant affords . aldehyde 33. Reductive amination of 33 with an amine (herein defined as R') provides compounds of type 1d.

Compounds of type 1g can be prepared according to - Scheme 10

Ar? ° “NH n Strong base 7

Za UJ —_— a = -_— 1 Mel Za

Ar! Ar! = : 7a 34 Ar? 1g

Enone 7a, prepared as described in Scheme 2, is treated with a strong base such as sodium hydride, optionally in the presence of a silylating agent such as trimethyisilyi chloride, followed by treatment with an alkylating agent such as methyl iodide to give, after purification, compound 34. This can be converted to compound 1g by methods analogous to those described above.

® -33-

In some cases the procedures described in Scheme 1-Scheme 10 may optionally be carried out in library or parallel synthesis format using resin bound . reagents either as reactant or to aid in purification, such as for instance, resin-bound isocyanate to scavenge excess amines or trisamine resin to scavange excess - 5 isocyanate.

In some cases, one compound of this invention can be converted to another compound of this invention by well-known functional group transformations. For instance, an R' group of this invention can be converted to another R' group of this invention using standard methods known by those skilled in the art, including for instance alkylation, reductive alkylation, acylation, sulfonylation, or hydrolysis reactions. In further example, compounds wherein R’ is a sulfide can be oxidized to the corresponding sulfoxide and sulfone and compounds where R is a nitrile can be converted to, among others, the analogous imidazole, oxazole, tetrazole, aldehyde, carboxylic acid, carboxamide or methylamine derivatives. Other possible transformations of one compound of this invention to another will be apparent to those . skilled in the art.

Yet another aspect of this invention are combinations of at least one compound ; of formula i, or a pharmaceutically acceptable salt or solvate of said compound and at . least one compound from the compounds as illustrated below.

Accordingly, another aspect of this invention is a method for treating obesity comprising administering to a mammal (e.g., a female or male human) a. an amount of a first compound, said first compound being a compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound; and b. an amount of a second compound, said second compound being an antiobesity and/or anorectic agent such as a B3 agonist, a thyromimetic agent, an . anoretic agent, or an NPY antagonist wherein the amounts of the first and second compounds result in a therapeutic effect. ; This invention is also directed to a pharmaceutical combination composition ] comprising: a therapeutically effective amount of a composition comprising at least : 30 one first compound, said first compound being a compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound

¢ a second compound, said second compound being an antiobesity and/or anorectic agent such as a RB; agonist, a thyromimetic agent, an anoretic, or an NPY antagonist; and/or optionally a pharmaceutical carrier, vehicle or diluent.

Another aspect of this invention is a kit comprising: a. an amount of a compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form; b. an amount of an antiobesity and/or anorectic agent such as a 3 agonist, a thyromimetic agent, an anoretic agent, or an NPY antagonist and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and

Cc. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.

Preferred antiobesity and/or anorectic agents (taken singly or in any combination thereof) in the above combination methods, combination compositions ~~: and combination kits are: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a PE cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake ; inhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine or fenfluramine), a dopamine agonist (such as bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte- stimulating hormone analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, the OB protein (hereinafter referred to as “leptin”), a leptin analog, a leptin receptor agonist, a galanin antagonist or a Gl lipase inhibitor ordecreaser (such as orlistat). Other anorectic agents include bombesin agonists, - dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucagon-like peptide-1 receptor such as Exendin and ciliary neurotrophic factors such as Axokine. )

Another aspect of this invention is a method of treating diabetes comprising administering to a mammal (e.g., a female or male human) a. an amount of a first compound, said first compound being a compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound; and

® -35- b. an amount of a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol

E dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidy! protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin - 5 mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, . rosaglitazone, pioglitazone or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide wherein the amounts of the first and second compounds result in a therapeutic effect.

This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of formula |, or a pharmaceutically acceptable salt or solvate of said compound; a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin . (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone, or -GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide; and optionally a pharmaceutical carrier, vehicle or diluent.

Another aspect of this invention is a kit comprising: a. an amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form; b. an amount of an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B . inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such ) as troglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide, ] glyburide, or chlorpropamide and a pharmaceutically acceptable carrier, vehicle or : 30 diluent in a second unit dosage form; and

C. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.

Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active comnonent, e.a , an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical Ce ~~ recommended daily dosage regimen for oral administration can range from about 1. - mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two to four divided doses.

This invention is also directed to pharmaceutical compositions for the treatment of metabolic disorders such as obesity, and eating disorders such as hyperphagia.

For preparing pharmaceutical compositions from the cornpounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid.

Solid form preparations include powders, tablets, dispersible granules, capsules, . cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral . 30 administration. Examples of pharmaceutically acceptable carriers and methods of oo manufacture for various compositions may be found in A. Gennaro (ed.),

Remington's Pharmaceutical Sciences, 18M Edition, (1990), Mack Publishing Co.,

Easton, Pennsylvania.

® -37 -

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral . injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal - 5 administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral ~ administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. : ;

The compounds of this invention may also be delivered subcutaneously. n Preferably the compound is administered orally. - SR ‘The invention disclosed herein is exemplified by the following preparations and : examples which should not be construed to limit the scope of the disclosure.

Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.

Where NMR data are presented, 1H spectra were obtained on either a Varian

VXR-200 (200 MHz, 1H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where LC/MS data are ) presented, analyses was performed using an Applied Biosystems API-100 mass } spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron, ) 33mm x 7mm |D; gradient flow: 0 min — 10% CH3CN, 5 min — 95% CH;CN, 7 min — : 95% CH3CN, 7.5 min — 10% CH3CN, 9 min — stop. The retention time and observed parent ion are given.

The following solvents and reagents may be referred to by their abbreviations in parenthesis:

-38- ®

Thin layer chromatography (TLC); ethyl acetate (AcOEt or EtOAc); sodium triacetoxyborohydride (NaBH(OAca)); di-t-butyl carbonate (BOC,0); s trifluoroacetate (TFA); ammonia chloride (NH4Cl); : titanium tetraisoproposice (Ti(O-iPr)s;

N,N'-diisopropylethylamine (iPr.NEt); triethylamine (EtzN or TEA), butoxycarbonyl! (n-Boc or Boc); nuclear magnetic resonance spectroscopy (H NMR); liquid chromatography mass spectrometry (LCMS); high resolution mass spectrometry (HRMS); hexane (hex), milliliters (mL); : millimoles (mmol); microliters (ul); - oo grams (g); : oo oo milligrams (mg); room temperature (ambient) about 25°C (rt).

EXAMPLES

The following examples illustrate the preparation of some of the compounds of the invention and are not to be construed as limiting the scope of the invention disclosed herein.

Method 1 )

Example 1

® -39-

CF,

F

NH

Ah) }

CN

Step 1 3-bromobenzonitrile (20g, 0.11 mole) was dissolved in 500 mi dry THF and the solution was cooled to —100 °C. n-Butyllithium (1.6 M in hexane, 68 ml, 0.11 mole) was added over one hour via an addition funnel. During this time, the temperature inside the reaction flask was kept under —95 °C. After n-butyllithium was added, the . reaction was stirred at -95 °C for 10 minutes. 1, 4-Dioxaspiro[4, 5]decan-8-one : (17.1g, 0.11 mole) in 100 ml dry THF was added via another addition funnel over one -. hour. During this time the reaction temperature was kept under —75 °C. The reaction was stirred for 30 minutes, and the temperature was slowly raised to —25 °C. The reaction was then quenched by adding 200 ml water and one liter of ethyl acetate was added. The organic layer was washed with water (3X400 ml), dried over sodium sulfate and solvent was removed by vacuum. The residue was recrystallized from ethyl acetate/hexane mixture to give rise to 15.5 g pure product. The crude product from mother liquor was purified by flash chromatography using hexane/ethyl acetate (70/30) as the eluent. An additional 8.0 g pure product was obtained from the column. (Total yield: 23.5g, 82%).

Step 2

The product from step 1 (1.5g, 5.8 mmole) was dissolved in 100 ml.acetone ) and toluenesulfonic acid monohydrate (0.2g) was added. The reaction was refluxed for one hour. Acetone was removed and residue was dissolved in 100 mL ethyl acetate. The organic layer was washed with water (3X100 ml), dried over sodium sulfate. After the solvent was removed, the residue (1.2g, 100%) was used in next

- 40 - od step without further purification. Alternatively, the product of step 1 can be treated with TFA as described in Example 91 to eliminate the hydroxyl group yielding the corresponding olefin.

Step 3

The product from step 2 (1.4 g, 6.5 mmole), 1-(2-aminoethyl)pyrrolidine (1 50, 13 mmole) and sodium cyanoborohydride (0.8g, 13 mmole) were stirred in 100 ml methylene chloride at room temperature overnight. The organic layer was washed with water (3X50 mi), dried over sodium sulfate and the solvent was removed by vacuum. The residue was purified by column chromatography using ethyl acetate/methanol/triethylamine (65/34/1) as the eluent. Two isomers were obtained from the column; trans-1-[2-(1-pyrrolidinyl)ethylamino]-4-(3-cyanophenyl)-4- hydroxycyclohexane, (0.91g, 45%). 1H NMR (300 MHz, CDCI3) $7.82 (s, 1 H), 7.75 (d,J=7.69Hz,1H),7.50 (d, J =7.69 Hz, 1 H), 7.40 (t, J = 7.69 Hz, 1 H), 2.80 (m, 1

H), 2.68 (t, J=6.04 Hz, 2 H), 2.57 (t, J = 6.04 Hz, 2 H), 2.48 (s, 4 H), 2.22 (s, 2 H), 1s 1.93(s, 2H), 1.73 (s, 4 H), 1.51 (m, 4 H).and cis-1-[2-(1-pyrrolidinyl)ethylamino}-4-(3- : cyanophenyl)-4-hydroxycyclohexane (0.40g, 20%). 1H NMR (300 MHz, CDCi3) 6 7.82 (s,1H),7.74(d,J=7.69 Hz, 1H), 7.53 (d, J=7.69 Hz, 1H), 743 (t, J=7.69 Hz, 1. .

H). 278 (t, J = 6.04 Hz, 2 H), 2.59 (t, J = 6.04 Hz, 2 H), 2.49 (m, 5 H), 1.56-1.96 (m, 8 -

H). ]

Step4 : ,

Trans-1-[2-(1-pyrrolidinyl)ethyl}-4-(3-cyanophenyl)-4-hydroxycyclohexane (25mg, 0.08 mmole) and 3-trifluoro-4-fluorophenylisocyanate (15 mg, 0.08 mmole) were stirred in 3 ml methylene chloride at room temperature overnight. The reaction solution was loaded directly onto a preparative TLC plate and the plate was developed with ethyl acetate. The major compound is the desired product, N'-(3- : trifluoro-4-fluorophenyt)-N-{trans-4-(3-cyanophenyl)-4-hydroxycyclohexyl]-N-[2-(1- pyrrolidinyl)ethyljurea (21 mg HCI salt, 49%). 1H NMR (300 MHz, CDCI3) & 11.2 (s, 1H), 7.84 (s, 1 H), 7.82 (d, J = 6.9 Hz, 1 H), 7.50-7.64 (m, 3 H), 7.41(dd, J = 6.2 and 25Hz1H),7.06(t, J=9.3Hz, 1H), 4.36 (tt, J =12, 3.7 Hz, 1 H), 3.06 tJ =4.0 Hz, 30 . 2H),2.50-2.70 (m, 8 H), 1.77-2.05 (m, 8 H), 1.28 (q, J = 12.4 Hz, 2 H).

( ’

Following procedures similar to those described in Example 1, the following compounds were prepared. Example 2 was prepared from commercially available 4-

E phenylcyclohexanone using the procedures described in Example 1, steps 3 and 4.

I i 7 I . M+1 2 hes 459 ~N™ . L ~~ NY 3 co 474] 475.166

Jol

IP NPNGLN

. OH : Sy 2 Ti 474] 475.166

NH ]

NN AN

: -

NY

Wi 463.2222 £ .

NH

- ~~

Sy

STRUCTURE HRMS NMR

M+1 3 a 458] 459.1968 ~N

SW

NPN ’

OH

Nw 7 ¢ F E 542 543.2198

F. a

OH x CC

F 1 508] 509.1923

F. F

NH -

INN H

OH

Sw

F 492| 493.2236 )

PS

F NH

ENON

Nn

Ex. | STRUCTURE Mass HRMS

M+1

F 442] 443.2262 20!

NH

". ENN

OH

AY

11 F 442] 443.2266

F~ ® “SNH

IENPNLN

. OH vd g

RN “Sy 12 a 501.1831] -

Nel A

ENN

OH

Ny “CL.

NH :

A AD

[0] N . OH ) : RY

STRUCTURE HRMS

M+1 14 lr 518| 519.2373[1H NMR (300 MHz, CDCI3) 11.2 (s, 1H), 7.84 (m, 2 H), 7.42-

F [10 (m, SH), 7.08(t, J=9.2

Hz, 1 H), 4.30 (br, 1 H), 3.40 (t,

NH DO J=3.7Hz, 2H),2.81(t,J=3.7

NENG Hz, 2 H), 2.73 (br, 4 H), 1.70- 2.00 (m, 12 H).

OH

2 Sy ai 484] 485.2113

F.

TL a

ENN

OH

SS

ZF NS

. } NN

In 568] 569.2343] . F . ]

ID

F F -

AA . -

Sy 17 nr 534] 535.2081 -X

NH

A iD

O N

OH a

Ex. STRUCTURE HRMS

M+1 18 . 518| 519.2373 - F -

T. F NH >

A

OH

Sy 19 F 468 469.241

F.

LD

ENN N

OH

3 | Ss. | 468] 469.241

F NH

JD

OH

Ny 21 501.1831 [of] NH OD

Ag ’ OH

STRUCTURE HRMS NMR

M+1 22 \ 500| 501.1831

NPN

]

NN ®

AN :

OH

Sy 23 Cl 484] 485.2125

TL

ID

Ay } OH

Sy 24 NE 568] 569.2354 f. yes . 1»)

Fr Ag :

OH

Sy

Wi . 534] 535.2094 }

ID

Ag

I EE SR EER Pt 6 SR I ers . Cel me mL Cl FE SE

Sn

Ex. STRUCTURE Mass] HRMS

M+1 26 F F . 518| 519.2376 . F : NH 9

NN

-

Sy 27 F 468] 469.2423

Cl.

LID

Ag

OH

: Ny : 28 468] 469.2419

F NH - 9

Ag :

OH

Nw 29 FF 543|LCMS(54 :

F 4.1)

F

) ~~ ~T0 . Cl )

Cl!

M+1 30 3 493(493.1(LC

A MS)

Ne ~~ :

N

~"N

Reed O cl 31 F 509(510.1(LC oa MS)

Os NH he ~"n “ ) cl 32 cl 525|526.1(LC 7 MS)

Neen oY O (o] i : 33 F F 4931494.1(LC or MS) 5 ~ or (o] 34 a c 525[526.1(LC

Io 5 5 .

N

~"N cl o so.

I I i 1 IL

M+1 cl F 560.1(LC : oY MS) ’ F - ~™

TO

“ ct 36 F 543|544.1(LC ov MS)

F

~N™ ~NY of

Cl 37 F 450] 451.2303

QO

NH

LD | ]

N

38 cl 467.2021 gel

NH

BY, ’

N

STRUCTURE HRMS NMR

M+1 39 Gi 482| 483.1747

INA

I

ANN 0

NN : .

N

40 450] 451.2317

F NH BD

NPN N

[> =

Cl

N . 41 c 482} 483.1785 "

Jel ; BP

NPN : ’

N

® 51. a Ec 1

M+1) 42 | cl 517.1988 - F.

LD

} F NN

N

43 F 501.2267

F.

VaR

FF ENN N o. | . _ NOOO — 44 F 501.2267

F

AT ID i

N -

F 4591 460.1914 ae!

IID

. ENN

Claims (57)

WHAT IS CLAIMED IS:

1. A compound represented by the structural formula X "yr R?

Y. : X ol ~R! Ar' formula or a pharmaceutically acceptable salt or solvate of said compound, isomer or racemic mixture wherein : Ar' is aryl, heteroaryl, (R7),-substituted aryl or (R”),-substituted heteroaryl, wherein p is a number from 1 to 3 and when p is more than 1, each R’ can be the same or different and is independently selected from the group consisting of alkyl, cycloalkyl, halo, -CN, alkoxy, -CFa, -OCFa, -C(O)N(R®)2, -N(R%)2, (C1-Cs)alkylene- N(R®), -S-alkyl, -S(O)-alkyl, -S(O5)-alkyl, -S(O2)N(R?),, -N(R®)C(O)R®, (C:- Ce)N(R®)C(O)R®, NO, -C(O)alkyl, C(O2)R®, C(R%).0R?8, C=NOR? and a cyclic moiety selected from the group consisting of a) Eh re) Nn" FF FH NF SN NF 0) QW dTS ME ET Pt 0 Nn N=N NN NT 0 N” TO wherein said cyclic moiety, together with Ar’, can optionally form a fused aromatic moiety such as indole, indolone, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, or benztriazole; and further wherein if two R’ groups are adjacent, said adjacent R’ moieties can optionally be joined together to form a methylenedioxy or ethylenedioxy moiety, -A# is aryl,-heteroaryl, (R’),-substituted aryl or (R7) -substituted heteroaryl, = wherein p is a number from 1 to 3 and when p is more than 1, each R’ can be the 25s same or different and is independently selected from the group consisting of alkyl,

® - 223 - cycloalkyl, halo, -CN, alkoxy, -CFa, -OCF3, -C(O)N(R®), -N(R®)z, (C1-Ce)alkylene- N(R?) -S-alkyl, -S(O)-alkyl, -S(Oz)-alkyl, -S(O2)N(R®)2, -N(R®)C(O)R®, (C:- Ce)N(R®)C(O)R®, NO, -C(O)alkyl, C(O2)R®, C(R%20R?, C=NOR® and a cyclic moiety selected from the group consisting of — a — — 9 ES Re SRE FREI FRE @ NTP t= of oN a hay en NN © NN NO nN” 0 wherein said cyclic moiety, together with Ar', can optionally form a fused aromatic moiety such as indole, indolone, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, or benztriazole; and further wherein if two R’ groups are adjacent, said adjacent R’ moieties can optionally be joined together to form a methylenedioxy or ethylenedioxy moiety; X is O, S or N-(CN); Y is a single bond or alkylene group; Z is a C4-Cg cycloalkylene or C4-Cg heterocycloalkylene wherein each of said C4-Cs cycloalkylene or Cs-Cg heterocycloalkylene group optionally containing one or 1s two double bonds inside the cyclic ring and optionally substituted with 1 to 4 R® groups on the ring wherein each R® is independently selected from the group consisting of alkyl, cycloalkyl, -OH, -N(R%)., -NR®COalkyl, alkoxy and -OC(O)-alkyl, with the proviso that when RE is ~OH or -N(R®),, R® is not attached to a carbon adjacent to a nitrogen and when two R® groups are -OH, neither RE is on the same carbon on Z and further that two R® groups can be optionally joined together so that Z and said two R® groups together form a bicycloalkylene or bicycloheteroalkylene group containing from 5 to 12 atoms;

N £S R'is s” , aryl, heteroaryl, = R3 (CHs—N~ [SR Pi JRO ne N~ (Ch), Ne (CHa)q ‘ where s and q independently number 0 to 6, the sum of sand qis 2 to 6 and r numbers 0 to 3; 3 NE: 0) 1 I A J , ’ y ’ [1 N. 3 ’ No z N ! [} N ’ kf R ’ R® ls ~ Ne 5 | 1 , Pi (5 Os NR [; N~ re i, Fd ' ~N , EE 3 4 [ ) (NFR (NSOR ’ OH ’ ’ ’ S eS oe oy “or? , YN AN LN 0 H Oz NS pt Nr oi LL i Ao NS SJ 0 1 OT Oe YN JL . ST Oo , uN , x

® -225 - Ry =O NO< : AO . ) : CN, el, : . : o Ry Ra : s o i ee AN, AN ! NA ' NN ’ 0 H Sky! el, ne Nw BQ Ry =) R 025~Rq HN—{ ‘ HN-S0, o lo} af vas ha N-R® ha N-R’ en bi —/ —/ / band oy R® R2 0 OO ool Phe Ben } R? , orR'is -N(R%)2, -N(H)C(O)alkyleneN(R®), -C(O)N(H)alkyleneN(R%), -C(O)N(alkylalkyleneN(R®., -alkyleneC(H)(OH)alkyleneN(R?),

-N(alkyhalkyleneN(R®)., -N(H)alkyleneC(O)R®, -N(alkyl)alkyleneN(alkyl)S(O2)R® or

—N(alkyl)alkyleneC(O)N(R%).;

R2is hydrogen or alkyl;

each R® is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, : alkoxyalkylene-, aryl, aralkyl, heteroaryl, heterocyclyl, heteroaralkyl, -S(Oz)alkyl,

-S(Oz)aryl,-S(O2)N(H)alky!, -S(O2)N(alkyl), -S(Oz)alkyl, -S(O2)heterocycloalkyl, -C(O)alkyl, -C(O)aryl, -C(O)heteroaryl, -C(O)heterocycloalkyl, -C(O)N(H)alkyl, -C(O)N(alkyl)2, -C(O)N(H)aryl, -C(O)Oalkyl, -C(O)Oaryl or alkylene-C(O)Oalkyl, wherein each of said alkyl, alkylene, alkoxy, aralkyl, aryl, heteroaryl, heteroaralkyl or cycloalkyl group can independently be nonsubstituted, halosubstituted or hydroxysubstituted;

R*is R®, alkoxy or -N(R®)., with the proviso that when R* is attached to a sulfur atom then R* is not hydrogen; :

RS is hydrogen, -N(R3),, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaralkyl, alkoxy or alkoxyalkylene-, wherein each of said alkyl, alkylene, alkoxy,

aralkyl, aryl, heteroaralkyl or cycloalkyl group can independently be nonsubstituted, halosubstituted or hydroxysubstituted; RB is hydrogen, alky! or cycloalky®; RY is hydrogen, -C(O)alkyl or ~S(O2)alkyi. R'%is R® or halogen; with the following provisos: : that each R® of -N(R?)2 can be same or different and is independently selected; that each R® and R® of -C(O)N(R®)., -N(R®). and -S(02)N(R®). can be the same or different and is independently selected; and that in the above chemical formulas, each R? and R* can be the same or different and is independently selected.

2. The compound of claim 1 wherein Ar' is aryl, heteroaryl, (R”),-substituted aryl or (R”),-substituted heteroaryl, wherein p is a number from 1 to 3 and when p is more than 1, each R’ can be the same or different and is independently selected from the group consisting of alkyl, cycloalkyl, halo, -CN, alkoxy, -CF3, -OCF3, -C(O)N(R®)z, -N(R®),, (C1-Ce)alkylene- N(R®). -S-alkyl, -S(0)-alkyl, -S(Oz)-alkyl, -S(02)N(R®)2, -N(R®)C(O)R®, (Cs- Cg)N(R®)C(O)R®, NO,, -C(O)alkyl, C(O2)R®, C(R®),0OR®, C=NOR?® and a cyclic moiety selected from the group consisting of pr— 0 aI Ear RA SU or SPR NH y 0) en RE ey IE LEN LPT tN NN NN N 0 N 0 wherein said cyclic moiety, together with Ar’, can optionally form a fused aromatic moiety such as indole, indolone, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, or benztriazole; and further wherein if two R’ groups are adjacent, said adjacent R” moieties can optionally be joined together to form a methylenedioxy or ethylenedioxy moiety, Af is aryl, heteroaryl, (R’),-substituted aryl or (R’),-substituted heteroaryl, wherein p is a number from 1 to 3 and when p is more than 1, each R’ can be the

® - 227 - same or different and is independently selected from the group consisting of alkyl, cycloalkyl, halo, -CN, alkoxy, -CF3, -OCF;3, -C(O)N(R®)z, -N(R®)2, (C:-Ce)alkylene- : N(R®)2 -S-alkyl, -S(O)-alkyl, -S(O2)-alky!, -S(O2)N(R®)z, -N(R®)C(O)R®, (C:- Cs)N(R®)C(O)R®, NO, -C(O)alkyl, C(O2)R®, C(R®).0R® C=NOR?® and a cyclic moiety selected from the group consisting of — = — = 9 ES RVR VEE Es PAS (8 oo ET Pg ST zN NAN ’ NN No No wherein said cyclic moiety, together with Ar', can optionally form a fused aromatic moiety such as indole, indolone, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, or benztriazole; and further wherein if two R’ groups are adjacent, said adjacent R” moieties can optionally be joined together to form a methylenedioxy or ethylenedioxy moiety; ’ Xis O; Y is a single bond or -(C4-Cs)alkylene- group; a : (R®)m Zis , or a C4-Cg cycloalkylene or C4-Cg heterocycloalkylene wherein each of said C4-Cs cycloalkylene or C4-Cs heterocycloalkylene group optionally containing one or two double bonds inside the cyclic ring and optionally substituted with 1 to 4 R® groups on the ring wherein each R® is independently selected from the group consisting of alkyl, cycloalkyl, -OH, alkoxy and -OC(O)-alkyl, with the proviso that when R® is -OH, R® is not attached to a carbon adjacent to a nitrogen and when two R°® groups are -OH, neither R® is on the same carbon on Z and further that two R® groups can be optionally joined together so that Z and said two R® groups together form a bicycloalkylene or bicycloheteroalkylene group containing from 5 to 12 atoms; R' is -NHC(O)(C2-Cs)alkyleneN(R?)z, -C(O)NH(Cz-Cs)alkyleneN(R%., -C(O)N(CHbs)(C2-Ca)alkyleneN(R%)., -alkyleneC(H)(OH)(C1-Cz)alkyleneN(R%);,

- 228 - ® -N(CH3)(C2-Cs)alkyleneN(R%)2, -N(H)(C2-Cs)alkyleneC(O)R®, -N(CH3)(Co- Ca)alkyleneN(CH3)S(02)R® or —N(CHa)(C,-Ca)alkyleneC(O)N(R>),, wherein each R® can be the same or different and is independently selected; ) R?is hydrogen or -(C4-Cg)alkyl; each R? is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkylene-, aryl, aralkyl, heteroaryl, heterocyclyl, heteroaralkyl, -S(O,)alkyl,

. -8(0g)aryl,-S(02)N(H)alkyl, -S(O2)N(alkyl)z, -S(O.)alkyl, -S(Oz2)heterocycloalkyl, -C(O)alkyl, -C(O)aryl, -C(O)heteroaryl, -C(O)heterocycloalkyl, -C(O)N(H)alkyl, -C(O)N(alkyl)z, -C(O)N(H)aryl, -C(O)Oalkyl, -C(O)Oaryl or alkylene-C(O)Oalkyi, wherein each of said alkyl, alkylene, alkoxy, aralkyl, aryl, heteroaryl, heteroaralkyl or cycloalkyl group can independently be nonsubstituted, halosubstituted or hydroxysubstituted; : R* is R3, (C,-Ce)alkoxy or -N(R?)2, with the proviso that when R* is attached to a sulfur atom then R* is not hydrogen; RS is hydrogen, -N(R%),, -(C;-Cg)alkyl, -(Cs-C7)cycloalkyl, -(C3-C7)cycloalkyl(C1- Cs)alkyl, aryl, aralkyl, heteroaralkyl, (C1-Cg)alkoxy or (C4-Cs)alkoxy(C1-Cs)alkylene-, wherein each of said alkyl, alkylene, alkoxy, aralkyl, aryl, heteroaralkyl or cycloalkyl group can independently be nonsubstituted, halosubstituted or hydroxysubstituted,; R® is -(C1-Ce)alkyl, (Ca-Cs)cycloalkyl, -OH, -O-(C4-Ce)alkyl, -OC(0)-(C1-Cs alkyl), with the proviso that when R® is -OH, R®is not attached to a carbon adjacent to a nitrogen and when two R® groups are -OH, neither R® is on the same carbon on Z; R® is hydrogen, -(Cy-Cg)alky! or -(C3-C7)cycloalkyl; with the following provisos that each R® of -N(R%). can be same or different and is independently selected; that each R® and R® of -C(O)N(R?),, -N(R%). and -S(02)N(R®), can be the same or different and is independently selected; and where in the above chemical formulas, each R® and R* can be the same or different and is independently selected. 3c

3. The compound of claim 1 wherein Ar' and Ar? are the same or different and are independently selected from phenyl, pyridyl, (R7),-substituted aryl or (R)p-substituted heteroary!, wherein p is a

9 -229 - number from 1 to 3 and when p is more than 1, each R’ can be the same or different and is independently selected from the group consisting of alkyl, cycloalkyl, halo, -CN, alkoxy, -CFs, -OCF3, -C(O)N(R®)2, -N(R®)2, (C1-Ce)alkylene-N(R®), -S-alkyl, -S(O)- alkyl, -S(02)-alkyl, -S(O2)N(R®)2, -N(R®)C(O)R?, (C1-Ce)N(R®)C(O)R®, NO,, -C(O)alkyl, C(O2)R? C(R®):0R® or C=NOR®; Xis O; : Y is a single bond or —CHz-, -CH2CHa-, ~CH2CH2CHz- or -CH2CH2CH2CH>-; JO R'is ; R?is hydrogen; and R3 is hydrogen, -(C4-Cg)alkyl, -(Ca-Cr)cycloalkylmethyl, (C4-Ce)alkoxy(C1- Cs)alkylene- or SOzalkyl.

4. The compound of claim 1 wherein Ar' and Ar? are the same or different and are independently selected from phenyl, pyridyl, (R")p-substituted aryl or (R")p-substituted heteroaryl, wherein pis a number from 1 to 3 and when p is more than 1, each R’ can be the same or different and is independently selected from the group consisting of alkyl, cycloalkyl, halo, -CN, alkoxy, -CF3, -OCFs, -C(O)N(R®)2, -N(R®)., (C1-Cs)alkylene-N(R®), -S-alkyl, -S(O)- alkyl, -S(O2)-alkyl, -S(O2)N(R®)2, -N(R®)C(O)R®, (C1-Ce)N(R®)C(O)R®, NO, -C(O)alkyl, C(02)R®, C(R®).0R® or C=NOR®; Xis O; Y is -CH2CHz-, -CH,CH,CH- or -CH>CH;CH2CHa-; R' is -N(R%)2 or -C(O)NH(C2-Ca)alkyleneN(R%); and : R® is hydrogen, -(Cy-Ce)alkyl, -ar(C1-Ce)alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, halo- substituted -(C1-Cg)alkyl, hydroxy-substituted -(C+-Ce)alkyl or -(Cs- C,)cycloalkyl, wherein each R® can be same or different and is independently selected.

5. The compound of claim 1 wherein oo eo. | Q

Ar' and Ar? are independently phenyl, pyridyl, R”-substituted phenyl or R"- substituted pyridyl, wherein said Ar' and Ar? are the same or different and is independently selected, and R’ numbers 1 to 3 which can be the same or different, . each being independently selected from the group consisting of alkyl, cycloalkyl, halo,

-CN, alkoxy, -CF3, -OCF3, -C(O)N(R®)2, -N(R®), -S-alkyl, -S(O)-alkyl, -S(Oy)-alkyl, : -S(02)N(R®)2, -N(R®)C(O)R®, -NO, . —_— — — Oo = y= =, = ~n 7, 2 NaN A ozN SN To NaN

N N

0) — —_— [——N N“—N NT 7 = \ H— | and = 1

NN ’ NAN ’ N=N N (0) N (0) wherein each R® and R® can be the same or different and is independently selected, or two adjacent R’ groups can be joined together to form a methylenedioxy or ethyelenedioxy group;

Xis O;

Yis -CH,CHo-, —CH>CH>CHo2- or —CH,CH,>CH,CHo-;

R'is

AT oD Dem _R® 0 oy J We Ty

® -231 - Ris hydrogen, -(C:-Ce)alkyl, -(Cs-Cr)cycloalkyl, -(C3-Cr)cycloalkyl(Ci-Ce)alkyl, (Cy-Ce)alkoxy(C1-Ce)alkylene-, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl, wherein each of said alkyl, alkylene, alkoxy, aralkyl, aryl, heteroaryl, heteroaralkyl or cycloalkyl group can independently be nonsubstituted, halosubstituted or hydroxysubstituted; R* is R3, (C;-Cg)alkoxy or -N(R®). wherein each R® can be same or different . and is independently selected, with the proviso that when R* is attached to a sulfur atom then R* is not hydrogen; R® is hydrogen, -(C-Ce)alkyl, -(C3-C7)cycloalkyl, -(Cs-Cr)cycloalkyl(C1-Ce)alkyl, aryl, aralkyl, heteroaralkyl, (C1-Cg)alkoxy or (Cs-Ce)alkoxy(C1-Ce)alkylene-, wherein each of said alkyl, alkylene, alkoxy, aralkyl, aryl, heteroaralkyl or cycloalkyl group can independently be nonsubstituted, halosubstituted or hydroxysubstituted; and R® is hydrogen, -(Cy-Cs)alkyl or -(C3-C7)cycloalkyl.

6. The compound of claim 5 wherein Ar' is R”-substituted phenyl and said Ris one group positioned at the 3-position of said substituted phenyl with respect to the linking point to Z.

7. The compound of claim 6 wherein R’ is -CN, -OCF3, chloro, -C(O)N(R®)z, N(R, or -N(R})C(O)R".

8. The compound of claim 5 wherein Ar' is pyridyl and Ar? is halo-substituted phenyl or (CF3)-substituted phenyl.

9. The compound of claim 5 wherein Ar' is pyridyl and Ar? is halo-substituted pyridyl or (CF3)-substituted pyridyl.

10. A compound selected from the group consisting of

Bel ¢ a x ] 1a oH cP Deon AN A : a A 3 F FF oN F 8 TOC AD J 1 F 2 pe POR N= [+] [os] Q i by BSW \ Wo Q © Sat i 3 FF F & & Og NH RAL ~ ™ mn N E F ° he of . St Ih 0 ™ Sn wm elt Bh o 233. , Q, Ayan) 1g) g om QQ " N od wo . NH ’ F ; oA nD NH @ “00 . Q ” [o] F Wy JL FE NH N F To Ayn) 4

L . 0 NN,

Q. a a N A, : rl oP vom 1@! NH 0 R F Sy oN NN Ci Lm Doe 0X QL (! =n ON .

a hel a . NH la’ on von Bel Pa ®) or F i F N F cl C1 M NH . oy AA Don - “ON OH N a ,,

F. 19} : NH °F A Q, Seas OH Sn a N,, Je : c NH Aino LL, “Oy . oH Sy a Ty F 1ST . NH o/s oy wD J Q F NK g I: Sw &

@® -235- Res ; <p oy oy ™

1 .., v- 5 0 Q a 1 oN a 0) Qe OM IN N N 1 5 0) — 0 eH 0 \ F F [2] cl 4 iS AA, 04M a N 1 N R, s NT SN H F . [«] PA a NZ OH x? : oN cl f Y $ go NS QO Eade p 9, : oN cl YOY JA, Hr TOA \ HO

® os” cass OY ~ a! F Se . 7 ° ¥ Ie XY 05 TEST | 3 D ¢ ~ N pam ~NY fa Khe 0 ? Tn | Oo Q, > NI ov LI AS 2% ho [] : ps ox Fro F nN } opty q

® - 237 - E 0 ~ I, . s F

0.6 2 a N ANA H Sa ’ Oe

) . Sw

N . . [o F “ § - A, 0 Sn () h E F ge) Q A & ~~ ) iD ° d 0 ~N a FoF Jl on Sa a” NH ~ Kit fq ot OH rr Sn

-238 - ® [o] OJ NE FH Ty : cl ci F oy ~ o Oy N N ASS Ao KT on CL Br ON cl F Y 1 X ; _CF3 ’ L F Nid Ox NH AN he Sa } x: - “nf OH CN F F oY Os NH Os NH Ny T \_ J UTaRY ‘SY _/ \ CN o a _ 239 - PCT/US02/38408 ve of LO) ob Y 3 On Fa pe a JO on AL Vv Eo 2 ~™ A Foo Ao So Se ci F PN AN - ~y 9 ~*y 9 Ag" A N : AS Sn F F

F. F : jo F > NH 9 4 D ’ ENN AA ¢ > ® My AN F CF, QL : F PD ro D- F H : F NPN ENN 0) : 2 Ii N

@® -241 - . CFs So “2

F. NH LA IO CN Il N cr g NH cl” g “NH A iD PN A Don 0 NTN 0 N “CN 8 Ny F Ci F. F 2 Cl NH PUD, ro AN “HOH 0 N NPN CN QL F CFa Fr F cl NH by | Att o 3 9 - Sn eo} CF; jel ag! Cl NH NH ) oo AD Anton Sn g “CN of] F F Ci F F XD NH ~N 9, AY Sy F Cl F~L-F F cl NH NH 9 AID NPN QO Ny Nn Fo Cl rr _D- OH I NH 0 AN ENN N ® XN Sn jd EE bd a 243 PCT/US02/38408 Cl Cl ci NH Je! A I cl NH 07 "NT ry So EN 2 CL Cl CN NH AH : “CN or a pharmaceutically acceptable salt or solvate thereof.

11. Use of at least one compound of claim 1 in the manufacture of a medicament for treating a metabolic disorder, an eating disorder or diabetes.

12. Use of at least one compound of claim 10 in the manufacture of a medicament for treating a metabolic disorder, an eating disorder or diabetes.

13. Use of claim 11 wherein said eating disorder is hyperphagia.

14. Use of claim 11 wherein said metabolic disorder is obesity.

15. Use of claim 12 wherein said eating disorder is hyperphagia. AMENDED SHEET a > -244. PCT/US02/38408

16. Use of claim 12 wherein said metabolic disorder is obesity.

17. Use of at least one compound of claim 1, or a pharmaceutically acceptable salt or solvate of said compound in the manufacture of a medicament for treating a disorder associated with obesity.

18. Use of at least one compound of claim 10, or a pharmaceutically acceptable salt or solvate of said compound in the manufacture of a medicament for treating a disorder associated with obesity.

19. Use of claim 17 wherein said disorder associated with obesity is at least one of type Il diabetes, insulin resistance, hyperlipidemia or hypertension.

20. Use of claim 18 wherein said disorder associated with obesity is at least one of type Il diabetes, insulin resistance, hyperlipidemia or hypertension.

21. Use of at least one compound of claim 1 or a pharmaceutically acceptable salt or solvate of said compound in the manufacture of a medicament for treating major depression, manic depression, anxiety, schizophrenia and sleep disorders.

22. Use of at least one compound of claim 10 or a pharmaceutically acceptable salt or solvate of said compound in the manufacture of a medicament for treating major depression, manic depression, anxiety, schizophrenia and sleep disorders.

23. Use of a first compound, said first compound being a compound of claim 1, or a pharmaceutically acceptable salt or solvate of said compecund; and a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a 3; agonist, a thryomimetic agent, an anorectic agent and an NPY antagonist; in the manufacture of a medicament for treating an eating disorder. AMENDED SHEET

¢ -245- PCT/US02/38408

24. Use of a first compound, said first compound being a compound of claim 1, or a pharmaceutically acceptable salt or solvate of said compound in the manufacture of a medicament for use with a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a RB, agonist, a thryomimetic agent, an anorectic agent and an NPY antagonist for treating an eating disorder.

25. Use of a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a 3; agonist, a thryomimetic agent, an anorectic agent and an NPY antagonist in the manufacture of a medicament for use with a first compound, said first compound being a compound of claim 1, or a pharmaceutically acceptable salt or solvate of said compound for treating an eating disorder.

26. Use of a first compound, said first compound being a compound of claim 10, or a pharmaceutically acceptable salt or solvate of said compound; and a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a (3; agonist, a thryomimetic agent, an anorectic agent and NPY antagonist; in the manufacture of a medicament for treating an eating disorder.

27. Use of a first compound, said first compound being a compound of claim 10, or a pharmaceutically acceptable salt or solvate of said compound in the manufacture of a medicament for use with a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a B; agonist, a thryomimetic agent, an anorectic agent and an NPY antagonist for treating an eating disorder.

28. Use of a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a 3; agonist, a AMENDED SHEET

! -246- PCT/US02/38408 thryomimetic agent, an anorectic agent and an NPY antagonist in the manufacture of a medicament for use with a first compound, said first compound being a compound of claim 10, or a pharmaceutically acceptable salt or solvate of said compound for treating an eating disorder.

29. A pharmaceutical composition which comprises a therapeutically effective amount of: a first compound, said first compound being a compound of claim 1, or a pharmaceutically acceptable salt or solvate of said compound; a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a 3, agonist, a thryomimetic agent, an anorectic agent and NPY antagonist; and a pharmaceutically acceptable carrier.

30. A pharmaceutical composition which comprises a therapeutically effective amount of: a first compound, said first compound being a compound of claim 1, or a pharmaceutically acceptable salt or solvate of said compound; a second compound, said second compound selected from the group consisting of an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidy! protease inhibitor, insulin, an insulin mimetic, metformin, acarbose, troglitazone, rosaglitazone, pioglitazone, GW-1929, a sulfonylurea, glipazide, glyburide, and chlorpropamide; and a pharmaceutically acceptable carrier.

31. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 in combination with at least one pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising a therapeutically effective AMENDED SHEET

V -247- PCT/US02/38408 amount of at least one compound of claim 10 in combination with at least one pharmaceutically acceptable carrier.

33. A process for making a pharmaceutical composition comprising combining at least one compound of claim 1, and at least one pharmaceutically acceptable carrier.

34. A substance or composition for use in a method of treating a metabolic disorder, an eating disorder or diabetes, said substance or composition comprising at least one compound of claim 1, and said method comprising administering a therapeutically effective amount of said substance or composition to a patient.

35. A substance or composition for use in a method of treating a metabolic disorder, an eating disorder or diabetes, said substance or composition comprising at least one compound of claim 10, and said method comprising administering a therapeutically effective amount of said substance or composition to a patient.

36. A substance or composition for use in a method of treatment of claim 34 wherein said eating disorder is hyperphagia.

37. A substance or composition for use in a method of treatment of claim 34 wherein said metabolic disorder is obesity.

38. A substance or composition for use in a method of treatment of claim 35 wherein said eating disorder is hyperphagia.

39. A substance or composition for use in a method of treatment of claim 35 wherein said metabolic disorder is obesity. AMENDED SHEET

\ - -248- PCT/US02/38408

40. A substance or composition for use in a method of treating a disorder associated with obesity, said substance or composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt or solvate of said compound, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammal in need of such treatment.

41. A substance or composition for use in a method of treating a disorder associated with obesity, said substance or composition comprising at least one compound of claim 10, or a pharmaceutically acceptable salt or solvate of said compound, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammal in need of such treatment.

42. A substance or composition for use in a method of treatment of claim 40 wherein said disorder associated with obesity is at least one of type Il diabetes, insulin resistance, hyperlipidemia or hypertension.

43. A substance or composition for use in a method of treatment of claim 41 wherein said disorder associated with obesity is at least one of type li diabetes, insulin resistance, hyperlipidemia or hypertension.

44. A substance or composition for use in a method of treating major depression, manic depression, anxiety, schizophrenia and sleep disorders, said substance or composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt or solvate of said compound, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammal in need of such treatment.

45. A substance or composition for use in a method of treating major depression, manic depression, anxiety, schizophrenia and sleep disorders, said AMENDED SHEET

Rr ¢ -249- PCT/US02/38408 substance or composition comprising at least one compound of claim 10 or a pharmaceutically acceptable salt or solvate of said compound, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammal in need of such treatment.

46. A substance or composition for use in a method of treating an eating disorder, said substance or composition comprising a first compound, said first compound being a compound of claim 1, or a pharmaceutically acceptable salt or solvate of said compound; and a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a 3; agonist, a thryomimetic agent, an anorectic agent and an NPY antagonist; and said method comprising administering said substance or composition to a mammal in need of such treatment.

47. A substance or composition for use with a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a RB, agonist, a thryomimetic agent, an anorectic agent and an NPY antagonist in a method of treating an eating disorder, said substance or composition comprising a first compound, said first compound being a compound of claim 1, or a pharmaceutically acceptable salt or solvate of said compound, and said method comprising administering said substance or composition and said second compound to a mammal in need of such treatment.

48. A substance or composition for use with a first compound, said first compound being a compound of claim 1, or a pharmaceutically acceptable salt or solvate of said compound in a method of treating an eating disorder, said substance or composition comprising a second compound, said second h compound being an antiobesity and/or anorectic agent selected from the group consisting of a 3; agonist, a thryomimetic agent, an anorectic agent and an NPY antagonist and said method comprising administering said substance or AMENDED SHEET

Co t -250- PCT/US02/38408 composition and said first compound to a mammal in need of such treatment.

49. A substance or composition for use in a method of treating an eating disorder, said substance or composition comprising a first compound, said first compound being a compound of claim 10, or a pharmaceutically acceptable salt or solvate of said compound; and a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a 3; agonist, a thryomimetic agent, an anorectic agent and an NPY antagonist, and said method comprising administering said substance or composition to a mammal in need of such treatment.

50. A substance or composition for use with a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a B, agonist, a thryomimetic agent, an anorectic agent and an NPY antagonist in a method of treating an eating disorder, said substance or composition comprising a first compound, said first compound being a compound of claim 10, or a pharmaceutically acceptable salt or solvate of said compound, and said method comprising administering said substance or composition and said second compound to a mammal in need of such treatment.

51. A substance or composition for use with a first compound, said first compound being a compound of claim 10, or a pharmaceutically acceptable salt or solvate of said compound, in a method of treating an eating disorder, said substance or composition comprising a second compound, said second compound being an antiobesity and/or anorectic agent selected from the group consisting of a B, agonist, a thryomimetic agent, an anorectic agent and an NPY antagonist, and said method comprising administering said substance or composition and said first compound to a mammal in need of such treatment.

52. A compound of any one of claims 1 to 10, substantially as herein AMENDED SHEET a t -251- PCT/US02/38408 described and illustrated.

53. Use of any one of claims 11 to 28, substantially as herein described and illustrated.

54. A composition of any one of claims 29 to 32, substantially as herein described and illustrated.

55. A process of claim 33, substantially as herein described and illustrated.

56. A substance or composition for use in a method of treatment of any one of claims 34 to 51, substantially as herein described and illustrated.

57. A new compound, a new use of a compound of claim 1 or claim 10, a new composition, a new process for making a composition, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET