PIPERIDINE DERIVATIVES FOR THE TREATMENT OF OBESITY

Field of invention

The present invention relates to urethane derivatives, to processes for preparing such compounds, to their use as Fatty Acid Synthase inhibitors, to methods for their therapeutic use, particularly in the treatment of obesity and diabetes mellitus, and to pharmaceutical compositions containing them.

Background of the invention

Obesity and diabetes are reaching epidemic proportions in the USA, EU, Japan and developing countries. Obesity is the major driver of the co-morbidities of the metabolic syndrome, particularly type 2 diabetes. Since no effective pharmacotherapies for obesity are available to date and current diabetes therapies do not stop the progression of the disease, there is a huge unmet medical need.

Fatty Acid Synthase (FAS) is a critical enzyme for endogenous lipogenesis and plays an important role in the modulation of key intermediates of lipid and carbohydrate cellular metabolism. FAS is highly expressed in the tissues with high metabolic activity

(for example liver, adipose tissue and brain) and there are good reasons to believe that a

FAS inhibitor would cause beneficial metabolic effects in peripheral tissues. In addition, inhibition of FAS in the hypothalamus may result in reduced food intake. The non-specific irreversible FAS inhibitors cerulenin and C-75 have been reported in the literature to decrease brain levels of orexigenic neuropeptides and to decrease food intake.

Therefore there is a need for an effective FAS inhibitor to treat obesity and diabetes.

Description of the invention

The present invention provides a compound of formula I

or a pharmaceutically acceptable salt thereof, in which

R ¹ represents 1) a C _1-6 alkyl group optionally substituted by one or two groups selected from A-S below and/or by one to five groups selected from T below: A) phenyl optionally substituted by one or more of the following i) halo; ii) cyano; iii) a Ci _-4 alkoxy group optionally substituted by one or more halo iv) hydroxy; v) a C _1-4 alkyl group optionally substituted by one or more halo; vi) carbamoyl; vii) N-C _1- βalkylcarbamoyl; viii) N,N-diCi.6alkylcarbamoyl ; ix) carboxy; x) Ci _-6 alkoxycarbonyl; xi) Ci- ₆ alkylthio; xii) Ci-oalkylsulfinyl; xiii) Q.oalkylsulfonyl; xiv) Ci-βalkylsulfonyloxy; xv) sulphamoyl; xvi) N-C^alkylsulphamoyl; xvii) N, N-diCi-βalkylsulphamoyl; xviii) benzyl xix) benzyloxy; xx) heteroaryl; xxi) heteroaryloxy; xxii) phenyl xxiii) phenoxy xxiv) phenylsulphamoyl; xxv) heteroarylsulphamoyl; xxvi) a carbon linked saturated or partially unsaturated 4 to 8 membered heterocyclic group as defined in c) below; xxvii) phenylsulfonyl ; xxviii) heteroarylsulfonyl; xxix) a group of formula νR ^c R ^d in which R ^c and R ^d independently represent: a) H; b) C _1-6 alkanoyl; c) a carbon linked saturated or partially unsaturated 4 to 8 membered heterocyclic group containing one or more N, S or O, wherein the S may be in its oxidised form of SO or SO ₂ , which is optionally fused to a benz ring and any ring is optionally substituted by one or more of the following: hydroxy, oxo, carboxy, a Ci^alkoxy group optionally substituted by one or more hydroxy or C^alkoxy, C _1-4 alkanoyl, benzoyl, amino, Ci _-3 alkylamino, di(C _1-3 alkyl)amino or a C _1-6 alkyl optionally substituted by one or more hydroxy or Ci-βalkoxy; d) a d-βalkyl group optionally substituted by one or more of the following: hydroxy; carboxy; a Ci_ ₆ alkoxycarbonyl group; a Ci-βalkoxy group; heteroaryl; a group of formula NR ^e R ^f in which R ^e and R ^f independently represent H; a C^alkanoyl group; a C _1- βalkylsulphonyl group; a C _1-6 alkoxycarbonyl group; a Cμδalkyl group optionally substituted by one or more hydroxy or Ci-βalkoxy , or R ^e and R ^f together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 4 to 8 membered heterocyclic ring optionally containing an additional sulphur including oxidised as SO or SO ₂ , oxygen or nitrogen and/or optionally fused to a benz ring and any ring is optionally substituted by one or more of the following: a Ci _-6 alkoxy group; carboxy; a Ci- ₆ alkylsulfonyl group; Ci _-4 alkanoyl; benzoyl; hydroxy; oxo; carboxy; or a group

optionally substituted by one or more hydroxy or by one or more C^alkoxy or by one or more carboxy; e) R ^c and R ^d together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 4 to 8 membered heterocyclic ring optionally containing an additional oxygen, sulphur, SO, SO ₂ or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a C _1-6 alkoxy group; C _{1- 4} alkanoylgroup; benzoyl; a d^alkoxycarbonyl group; a Ci-βalkylsulfonyl group; carbamoyl; N-Ci- ₆ alkylcarbamoyl; N, N-diC^ealkylcarbamoyl; hydroxy; oxo; carboxy; a Ci-βalkyl group (which is optionally substituted by one or more of the following: a C ₁ . o βalkoxy group, hydroxy or a group of formula νR ^e R ^f in which R ^e and R ^f are as defined above) or a group of formula NR ^e R ^f in which R ^e and R ^f are as defined above; f) a Ci-βalkylsulphonyl group; g) phenylsulfonyl; h) heteroarylsulfonyl; s i) benzoyl; j) phenyl optionally substituted by one or more of the following: halo; C _1-3 alkyl; C _{1- 3 alkoxy; a C 1-6 alkanoylamino group; carbamoyl; N-Q-βalkylcarbamoyl; N,N-diC]. δ alkylcarbamoyl; k) heteroaryl optionally substituted by one or more carboxy; fluoro; hydroxy; a C] -3 alkoxy o group optionally substituted on C2 or C3 by carboxy; a group νR ^c R ^d in which R ^c and R ^d are as defined above; or a group CONR ^e R ^f in which R ^e and R ^f are as defined above;}

1) a C _3-1 ocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged and is optionally substituted by one or more carboxy; fluoro; hydroxy; a

C _1-3 alkoxy group optionally substituted on C2 or C3 by carboxy; a group NR ^e R ^f in which 5 R ^e and R ^f are as defined above; or a group CONR ^e R ^f in which R ^e and R ^f are as defined above; m) a C _1-6 alkoxycarbonyl group;

B) a heteroaryl group which is optionally substituted by groups i) to xxix) as described for phenyl above; Q C) a group of formula NR ^c R ^d in which R ^c and R ^d are as defined above;

D) a C _3-7 cycloalkyl group optionally substituted by one or more hydroxy or a group of formula NR ^e R ^f in which R ^e and R ^f are as defined above;

E) a carbon linked saturated or partially unsaturated 4 to 8 membered heterocyclic group containing one or more N, S or O, wherein the S may be in its oxidised form of SO or SO ₂ , which is optionally fused to a benz ring and/or is optionally substituted by one or more of the following: hydroxy; oxo; a C _1-6 alkoxy group; carboxy; hydroxy; C^alkanoyl;

5 a Cμ _δ alkylsulfonyl group; amino; Ci _-3 alkylamino; di(Ci _-3 alkyl)amino; or a C^alkyl optionally substituted by one or more hydroxy or C^alkoxy;

F) a C ₁ .6 alkoxycarbonyl group;

G) a C _2-6 alkynyl group:

H) a group -C0NR°R ^d in which R° and R ^d are as defined above; o I) a Cμβalkoxy group;

J) a C _2-6 alkenyl group:

K) a C^alkyl group;

L) a Ci-βalkylsulphonyl group;

M) phenylsulfonyl; s N) heteroarylsulfonyl;

O) benzoyl;

P) a Ci-βalkanoyl group

Q) hydroxy;

R) oxo; o S) carboxy;

T) fluoro or R ¹ represents

2) a C _3-7 cycloalkyl group optionally substituted by one or two groups selected from A to T above; 5 3) a C _2-6 alkynyl group optionally substituted by one or two groups selected from A to T above;

4) a carbon linked saturated or partially unsaturated 4 to 8 membered heterocyclic group containing one or more N, S or O, wherein the S may be in its oxidised form of SO or

SO ₂ , which is optionally fused to a benz ring and any ring is optionally substituted by 0 a group A to T as defined above one or more of the following: hydroxy, oxo, carboxy, a

C^alkoxy group, hydroxy, a d-βalkylsulfonyl group, Ci _-4 alkanoyl, benzoyl, amino, G ₁ .

₃ alkylamino, (Ii(C _1-3 alkyl)amino or a Ci^alkyl optionally substituted by one or more hydroxy or C _1-6 alkoxy;

5) a C _2-6 alkenyl group optionally substituted by one or two groups selected from A to T above; 6) optionally substituted phenyl including optional fusion of the phenyl ring to a saturated or partially unsaturated 5 to 6 membered heterocyclic ring optionally containing one, two or three hetero atoms selected from oxygen, sulphur optionally in its oxidised forms of SO or SO ₂ or nitrogen wherein the heterocyclic ring is optionally substituted by one or more of the following: a C^alkoxy group; a Ci _-6 alkanoyl group;carboxy; a C _1-6 alkylsulfonyl group; a Ci-βalkoxycarbonyl group; carbamoyl; N-Ci-βalkylcarbamoyl; N, N-diQ. βalkylcarbamoyl; hydroxy; oxo; a Ci^alkyl group (which is optionally substituted by one or more of the following: a Q-βalkoxy group, hydroxy or a group of formula νR ^c R ^d in which R° and R ^d are as defined above) and wherein the phenyl ring is optionally substituted by one or more of the groups i to xxix listed above or by a heteroaryl group optionally substituted by one or more groups i) to xxix) above or by an ureido group of formula R ^m R ⁿ N-C(O)-NH- in which R ^m and R ⁿ independently represent H, a C _1-6 alkyl group optionally substituted by a group, or R ^m and R ⁿ together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 4 to 8 membered heterocyclic ring optionally containing an additional sulphur including oxidised as SO or SO ₂ , oxygen or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a d-βalkoxy group; hydroxy; oxo; carboxy; a Ci _-6 alkylsulfonyl group; or a C^alkyl group optionally substituted by one or more hydroxy or C^alkoxy; 7) optionally substituted heteroaryl including N-oxides and S-oxides thereof optionally substituted by one or more of the groups i to xxi listed above; wherein any alkyl chain mentioned in any of the definitions from A to P above or in any of the definitions i to xxix above is optionally substituted by 1) one group selected from: carboxy; hydroxy; a C _1-3 alkoxy group optionally substituted on C2 or C3 by carboxy; a group NR ^c R ^d in which R ^c and R ^d are as defined above; or a group CONR ^e R ^f in which R ^e and R ^f are as defined above; and /or by 2) from one to five fluoro; and further wherein any cycloalkyl, phenyl, heteroaryl ring or carbon linked saturated or partially saturated 4 to 8 membered heterocyclic group in the list of optional substituents

from A to P above or in any of the definitions i to xxix above, for which specific substitution has not been previously mentioned, is optionally substituted by one group selected from: carboxy; hydroxy; a Ci _-3 alkoxy group optionally substituted on C2 or C3 by carboxy; a group NR ^c R ^d in which R° and R ^d are as defined above; or a group CONR ^e R ^f in which R ^e and R ^f are as defined above; and /or is optionally substituted by one to five fluoro;

R ² represents H, halo, a Ci_ ₃ alkyl group, trifluoromethoxy or cyano; R ³ represents H, halo, a Ci _-3 alkyl group, trifluoromethoxy or cyano; R ⁴ represents i) H, ii) a C^alkyl group optionally substituted by one or more halo iii) a C _{1- 3} alkoxy group optionally substituted by one or more halo iv) halo, v) nitro, vi) cyano, vii) a C _1-6 alkylS(O) _y (O) _z - wherein y is 0,1 or 2 and z is 0 except when y is 2 when z is 0 or 1 viii) a group CH ₂ NR ^U R ^V in which R ^u and R ^v independently represent H; a C _1-3 alkylsulphonyl group, a C _1-3 alkanoyl group or a Ci_ ₃ alkyl group or R ^u and R ^v together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl; ix) a group CO ₂ R ^W in which R ^w is a Ci _-3 alkyl group; or x) a group CONR ^x R ^y in which R ^x and R ^y independently represent H; or a C _1-3 alkyl group or R ^x and R ^y together with the nitrogen atom to which they are attached represent azetidinyl; pyrrolidinyl, piperidinyl or morpholinyl; R ⁵ and R ⁵ independently represent H, halo, cyano, C _1-3 alkyl optionally substituted by one or more halo or C _1-3 alkoxy optionally substituted by one or more halo;

R ⁶ and R ⁶ independently represent H, halo, cyano, C _1-3 alkyl optionally substituted by one or more halo or C _1-3 alkoxy optionally substituted by one or more halo; and

R ⁷ is H or OH.

In a first group of compounds of formula I, R ⁷ is H. In a particular group of compounds of formula II

or a pharmaceutically acceptable salt thereof,

in which

R ¹ represents 1) a C^alkyl group optionally substituted by one or more of the following: a) phenyl b) pyridyl or c) a Ci _-3 alkoxy group 2) a C _3-7 cycloalkyl group or 3) phenyl ; R ² represents H, halo, a Ci _-3 alkyl group; or trifluoromethoxy; R ³ represents H, halo, a C _1-3 alkyl group; or trifluoromethoxy; provided that one of R ² and R ³ is other than H; R ⁴ represents cyano.

Further sub-definitions of the meaning of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5' R ⁶ , R ^6' and R ⁷ in compounds of formula I now follow. It will be understood that any combination of these sub-definitions may be used instead of the original definitions where appropriate in any of the compound groups, claims or embodiments defined hereinbefore or hereinafter. In one group of compounds of formula I or of formula HA, R ¹ represents a Ci_ ₆ alkyl group optionally substituted by 3-pyridyl or 4-pyridyl. In a second group of compounds of formula I or of formula HA, R ² represents methyl and R ³ is H.

"Pharmaceutically acceptable salt", where such salts are possible, includes both pharmaceutically acceptable acid and base addition salts. A suitable pharmaceutically acceptable salt of a compound of formula I is, for example, an acid-addition salt of a compound of formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a base-addition salt of a compound of formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a sodium, calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamme, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound. Isomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The enantiomers may be isolated by

separation of racemate for example by fractional crystallisation, resolution or HPLC. The diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography. Alternatively the stereoisomers may be made by chiral synthesis from chiral starting materials under conditions that will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent. All stereoisomers are included within the scope of the invention. AU tautomers, where possible, are included within the scope of the invention. The present invention also encompasses compounds containing one or more isotopes for example ¹⁴ C, ¹¹ C or ¹⁹ F and their use as isotopically labelled compounds for pharmacological and metabolic studies. The present invention also encompasses prodrugs of a compound of formula I that is compounds which are converted into a compound of formula I in vivo. The following definitions shall apply throughout the specification and the appended claims.

The term "C _3- iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, bicyclo(2.2.1)heptyl, bicyclo(2.2.2)octyl, perhydroindanyl and adamantyl.

The term "heteroaryl" includes pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- oxadiazolyl, triazolyl, furazanyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl quinolyl, isoquinolyl, benzthienyl, benzofuranyl, benzofurazanyl, benzoxazolyl, benzimidazolyl, indolyl, benzthiazolyl, indazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8- naphthyridinyl, pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl or imidazopyridinyl. The term "heteroaryl including N-oxides" includes heteroaryls as described immediately above and in addition N-oxides of such heteroaryls where such N-oxides are known to those skilled in the art to exist and are known to be stable at ambient conditions for example pyridine-N-oxides.

The term "a carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more ν, S, SO, SO ₂ or O" includes oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-l,3-thiazolyl, 1,3-thiazolidinyl, 1,3-oxazolidinyl, oxepanyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,

thiamorpholinyl (perhydro-l,4-thiazinyl), (8-oxa-3-azabicyclo[3.2.1]octyl), (7-oxa-3- azabicyclo[3.1.1 ]heptyl), perhydroazepinyl, perhydrooxazepinyl, tetrahydro- 1 ,4-thiazinyl, 1-oxotetrahydrothienyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl each of which amy be optionally substituted as previously described.

When two substituents on an amine together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional oxygen, sulphur, SO, SO ₂ or nitrogen O and/or optionally fused to a benz ring then such rings include azetidino, pyrrolidino, morpholino, piperidino, imidazolidinyl, imidazolinyl, piperazino, thiamorpholino (perhydro-1,4- thiazinyl), homopiperazino, perhydroazepino, perhydrooxazepino, (2,3-dihydro-l,3- thiazolyl, 1,3-thiazolidinyl, 1,3-oxazolidinyl, oxepanyl , oxazepanyl, dihydropyrimidinyl, tetrahydropyrimidinyl, and homopiperidinyl, each of which is optionally substituted as previously described.

Unless otherwise stated or indicated, the term "alkyl" denotes either a straight or branched alkyl group. Examples of said alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl , t-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and isohexyl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and tertiary butyl.

Unless otherwise stated or indicated, the term "alkoxy" denotes a group O-alkyl, wherein alkyl is as defined above.

Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine or iodine. An is acetoxy. Examples of "Cμδalkoxycarbonyl" include C] _-4 alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of "C _1-6 alkoxycarbonylamino" include methoxycarbonylamino, ethoxycarbonylamino, n- and ^-butoxycarbonylamino. Examples of "C^alkoxy" include methoxy, ethoxy and propoxy. Examples of "Cμβalkanoylamino" include formamido, acetamido and propionylamino. Examples of "C _1-6 alkylS(O) _a wherein a is 0 to 2" include Ci _-4 alkylsulphonyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of "C^alkylsulphonylamino" include methylsulphonylamino,

ethylsulphonylamino and propylsulphonylamino. Examples of "Ci _-6 alkylsulphonyl-N-(C _1-6 alkyl)amino" include methylsulphonyl-N-methylamino, ethylsulphonyl-N-methylamino and propylsulphonyl-N-ethylamino. Examples of "Ci-ealkanoyl" include C _1-4 alkanoyl, propionyl and acetyl. Examples of include methylamino and ethylamino. Examples of "N,N-(Ci _-6 alkyl) ₂ amino" include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of "C _2-6 alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C _2-6 alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of "N-(Ci _-6 alkyl)sulphamoyl" are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of "N-(Ci- ₆ alkyl) ₂ Sulphamoyl" are N,N-(dimethyl)sulphamoyl and

N-(methyl)-N-(ethyl)sulphamoyl. Examples of "^(C^ealky^carbamoyl" are N-(Ci- ₄ alkyl)carbamoyl, methylaminocarbonyl and ethylaminocarbonyl. Examples of "N,N-(Ci. ₆ alkyl)2carbamoyl" are N,N-(C _]-4 alkyl)carbamoyl, dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "C _3-8 Cy cloalkyl ring" are cyclopropyl and cyclohexyl. Examples of "(heterocyclic group)C _1-6 alkyl" include pyridylmethyl,

3-morpholinopropyl and 2-pyrimid-2-ylethyl. Examples of "C _3- 8cycloalkylCi-6cycloalkyl" include cyclopropylmethyl and 2-cyclohexylpropyl. "N-(Ci- ₆ alkyl)sulphamoylamino" are N-(methyl)sulphamoylamino andN-(ethyl)sulphamoylamino. Examples of "N-(C _1- 6alkyl) ₂ sulphamoylamino" are N,N-(dimethyl)sulphamoylamino and N-(methyl)-N-(ethyl)sulphamoylamino. Examples of "Ci-ealkylsulphonylaminocarbonyl" include methylsulphonylaminocarbonyl, ethylsulphonylaminocarbonyl and propylsulphonylaminocarbonyl.

Specific compounds of the invention include one or more including any combination of the following compounds below labelled as List 1: 2-methylpropyl ν-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]carbamate; propan-2-yl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]carbamate benzyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]carbamate; phenyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]carbamate; benzyl N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl ]carbamate; benzyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-(trifluorome thoxy)phenyl]- carbamate;

benzyl N-[3-[4-(4-cyanophenyl)piperidine-l-carbonyl]-4-methyl-pheny l]carbamate; benzyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-fluoro-pheny l]carbamate; benzyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2,4-dimethyl-phenyl]carbamate;

2-methylpropyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2,4-dimethyl- 5 phenyl] carbamate; pyridin-3-ylmethyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-metliyl- phenyl]carbamate; pyridin-4-ylmethyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyljcarbamate; i o methyl N- [5 -[4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] carbamate ;

2-methoxyethyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyljcarbamate; phenethyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]carbamate ethyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]carbamate; 15 propyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-pheny l]carbamate; benzyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-phen yl]carbamate; tert-Butyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-pheny l]carbamate; benzyl N-[5-[4-[4-(dimethylcarbamoyl)phenyl]piperidine-l-carbonyl]- 2-methyl- phenyl] carbamate; 20 benzyl N-[5-[4-(4-carbamoylphenyl)piperidine-l-carbonyl]-2-methyl-p henyl]carbamate;

2-methylpropyl N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl ]- carbamate; phenyl N-[2-chloro-5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]phenyl]carbamate;

2-methylpropyl N-[3-[4-(4-cyanophenyl)piperidine-l-carbonyl]-4-methylphenyl ]- 25 carbamate;

2-methylpropyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-fluorophenyl]carbamate;

2-methylpropyl N-[3-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]carbamat e; and benzyl N-[3-[4-(4-cyanophenyl)piρeridine- 1 -carbonyl]phenyl] carbamate or a pharmaceutically-acceptable salt thereof. 30 A compound of the Formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula I are

provided as a further feature of the invention and are illustrated by the following representative process variants. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated that are within the ordinary skill of an organic chemist.

According to a further aspect of the present invention provides a process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5' , R ⁶ , R ⁶ , and R ⁷ are, unless otherwise specified, as defined in formula I) which process comprises : (a) reacting a compound of formula VI

with a compound of formula VII R ¹ OC(O)X

VII wherein X is a leaving group, for example halo, e.g. chloro, in the presence of a diluent, for example an organic liquid, e.g. dichloromethane, optionally in presence of a base, for example pyridine, at a temperature in the range of 0-150 ⁰ C.

Compounds of formula I may also be prepared by reacting a compound of formula VIII

VIlI with a compound of formula IX

IX in which X represents a leaving group for example halo, e.g. chloro, in the presence of a diluent for example a solvent e.g. dichloromethane and optionally in the presence of a base, for example an organic amine e.g DIPEA, at a temperature in the range of 0-150 ⁰ C. Compounds of formula I may also be prepared by reacting a compound of formula VIII

VIII with a compound of formula X

X

in which X represents a replaceable group, eg. Cl, Br, I, OMesyl, or OTriflyl in the presence of carbon monoxide and in the presence of a metal catalyst, eg. Pd or derivatives thereof, and in a solvent such as an alcohol, THF, toluene, or DMF, and in the temperature range 0 - 15O ⁰ C. The carbon monoxide may be gaseous or in the form of a metal carbonyl, eg. Molybdenum hexacarbonyl. Compounds of formula I may also be prepared by reacting a compound of formula VIII

VIII with a compound of formula XI

Xl optionally in the presence of a coupling agent and optionally in the presence of a diluent for example a solvent at a temperature in the range of 0-15O ⁰ C.

Examples of coupling agents are Dichlorotriphenyl phosphorane (DCTPP), 1-ethyl-

3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC), O-benzotriazol-1-yl-

N,N,N',N'-tetramethyluronium hexafluorophosphate (HTBU), O-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 4-(4,6-dimethoxy-l ,3,5- triazin-2-yl)-4-methylmorpholinium chloride (DMTMM).

Examples of optional additives are: 1 -hydroxy benzotriazole (HOBt), 4- dimethylamino pyridine (DMAP), di-ωo-propylethylamine (DIPEA), and triethylamine

(TEA). Examples of suitable solvents are: dimethyl formamide (DMF), chloroform, dichloromethane (DCM), and tetrahydrofuran (THF).

Certain compounds of formula I may be converted into other compounds of formula I by methods known to those skilled in the art. For example, compounds of formula I

Compounds of formula I in which R ¹ represents an optionally substituted pyridyl- s N-oxide may be prepared by reacting a compound of formula I in which R ¹ represents an optionally substituted pyridyl with an oxidising agent for example urea hydrogen peroxide or 3-chloroperbenzoic acid, in the presence of a diluent for example dichloromethane or acetonitrile at a temperature in the range of 0-150°C.

In other processes compounds of formula I containing a sulphide group may be I ₀ oxidised to SO or SO ₂ for example by use of potassium peroxymonosulfate, nitriles may be reduce to aniinomethyl compounds, amines may be acylated or sulphonated to give amides or sulphonamides, respectively, activated heteroaryl halides may be hydrolysed to hydroxy groups, and esters may be hydrolysed to acids.

It will be appreciated by those skilled in the art that certain functional groups may require is protection before certain transformations are attempted followed by deprotection after the particular transformation. Such methods are well known to those skilled in the art and are described in "Protective Groups in Organic Synthesis", 2 Edition (1991) by Greene and

Wuts.

Certain intermediates of formula VI are believed to be novel and are herein claimed

20 as another aspect of the present invention. Pharmaceutical preparations

The compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of

25 pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.

Suitable daily doses of the compounds of the invention in the therapeutic treatment

₃ o of humans are about 0.001-10 mg/kg body weight, preferably 0.01-1 mg/kg body weight. Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in

the range of 0.5mg to 500mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25mg, 50mg, lOOmg and 250mg.

According to a further aspect of the invention there is also provided a pharmaceutical formulation comprising a compound of formula I, or pharmaceutically acceptable salt thereof, including the compound of the proviso, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers. Pharmacological properties

The compounds of formula (I) are useful for the treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating), dyslipidaemia and the treatment of type 2 diabetes mellitus.

The present compounds of formula (I) are useful for the prophylaxis and/or treatment of clinical conditions associated with inherent or induced reduced sensitivity to insulin (insulin resistance) and associated metabolic disorders (also known as the metabolic syndrome). These clinical conditions will include, but will not be limited to, general obesity, abdominal obesity, arterial hypertension, hyperinsulinaemia, hyperglycaemia, type 2 diabetes and the dyslipidaemia characteristically appearing with insulin resistance. This dyslipidaemia, also known as the atherogenic lipoprotein profile, is characterised by moderately elevated non-esterified fatty acids, elevated very low density lipoprotein (VLDL) triglyceride rich particles, high Apo B levels, low high density lipoprotein (HDL) levels associated with low apoAI particle levels and high Apo B levels in the presence of small, dense, low density lipoproteins (LDL) particles, phenotype B. The compounds of the present invention are expected to be useful in treating patients with combined or mixed hyperlipidemias or various degrees of hypertriglyceridemias and postprandial dyslipidemia with or without other manifestations of the metabolic syndrome.

Treatment with the present compounds is expected to lower the cardiovascular morbidity and mortality associated with atherosclerosis due to their antidyslipidaemic as well as anti-inflammatory properties. The cardiovascular disease conditions include macro- angiopathies of various internal organs causing myocardial infarction, congestive heart failure, cerebrovascular disease and peripheral arterial insufficiency of the lower

extremities. Because of their insulin sensitizing effect the compounds of formula I are also expected to prevent or delay the development of type 2 diabetes from the metabolic syndrome and diabetes of pregnancy. Therefore the development of long-term complications associated with chronic hyperglycaemia in diabetes mellitus, such as the micro-angiopathies causing renal disease, retinal damage and peripheral vascular disease of the lower limbs, is expected to be delayed. Furthermore the compounds may be useful in treatment of various conditions outside the cardiovascular system whether or not associated with insulin resistance, like polycystic ovarian syndrome, obesity, cancer and states of inflammatory disease including neurodegenerative disorders such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease and multiple sclerosis.

The compounds of formula I may also be useful in the treatment of metabolic syndrome and Prader-Willi syndrome.

In another aspect the present invention provides a compound of formula I as previously defined for use as a medicament. In a further aspect the present invention provides the use of a compound of formula

I in the preparation of a medicament for the treatment or prophylaxis of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating) and for the treatment or prophylaxis of dyslipidaemia and for the treatment or prophylaxis of type 2 diabetes mellitus.

In a still further aspect the present invention provides a method of treating obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating) dyslipidaemia and type 2 diabetes mellitus comprising administering a pharmacologically effective amount of a compound of formula I, including the compound of the proviso, to a patient in need thereof. Combination Therapy The compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of obesity such as other anti-obesity drugs, that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fat

absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/motivation, food intake, or G-I motility.

The compounds of the invention may further be combined with another therapeutic agent that is useful in the treatment of disorders associated with obesity such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes, sleep apnea, asthma, heart disorders, atherosclerosis, macro and micro vascular diseases, liver steatosis, cancer, joint disorders, and gallbladder disorders. For example, a compound of the present invention may be used in combination with a another therapeutic agent that lowers blood pressure or that decreases the ratio of LDL:HDL or an agent that causes a decrease in circulating levels of LDL-cholesterol. In patients with diabetes mellitus the compounds of the invention may also be combined with therapeutic agents used to treat complications related to microangiopathies.

The compounds of the invention may be used alongside other therapies for the treatment of obesity and its associated complications the metabolic syndrome and type 2 diabetes, these include biguanide drugs, insulin (synthetic insulin analogues) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha- glucosidase inhibitors).

In another aspect of the invention, the compound of formula I, or a pharmaceutically acceptable salt thereof may be administered in association with a PPAR modulating agent. PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art. In addition the combination of the invention may be used in conjunction with a sulfonylurea. The present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent. The cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3- hydroxy-3-methylglutaryl coenzyme A reductase). Suitably the HMG-CoA reductase inhibitor is a statin.

In the present application, the term "cholesterol-lowering agent" also includes

chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.

The present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor). The present invention also includes a compound of the present invention in combination with a bile acid binding resin.

The present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel. According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from: a CETP (cholesteryl ester transfer protein) inhibitor; a cholesterol absorption antagonist; a MTP (microsomal transfer protein) inhibitor ; a nicotinic acid derivative, including slow release and combination products; a phytosterol compound ; probucol; an anti-coagulant; an omega-3 fatty acid ; another anti-obesity compound for example sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine; an aldose reductase inhibitor; a glycogen phosphorylase inhibitor; a glycogen synthase kinase inhibitors; a glucokinase activator; a haemostasis modulator; an antithrombotic; an activator of fibrinolysis; an antiplatelet agent;

a thrombin antagonist; a factor Xa inhibitor; - a factor Vila inhibitor; an antiplatelet agents; a 5 HT transporter inhibitor; an antihypertensive compound for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergic blocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixed alpha/beta adrenergic blocker, an adrenergic stimulant, calcium channel blocker, an AT-I blocker, a saluretic, a diuretic or a vasodilator; a melanin concentrating hormone (MCH) modulator; an NPY receptor modulator; for example an NPY agonist or an NPY2 agonist or an NPY5 antagonist; an Mc4r modulator for example an Mc4r agonist; an Mc3r modulator for example an Mc3r agonist; an orexin receptor modulator for example an antagonist; a phosphoinositide-dependent protein kinase (PDK) modulator; or modulators of nuclear receptors for example LXR, FXR, RXR, GR, ERRα, β, PPARα, β, γ, δ and RORalpha; a monoamine transmission-modulating agent, for example a selective serotonin reuptake inhibitor (SSRI), a noradrenaline reuptake inhibitor (NARI), a noradrenaline-serotonin reuptake inhibitor (SNRI), a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressive agent (TCA), a noradrenergic and specific serotonergic antidepressant

(NaSSA); an antipsychotic agent for example olanzapine and clozapine; a serotonin receptor modulator; a leptin/leptin receptor modulator; a CBl receptor modulator for example an inverse agonist or an antagonist; a GLK receptor modulator; a DPP-IV inhibitor; a cholesterol absorption inhibitor; a GLP-I agonist;

an SGLT-2 inhibitor; a DGATl inhibitor; a DGAT2 inhibitor; a DGAT2 inhibitor anti-sense oligonucleotide; a ghrelin antibody; a ghrelin antagonist; an l lβ HSD-I inhibitor; an UCP- 1,2 or 3 activator; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warmblooded animal, such as man in need of such therapeutic treatment. According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of very low calorie diets (VLCD) or low-calorie diets (LCD).

Therefore in an additional feature of the invention, there is provided a method for the treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provided a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula I, or a pharmaceutically acceptable salt thereof, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms.

According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the the treatment of obesity and its associated complications in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.

According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.

Furthermore, a compound of the invention may also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatohepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions.

It will be understood that there are medically accepted definitions of obesity and being overweight. A patient may be identified by, for example, measuring body mass index (BMI), which is calculated by dividing weight in kilograms by height in metres squared, and comparing the result with the definitions. The compounds of the invention may also be useful as anti-cell-proliferation (such as anti-cancer) agents and are therefore useful in methods of treatment of the human or animal body.

Such properties are expected to be of value in the treatment of disease states associated with cell cycle and cell proliferation such as cancers (solid tumors and leukemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma,

atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.

The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-

morpholinopropoxy)quinazolin~4-amine, N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4- fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;

(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin);

(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapy approaches, including for example ex-vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

The compounds of the present invention may also be useful as anti-infective agents or as anti-bacterial agents.

The compounds of the present invention may also be useful as in decreasing sebum production following topical application. Pharmacological Activity

The compounds of the present invention are Fatty Acid Synthase inhibitors. The activity of the compounds of the invention was demonstrated using the following assay. Human and Rat FAS Enzyme Assay.

Fatty acid synthase is an enzyme complex that harbours seven enzymatic activities catalysing the reductive synthesis of long chain fatty acids from acetyl CoA and malonyl CoA to palmitate. When acetyl CoA and malonyl CoA are forming palmitate NADPH is consumed forming NADP. Since NADPH is fluorescent but not NADP the reaction can be measured by analysing the decrease in fluorescence.

Compounds were added to a black 384 well plate (Matrix) in a volume of 5μl consisting of 20% DMSO and 80% Tris buffer pH 7.5, at a top concentration of ImM. NADPH, 30μl of 166.6μM, formulated in assay buffer (0.1M Tris ph7.5, O.lmM EDTA ₅ ImM glutathione, 0.05%BSA), was then added to all of the wells of the plate. Fatty acid synthase Human or rat enzyme (0.4μg, produced in house), dissolved in 2OmM Tris/HCl pH 7.5, 5mM BOG ₅ ImM TCEP,10% glycerol,lmM EDTA,150mM NaCl, was then added to the plate in a volume of lOμl. Enzyme was added to all but the last two columns of the plate, to which, lOμl of assay buffer was added (0.1M Tris ph7.5, O.lmM EDTA, ImM glutathione, 0.05%BSA) to provide a no enzyme assay control. Following a 15-minute incubation period, at room temperature, the plates were read on an Envision plate reader using 340nm excitation and 460nm emission filters. This served as a time zero background read. Substrates (an equal mix of both malonyl and acetyl CoA) were then added to the plates in a total volume of 5μl. The concentrations of malonyl and acetyl CoA in the mixture were 500μM and 150μM respectively. Both were prepared as 1OmM stock solutions in distilled water and were subsequently diluted to working concentrations in assay buffer. Plates were then incubated for a further 60 minutes, at room temperature, before being read again on the Envision reader using the same parameters as previously used. The data was analysed by subtracting the background time zero data from that

generated following the final 60 minute incubate and the percent inhibition compared to the maximum and minimum assay controls was determined. Sigmoid curves were fitted using Origin 7.5 Client software and IC50 values were determined.

The compounds of the present invention were found to inhibit the activation of Fatty Acid Synthase with IC50S in a range of about 0.00 lμM to about 30μM in the above assay. In a preferred range, the examples of the present invention inhibited the activition of Fatty Acid Synthase with IC ₅ oS in a range of about 0.00 lμM to about 5.0μM. In a more preferred range, the compounds inhibit the activation of Fatty Acid Synthase with IC _50S in a range of about 0.00 lμM to about O.lμM.

The compound of Example 1 had an ICs ₀ Of 0.4 μM, the compound of Example 3 had an IC5 ₀ of 0.4 μM and the compound of Example 7 had an IC5 ₀ of 1.7 μM.

The results obtained are given in Table 1 in which Ex. No. stands for Example Number and Inhib (%) stands for the % inhibition at a concentration of lOOμmolar.

The following compounds do not have IC ₅₀ S in the range of about 0.00 lμM to about 30μM in the above assay: tert-butyl N-[3-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]carbamat e 2-methylpropyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2- (trifluoromethoxy)phenyl]carbamate

2-methylpropyl N-[2-methyl-5-[4-(4-methylsulfonylphenyl)piperidine- 1 - carbonyl]phenyl]carbamate and

2-methylpropyl N-[3-[4-(4-cyanophenyl)piperidine-l-carbonyl]-4-fluorophenyl ]carbamate These compounds are excluded from the claims of the present application by means 5 of a proviso.

The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius ( ⁰ C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 ⁰ C, unless otherwise o stated;

(ii) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals;

4.5-30 mmHg) with a bath temperature of up to 60 °C;

(iii) chromatography means flash chromatography on silica gel; thin layer chromatography s (TLC) was carried out on silica gel plates;

(iv) in general, the course of reactions was followed by TLC and / or analytical LC-MS, and reaction times are given for illustration only;

(v) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data; o (vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;

(vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard 5 when the solvent is CDCl ₃ (when the solvent is d _6- -DMSO, it locks on to the 2.49 DMSO peak), determined at 300 MHz unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad;

(viii) chemical symbols have their usual meanings; SI units and symbols are used;

(ix) solvent ratios are given in volume:volume (v/v) terms; and 0 (x) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP);

values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is MH ⁺ ;

[A] When Cl is present in the molecule, the m/z value for the (M+H) ⁺ molecular ion is based on the ³⁵ Cl isotope. When there are multiple chlorine atoms in the molecule, the m/z is based on the first peak of the isotope pattern.

(xi) unless stated otherwise compounds containing an asymmetrically substituted carbon and/or sulphur atom have not been resolved;

(xii) where a synthesis is described as being analogous to that described in a previous example the amounts used are the millimolar ratio equivalents to those used in the previous example;

(xvi) the following abbreviations have been used:

ACN Acetonitrile

DIPEA Di-/sø-propylethylamine

EDAC N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride EtOAc Ethyl acetate

DMA Dimethyl acetamide

DMAP 4-dimethylamino pyridine

DMTMM 4-(4,6-Dimethoxy-l ,3,5-Triazin-2-Yl)-4-Methylmorpholinium

Chloride HATU 0-(7-Azabenzotriazol-l-Yl)-N,N,N',N'-Tetramethyluronium

Hexafluoro-phosphate

HTBU O-benzotriazol- 1 -yl-N,N,N',N'-tetramethyluronium hexafluorophosphate

HOBT 1-Hydroxybenzotriazole NMP N-methyl pyrrolidone

EtOH Ethanol

MeOH Methanol

TEA Triethylamine

TFAA Trifluoroacetic Anhydride THF Tetrahydrofuran

Example 1

2-methylpropyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl- phenyljcarbamate

/so-butyl chloroformate (82 μL, 0.63mmol) was added to a stirred suspension of 4-[l-(3- amino-4-methyl-benzoyl)-4-piperidyl]benzonitrile (Intermediate A, 200 mg, 0.63mmol) and pyridine (51 μL, 0.63 mmol) in DCM (5 mL), and the reaction mixture was stirred at ambient temperature for 24hrs. The reaction mixture was then washed sequentially with saturated sodium bicarbonate solution (20 mL), water (20 mL) and brine (20 mL), filtered and reduced in vacuo to give a brown oil which was purified by chromatography (12 g silica column, Optix, eluting with a gradient consisting of 30-70% EtOAc in zsohexane) to give the title compound as a colourless solid (164 mg), ¹ H NMR (300.072 MHz, CDCl ₃ ) δ 0.97 (6H, d),1.57 - 1.92 (4H, m),1.98 (IH, 9),2.28 (3H, s),2.77 - 2.92 (2H, m),2.98 - 3.23 (IH, m),3.95 (2H, d),4.00 - 4.09 (IH, m),4.76 - 4.99 (IH, m),6.53 (IH, s),7.10 - 7.24 (2H, m),7.33 (2H, d),7.60 (2H, d),7.91 (IH, s), m/z 420 (M+H) ⁺ . Method 2 Example 2 Propan-2-yl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]carbamate

Triphosgene (62 mg, 0.21 mmol) was added to a solution of 4-[l-(3-amino-4-methyl- benzoyl)-4-piperidyl]benzonitrile (Intermediate A, 167 mg, 0.52 mmol ) and DIPEA (180 μL) in anhydrous THF (8 mL). The reaction mixture was purged with nitrogen and stirred at ambient temperature for 3 ¹ A hrs. The reaction mixture was filtered and the filtrate added to a reaction tubes containing 2-propanol (1 mL, large excess). The reaction mixture was then heated with stirring at 65°C for 3hrs, and then concentrated in vacuo. The residue was purified by chromatography (Optix 10™ , 12 g silica column, gradient eluting with hexane containing 40-80% EtOAc) to give the title compound (133 mg, 63%), ¹ H NMR (300.073

MHz, dmso) δ 1.24 (d, 6H), 1.48 - 1.94 (m, 4H), 2.22 (s, 3H), 2.74 - 3.21 (m, 3H), 3.56 4.00 (m, IH), 4.37 - 4.75 (m, IH), 4.76 - 4.94 (m, IH), 7.06 - 7.14 (m, IH), 7.23 (d, IH), 7.44 (s, 2H), 7.50 (d, 3H), 7.76 (d, 2H), 8.82 (s, IH), m/z 406 (M+H) ⁺ .

It will be appreciated that alternative solvents, reagents, additives and conditions may be used in the above reactions. Examples of suitable solvents are THF, DCM, other; examples of bases are TEA, DIPEA and pyridine, and the reactions may be performed at temperatures between O ⁰ C and the boiling point of the solvent.

The following compounds were prepared in a manner essentially similar to that described for Example 1, starting from the appropriate intermediate and chloroformate Example 3 benzyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-pheny l]carbamate

Prepared from Intermediate A ¹ H NMR (300.072 MHz, CDCl ₃ ) δ 1.57 - 1.98 (4H, m), 2.27 (3H, s),2.77 - 2.92 (2H, m),2.98 - 3.23 (IH, m), 3.90 - 4.09 (IH, m),4.76 - 4.99 (IH, m), 5.21 (2H, s),6.64 (IH, s),7.10 - 7.21 (2H, m),7.31-7.43 (7H, m),7.61 (2H, d),7.91 (IH, s), m/z 454 (M+H) ⁺ . Example 4 phenyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-pheny l]carbamate

Prepared from Intermediate A ¹ H NMR (300.072 MHz, CDCl ₃ ) δ 1.53 - 1.98 (4H, m),2.35 (3H, s),2.75 - 2.89 (2H, m),2.97 - 3.22 (IH, m),3.85 - 4.07 (IH, m),4.71 - 4.97 (IH, m),7.03 (IH, s),7.14 - 7.31 (7H, m),7.36 - 7.43 (2H, m),7.58 (2H, d),7.90 (IH, s), m/z 440 (M+H) ⁺ . Example 5 benzyl N-[2-chloro-5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]phenyl]carbamate

Prepared from Intermediate B

¹ H NMR (300.073 MHz, dmso) δ 1.37 - 2.08 (m, 4H), 2.66 - 3.18 (m, 3H), 3.52 - 3.79

(m, IH), 4.42 - 4.78 (m, IH), 5.16 (s, 2H), 7.21 - 7.28 (m, IH), 7.29 - 7.45 (m, 5H),

7.46 - 7.57 (m, 3H), 7.67 (s, IH), 7.77 (d, 2H), 9.32 (s, IH), m/z 474 (M+H) ⁺ [A].

Example 6 benzyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-

(trifluoromethoxy)phenyl]carbamate

Prepared from Intermediate C ¹ H NMR (300.072 MHz, CDCl ₃ ) δ 1.63 - 1.96 (4H, m),2.79 - 2.94 (2H, m), 3.05 - 3.27 (IH, m), 3.84 - 4.02 (IH, m), 4.77 - 4.97 (IH, m), 5.22 (2H, s),7.10 (IH, s),7.14 - 7.19 (IH, m),7.27 - 7.43 (8H, m),7.62 (2H, d),8.34 (IH, s), m/z 524 (M+H) ⁺ . Example 7 benzyl N-[3-[4-(4-cyanophenyl)piperidine-l-carbonyl]-4-methyl-pheny l]carbamate

Prepared from Intermediate D

¹ H NMR (300.072 MHz, CDCl ₃ ) δ 1.46 - 2.00 (4H, m),2.27 (3H, d),2.81 (2H, t),3.07 (IH, t),3.63 (IH, d),4.91 - 4.99 (IH, m),5.18 (2H, s),7.00 - 7.17 (2H, m),7.24 - 7.40 (9H, m),7.60 (2H, d), m/z 454 (M+H) ⁺ . Example 8 benzyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-fluoro-phenyl]carbamate

Prepared from Intermediate E ¹ H NMR (400.132 MHz, DMSO) δ 1.54 - 1.96 (m, 4H), 2.74 - 3.23 (m, 3H), 3.60 - 3.81 (m, IH), 4.50 - 4.73 (m, IH), 5.17 (s, 2H), 7,19 - 7.25 (m, IH), 7.27 - 7.46 (m, 6H), 7.52 (d, 2H), 7.74 - 7.82 (m, 3H), 9.67 (s, IH), m/z 458 (M+H) ⁺ . Example 9 benzyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2,4-dimethyl-p henyl]carbamate

Prepared from Intermediate F

¹ H NMR (300.072 MHz, CDCl ₃ ) δl.75 (2H, m), 2.00 (IH, m), 2.22 (3H, s), 2.27 (3H, s), 2.80 - 2.84 (2H, m), 3.10 (IH, m), 3.71 (IH, m), 4.97 (IH, d), 5.20 (2H, s), 6.44 (IH, s), 7.03 (IH, s), 7.34 - 7.40 (7H, m), 7.60 - 7.63 (2H, d), m/z 468 (MH-H) ⁺ . Example 10

2-methylpropyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2,4-dimethyl- phenyl] carbamate

Prepared from Intermediate F

¹ H NMR (300.072 MHz, CDCl ₃ ) δθ.95 - 0.98 (6H, d), 1.75 (2H, m), 1.91 - 2.00 (IH, m), 2.24 - 2.25 (6H, s), 2.82 (2H, m), 3.10 (IH, s), 3.72 (IH, m), 3.93 - 3.95 (2H, d), 4.96 (IH, m), 6.34 (IH, s), 7.02 (IH, s), 7.32 (2H, d), 7.61 (2H, d), m/z 434 (M+H) ⁺ . Example 11

Pyridin-3 -ylmethyl N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl- phenyl] carbamate

Method 2 from Intermediate A

¹ H NMR (300.073 MHz, dmso) δ 1.46 - 1.96 (m, 4H), 2.22 (s, 3H), 2.77 - 3.18 (m, 3H), 3.56 - 3.98 (m, IH), 4.32 - 4.82 (m, IH), 5.19 (s, 2H), 7.12 (d, IH), 7.25 (d, IH), 7.39 - 7.47 (m, 2H), 7.50 (d, 2H), 7.76 (d, 2H), 7.86 (d, IH), 8.55 (d, IH), 8.65 (s, IH), 9.11 (s, lH), m/z 455 (M+H) ⁺ . Example 12

Pyridin-4-ylmethyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]carbamate

Method 2 from Intermediate A ¹ H NMR (300.073 MHz, dmso) δ 1.48 - 1.93 (m, 4H), 2.25 (s, 3H), 2.79 - 3.17 (m, 3H), 3.58 - 3.96 (m, IH), 4.36 - 4.78 (m, IH), 5.19 (s, 2H), 7.13 (d, IH), 7.26 (d, IH), 7.38 (d, 2H), 7.44 - 7.53 (m, 3H), 7.76 (d, 2H), 8.57 (d, 2H), 9.21 (s, IH), m/z 455 (M+H) ⁺ . Example 13 Methyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-pheny l]carbamate

Method 2 from Intermediate A

¹ H NMR (300.073 MHz, dmso) δ 1.49 - 1.95 (m, 4H), 2.22 (s, 3H), 2.74 - 3.23 (m, 3H), 3.57 - 3.98 (m, 4H), 4.33 - 4.85 (m, IH), 7.11 (d, IH), 7.24 (d, IH), 7.45 (s, IH), 7.50 (d, 2H), 7.76 (d, 2H), 8.93 (s, IH), m/z 378 (M+H) ⁺ . Example 14

2-methoxyethyl N-[5-[4-(4-cyanophenyl)piperidme-l-carbonyl]-2-methyl- phenyl]carbamate

Method 2 from Intermediate A ¹ H NMR (300.073 MHz, dmso) δ 1.49 - 1.92 (m, 4H), 2.23 (s, 3H), 2.76 - 3.22 (m, 3H),

3.29 (s, 3H), 3.56 (t, 2H), 3.63 - 3.97 (m, IH), 4.18 (t, 2H), 4.34 - 4.86 (m, IH), 7.11 (d,

IH), 7.24 (d, IH), 7.43 (s, IH), 7.50 (d, 2H), 7.76 (d, 2H), 9.02 (s, IH), m/z 422

(M+H) ⁺ .

Example 15 Phenethyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]carbamate

Method 2 from Intermediate A

¹ H NMR (300.073 MHz, dmso) δ 1.47 - 1.93 (m, 4H), 2.20 (s, 3H), 2.75 - 3.19 (m, 5H),

3.50 - 4.00 (m, IH), 4.27 (t, 2H), 4.38 - 4.83 (m, IH), 7.11 (d, IH), 7.16 - 7.34 (m, 5H),

7.39 (s, IH), 7.50 (d, 2H), 7.76 (d, 2H), 8.92 (s, IH), m/z 468 (M+H) ⁺ .

Example 16

Ethyl N-[5-[4~(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]carbamate

Method 2 from Intermediate A

¹ H NMR (300.073 MHz, dmso) δ 1.23 (t, 3H), 1.48 - 1.94 (m, 4H), 2.23 (s, 3H), 2.73 3.22 (m, 3H), 3.56 - 3.98 (m, IH), 4.10 (q, 2H), 4.35 - 4.82 (m, IH), 7.06 - 7.14 (m, IH), 7.24 (d, IH), 7.45 (s, IH), 7.50 (d, 2H), 7.76 (d, 2H), 8.89 (s, IH), m/z 392 (M+H) ⁺ . Example 17 Propyl N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]carbamate

Method 2 from Intermediate A

¹ H NMR (300.073 MHz, dmso) δ 0.92 (t, 3H), 1.49 - 1.94 (m, 6H), 2.23 (s, 3H), 2.76 - 3.22 (m, 3H), 3.55 - 3.94 (m, IH), 4.02 (t, 2H), 4.34 - 4.80 (m, IH), 7.10 (d, IH), 7.24 (d, IH), 7.44 (s, IH), 7.50 (d, 2H), 7.76 (d, 2H), 8.89 (s, IH), m/z 406 (M+H) ⁺ . Example 18 Benzyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-phen yl]carbamate

Method 1 from Intermediate G ¹ H NMR (300.073 MHz, dmso, 3O ⁰ C) δl.51 - 1.70 (2H, m), 1.70 - 1.88 (2H, m), 2.78 -

3.21 (3H, m), 3.83 (3H, s), 3.60 - 4.73 (2H, m), 5.14 (2H, s), 7.06 (IH, d J = 7.6 Hz), 7.14 - 7.20 (IH, m), 7.27 - 7.45 (5H, m), 7.49 (2H, d J = 11.7 Hz), 7.72 - 7.82 (3H, m), 8.70 (IH, s), m/z 470 (M+H) ⁺ .

Example 19 tert-Butyl N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-pheny l]carbamate

The title compound was prepared using the method described in Synthetic

Communications 31(21) p3273 (2001), starting from 4- [1 -(3 -amino-4-methyl-benzoyl)-4- piperidyl]benzonitrile (Intermediate A):

¹ H NMR (300.073 MHz, dmso) δ 1.45 (s, 9H),1.53 - 1.70 (m, 2H), 1.70 - 1.91 (m, 2H),

2.21 (s, 3H),2.68 - 3.00 (m, 1H),3.OO - 3.23 (m, 1H),3.61 - 3.94 (m, 1H),4.21 - 4.83 (m,

1H),7.O4 - 7.12 (m, 1H),7.17 - 7.25 (m, 1H),7.38 (s, 1H),7.5O (d, 2H),7.75 (d, 2H),8.59 (s,

IH) (NB signal due to piperidyl 4-H v. broad and obscured by surrounding signals), m/z

420 (M+H) ⁺ , 464 (M+MeCN+H) ⁺ .

Example 20

Benzyl N-[5-[4-[4-(dimethylcarbamoyl)phenyl]piperidine-l-carbonyl]- 2-methyl- phenyl]carbamate

Method 1 from Intermediate H ¹ H NMR (300.073 MHz, dmso) δ 1.48 - 1.89 (m, 4H), 2.23 (s, 3H), 2.67 - 3.05 (m, 9H), 3.60 - 3.86 (m, IH), 4.49 - 4.71 (m, IH), 5.14 (s, 2H), 7.12 (d, J= 7.6 Hz, IH), 7.25 (d, J = 7.9 Hz, IH), 7.31 - 7.48 (m, 10H), 9.06 (s, IH), m/z 500 (M+H) ⁺ . Example 21 Benzyl N-[5-[4-(4-carbamoylphenyl)piperidine-l-carbonyl]-2-methyl-p henyl]carbamate

Method 1 from Intermediate I

¹ H NMR (300.073 MHz, dmso) δ 1.49 - 1.91 (m, 4H), 2.23 (s, 3H), 2.69 - 3.17 (m, 3H),

3.50 - 3.99 (m, IH), 4.44 - 4.78 (m, IH), 5.14 (s, 2H), 7.09 - 7.14 (m, IH), 7.22 - 7.27

(m, 2H), 7.31 - 7.44 (m, 7H), 7.46 (s, IH), 7.80 (d, J= 8.1 Hz, 2H), 7.87 (s, IH), 9.06 (s,

IH), m/z 472 (M+H) ⁺ . The following Examples were prepared in a similar manner.

Example 22

2-methylpropyl N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl ]carbamate

Example 23

Phenyl N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl ]carbamate o Example 24

2-methylpropyl N-[3-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-4- methylphenyl] carbamate

Example 25

2-methylpropyl N-[5 -[4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-fluorophenyl] carbamate s Example 26

2-methylpropyl N- [3 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl]phenyl] carbamate

Example 27

Benzyl N-[3-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]carbamat e

Preparation of Intermediates o Intermediate A

4-[l-(3-amino-4-methyl-benzoyl)-4-piperidyl]benzonitrile

A solution of 3-amino-4-methyl benzoic acid (4.05 g, 26.792 mmol), 4-(4'-cyanophenyl) piperidine (5 g, 26.79 mmol), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide 5 hydrochloride [EDAC] (5.64 g, 29.47 mmol, 1.1 eq) and DMAP (328 mg, 2.68 mmol, 0.1 eq) in DMF (60 mL) was stirred at ambient temperature for 2 hrs. Ethyl acetate (200 mL) was added and the resulting solution was washed sequentially with KHSO ₄ solution (100 mL of 2M), and brine (100ml); a precipitate formed and was filtered off to give the title compound as a colourless solid (5.25 g), ¹ H NMR (300.073 MHz, DMSO- d ⁶ , 30 ⁰ C) δ 0 1.47 - 1.67 (2H, m), 1.68 - 1.89 (2H, m), 2.05 (3H, s), 2.68 - 3.15 (3H, m), 3.59 - 4.13 (IH,

m), 4.22 - 4.76 (IH, m), 4.97 (2H, s), 6.45 - 6.53 (IH, m), 6.63 (IH, s), 6.90 - 6.99 (IH, _m ) ₅ 7.44 . 7.54 (2H, m), 7.71 - 7.81 (2H, m), m/z 320 (MH-H) ⁺ . Intermediate B 4-[l-(3-amino-4-chloro-benzoyl)-4-piperidyl]benzonitrile

The title compound was prepared in a manner similar to that described for Intermediate A, starting from 3-amino-4-chloro-benzoic acid and 4-(4'-cyanophenyl)piperidine; ¹ H NMR (300.073 MHz, dmso) δ 1.38 - 2.05 (m, 4H), 2.68 - 3.20 (m, 3H), 3.55 - 3.94 (m, IH), 4.30 - 4.79 (m, IH), 5.50 (s, 2H), 6.56 (d, IH), 6.81 (s, IH), 7.22 (d, IH), 7.49 (d, 2H), 7.76 (d, 2H)m/z 340 (M+H) ⁺ [A]. Intermediate C 4-[l-[3-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]benzo nitrile

3 -nitro-4-(trifluoromethoxy)benzoic acid

4-(trifluoromethoxy) benzoic acid (4 g, 26.3 mmol) was added slowly to a stirred mixture of concentrated sulfuric acid ((6.6 mL, 65.7 mmol) and concentrated nitric acid (4 mL, 44.7 mmol) at 4O ⁰ C. When the addition was complete, the reaction mixture was heated to 5O ⁰ C and became a pale yellow slurry. After Ih the reaction appeared to have gone to completion and so was poured onto ice and water. A white precipitate formed which was isolated by filtration and washed with water to give the title compound as a colourless crystalline solid (4.2 g), ¹ H NMR (300.073 MHz, DMSO-d ₆ ) δ7.83 - 7.87 (IH, m), 8.32 - 8.36 (IH, m), 8.56 (IH, d), m/z 198 (M+H) ⁺ . Step 2; 3-amino-4-(trifluoromethoxy)benzoic acid

A solution of 3-nitro-4-(trifluoromethoxy)benzoic acid (Step 1) (3.51 g, 14 mmol) in MeOH (150 mL) was hydrogenated at ambient temperature and pressure in the presence of 10% palladium on charcoal catalyst (500 mg). The catalyst was removed by filtration and washed through with more MeOH. The filtrate and washings were combined and evaporated to give the title compound as a pale cream solid (2.9 g), ¹ H NMR (300.073 MHz, dmso) δ 5.60 (br s, 2H),7.07 - 7.23 (m, 2H),7.39 - 7.46 (m, 1H),12.O2 - 13.40 (br s, IH), m/z 220 (M-H)-. Step 3: 4- [ 1 - [3 -amino-4-(trifluoromethoxy)benzoyl] -4-piperidyl]benzonitrile

A mixture of 3-amino-4-trifluoromethoxy benzoic acid (Step 2) (2.8 g, 12.66 mmol), 4-(4'- cyanophenyl)piperidine (2.36 g, 12.66 mmol, 1 eq), N-(3-Dimethylaminopropyi)-N'- ethylcarbodiimide hydrochloride (EDAC) (2.67 g, 13.93 mmol, 1.1 eq) and DMAP (155 mg, 1.27 mmol, 0.1 eq) in DMF (30 mL) was stirred at room temperature for 2 hrs. EtOAc (200 mL) was added and the resulting mixture washed sequentially with aqueous potassium bisulfate solution (100 mL of 2M KHSO ₄ ), brine (100 mL), dried (MgSO ₄ ), filtered and reduced in vacuo to give a brown oil. Ethyl acetate was added and the resulting colourless solid isolated by filtration. A precipitate also appeared during the extraction process; this was isolated and the solids combined to give the title compound (3.16 g), ^H NMR (300.072 MHz, CDCl ₃ ) δ 1.43 - 2.02 (4H, m),2.77 - 3.22 (3H, m),3.80 - 4.21 (3H, m),4.63 - 5.03 (IH, m),6.72 - 6.77 (IH, m),6.87 (IH, d),7.13 - 7.18 (IH, m),7.32 (2H, d),7.61 (2H, d), m/z 390 (M+H) ⁺ . Intermediate D 4- [ 1 -(5 -amino-2-methyl-benzoyl)-4-piperidyl]benzonitrile

4-[l-(2-methyl-5-nitro-benzoyl)-4-piperidyl]benzonitrile

A mixture of 2-methyl-5-nitrobenzoic acid (5g, 27.6mmol), 4-(4'-cyanophenyl)piperidine (5.14g, 27.6mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (5.82g, 30.36mmol) and DMAP (338mg, 2.76 mmol) in DMF (50 mL) was stirred at room temperature for 2 hrs. Ethyl acetate (200ml) was added and the resulting solution washed with dilute hydrochloric acid (100 mL of IM), NaHCO ₃ , brine (100 mL). At this point a colourless solid precipitated, which was isolated by filtration and dried . The filtrate was dried (MgSO4), filtered and reduced in vacuo to give a white solid. This was chromatographed (12O g silica column, Companion, eluting with a gradient consisting of 0- 50% ethyl acetate in isohexane) to give a colourless solid which was identical to that isolated previously. The solids were combined to give the title compound (4 g), ¹ H NMR (300.072 MHz, CDCl ₃ ) δl.64 - 2.11 (4H, m),2.42 - 2.53 (3H, m),2.79 - 3.00 (2H, m),3.09 - 3.23 (IH, m),3.55 (IH, d),4.98 (IH, d),7.29 - 7.36 (2H, m),7.42 (IH, d),7.63 (2H, d),8.04 - 8.18 (2H, m), m/z 348 (M-H)-.

Step 2; 4-[ 1 -(5-amino-2-methyl-benzoyi)-4-piperidyi]benzonitrile

A solution of 4-[l-(2-methyl-5-nitro-benzoyl)-4-piperidyl]benzonitrile (4g, 11.45 mmol) in ethanol / THF (200 mL of a 1 : 1 mixture) was placed under an atmosphere of argon and treated with 10% palladium on carbon catalyst (0.6 g, 15% by weight). The reaction mixture was stirred under a hydrogen atmosphere for 4hrs. The catalyst was removed by filtration through celite, and the filtrate evaporated in vacuo to give a yellow foam. Some starting material still remained so the hydrogenation was repeated as above, with stirring for a further 1 hr. The isolation was repeated as above to give a yellow foam. EtOAc was added and the solution washed with water and brine; the solvent was removed in vacuo to give the title compound as a yellow solid (3.3g), ¹ H NMR (400.132 MHz, DMSO) δ 1.39 - 1.62 (2H, m),1.69 - 1.78 (IH, m),1.88 (IH, d),1.99 - 2.12 (3H, m),2.80 (IH, t),2.90 - 2.99

(IH, m),3.08 (IH, t),3.45 - 3.51 (IH, m),4.63 - 4.72 (IH, m),5.01 (2H, s),6.37 (IH, d),6.48 - 6.52 (IH, m),6.89 (IH, d),7.46 - 7.52 (2H, m),7.78 (2H, d), m/z 320 (M+H) ⁺ . Intermediate E 4-[ 1 -(3-amino-4-fluoro-benzoyl)-4-piperidyl]benzonitrile

The title compound was prepared in a manner similar to that described for Intermediate A, starting from 3-amino-4-fluoro-benzoic acid and 4-(4'-cyanophenyl)piperidine, ¹ H NMR

(300.073 MHz, dmso) δ 1.43 - 2.00 (m, 4H), 2.68 - 3.23 (m, 3H), 3.59 - 4.05 (m, IH),

4.21 - 4.88 (m, IH), 5.29 (s, 2H), 6.49 - 6.61 (m, IH), 6.80 (d, IH), 6.95 - 7.08 (m, IH),

7.49 (d, 2H), 7.76 (d, 2H), m/z 324 (M+H) ⁺ .

Intermediate F

4-[ 1 -(5-amino-2,4-dimethyl-benzoyl)-4-piperidyl]benzonitrile

4-[l-(2,4-dimethyl-5-nitro-benzoyl)-4-piperidyl]benzonitr ile

The title compound was prepared in a manner similar to that described for Intermediate C,

Step 1, starting from 2,4-dimethyl-5-nitro-benzoic acid and 4-(4'-cyanophenyl)piperidine;

¹ H NMR (300.072 MHz, CDCl ₃ ) δ 1.44 - 1.64 (m, IH), 1.66 - 1.91 (m, 2H), 1.95 - 2.09

(m, IH) ,2.30 - 2.49 (br s, 3H), 2.61 (s, 3H), 2.79 - 2.95 (m, 2H), 3.05 - 3.26 (m, IH), 3.59

(d, IH), 4.95 (d, IH), 7.22 (s, IH), 7.32 (d, 2H), 7.61 (d, 2H), 7.81 (br s, IH), m/z 405

(M+MeCN+H) ⁺ .

Step 2: 4- [ 1 -(5 -amino-2,4-dimethyl-benzoyl)-4-piperidyl]benzonitrile

The title compound was prepared in a manner similar to that described for Intermediate C, Step 2, starting from 4-[l-(2,4-dimethyl-5-nitro-benzoyl)-4-piperidyl]benzonitrile , and using a methanol / THF mixture (1:1) as solvent; ¹ H NMR (300.073 MHz, dmso) δ 1.36 - 1.63 (m, 2H), 1.64 - 1.79 (m, IH), 1.80 - 1.95 (m, IH), 1.96 - 2.08 (br s, 3H), 2.02 (s, 3H),

2.69 - 2.85 (m, IH), 2.85 - 2.97 (m, IH), 2.98 - 3.12 (m, IH), 3.40 - 3.56 (m, IH), 4.59 -

4.70 (m, IH), 4.73 (br s, 2H), 6.30 - 6.55 (br m, IH), 6.78 (s, IH), 7.47 (d, 2H), 7.77 (d, 2H); peak broadening is observed due to conformations of amide group, m/z 334 (M+H) ⁺ . Intermediate G o 4-[l-(3-amino-4-methoxy-benzoyl)-4-piperidyl]benzonitrile

A stirred mixture of 4-(4'-cyanophenyl)piperidine (3 g, 16 mmol), 3-amino-4- methoxybenzoic acid (2.675 g, 16 mmol, 1 eq) and DIPEA (4.2 ml, 24 mmol, 1.5 eq) in DCM (100 mL) was blanketed with nitrogen and treated with N-(3-Dimethylaminopropyl)- 5 N'-ethylcarbodiimide hydrochloride (EDAC) (3.4 g, 17.6 mmol, 1.1 eq). The reaction mixture was stirred for three days. Addition of water to the reaction mixture resulted in an emulsion. Evaporation of most of the DCM resulted in the formation of a solid precipitate. The solid was isolated by filtration and washed with EtOAc (2 x 75 mL portions) to give a colourless solid (2.5 g). The ethyl acetate washings were combined and added to the o aqueous filtrate; the phases were separated and the organic phase washed with water, dried (MgSO ₄ ) and evaporated to give a further 2 g of colourless solid. The solids thus prepared were identical and combined to give the title compound as (4.5 g, 83%), ¹ H NMR (300.073 MHz, dmso, 30°C) δ 1.48 - 1.67 (2H, m), 1.71 - 1.87 (2H, m), 2.80 - 3.08 (3H, m), 3.78 (3H, s), 3.88 - 4.63 (2H, m), 4.84 (2H, s), 6.56 - 6.64 (IH, m), 6.67 - 6.73 (IH, " ₅ m), 6.80 (IH, dJ = 8.1 Hz), 7.49 (2H, dJ = 8.1 Hz), 7.76 (2H, dJ = 9.4 Hz), m/z 336 (M+H) ⁺ .

Intermediate H

4-[l-(3-amino-4-methyl-benzoyl)-4-piperidyl]-N,N-dimethyl -benzamide

Step 1: Methyl 4-[l-(4-methyl-3-nitro-benzoyl)-4-piperidyl]benzoate

A solution of 4-methyl-3-nitrobenzoyl chloride (3.9 g, 19.55 mmol) in DCM (50 niL) was added dropwise to a solution of methyl 4-(4-piperidyl)benzoate (5 g, 19.55 mmol) and DIPEA in DCM (100 mL). The reaction mixture was stirred at ambient temperature for 72 hrs. The reaction mixture was then washed sequentially with saturated aqueous sodium hydrogen carbonate solution, IM aqueous citric acid and water. The solvent was dried (phase separating cartridge) and evaporated to give the title compound as a brown waxy solid (6.85 g, 92%), ¹ H NMR (300.073 MHz, DMSOd ₆ ) δl.56-1.95 (4H, m, 2.56 (3H, s), 2.94 (2H, t), 3.60 - 3.67 (IH, m), 3.86 (3H, s), 4.64 (IH, s), 7.46 (2H, d), 7.60 (IH, d), 7.71 - 7.74 (IH, m), 7.92 (2H, d), 8.05 (IH, d), m/z 383 (M+H) ⁺ . Step 2: 4- [ 1 -(4-methyl-3 -nitro-benzoyl)-4-piperidyl]benzoic acid

A suspension of methyl 4-[l-(4-methyl-3-nitro-benzoyl)-4-piρeridyl]benzoate (Step 1) (5.68 g, 14.9 mmol) in MeOH (57 mL) was treated with aqueous sodium hydroxide solution (19 mL of 2M, 37.1 mmol, 2 eq.) and the reaction mixture stirred at 5O ⁰ C for two hrs. More MeOH (25 mL) was added and stirring for continued for one hr. The reaction mixture was cooled and treated with 2M aqueous hydrochloric acid to <pH5, diluted with

EtOAc, and the organic layer separated. The aqueous portion was shaken with more EtOAc and the organic layer again separated. The organic extracts were combined, washed with brine, dried over MgSO ₄ , filtered and evaporated to give the title compound as a yellow solid (4.92 g), ¹ H NMR (300.073 MHz, dmso) δ 1.56 - 1.77 (m, 4H), 2.54 (s, 3H), 2.68 - 3.00 (m, 3H), 3.51 - 3.73 (m, IH), 4.52 - 4.71 (m, IH), 7.41 (d, J= 8.3 Hz, 2H), 7.58 (d, J= 7.9 Hz, IH), 7.70 (d, J= 9.4 Hz, IH), 7.87 (d, J= 8.2 Hz, 2H), 8.02 (s, IH), 12.69 - 12.99 (m, IH), m/z 367 (M-H) ^" . Step 3: N,N-dimethyl-4-[l-(4-methyl-3-nitro-benzoyl)-4-piperidyl]ben zamide

A solution of 4-[l-(4-methyl-3-nitro-benzoyl)-4-piperidyl]benzoic acid (Step 2) (2.89 g, 7.84 mmol), dimethylamine (5.89 mL of a 2M solution in THF, 11.8 mmol, 1.5 eq.), DIPEA (2.7 mL, 15.7 mmol, 2 eq.), and DMAP (2.1 g, 17.3.mmol, 2.2 eq.) in DCM (58 mL) was treated with EDAC (1.8 g, 9.4 mmol, 1.2 eq.), and the reaction mixture stirred for 16 hrs at ambient temperature. Further reagents were added and the reaction mixture stirred for a further 16 hr by which time reaction was essentially complete. The reaction mixture was washed with water and the phases separated. The organic portion was concentrated to a brown solid. The crude product was re-dissolved in DCM and the solution washed sequentially with water, citric acid solution (IM in water) and saturated sodium bicarbonate solution. The organic phase was dried (MgSO ₄ ), filtered and concentrated to a brown solid, which was purified by chromatography (12Og silica column, gradient eluting with 10 - 50% EtOAc in iso-hexane) to give the title compound as a yellow gum, (1.74 g), ¹ H NMR (300.073 MHz, dmso) δ 1.57 - 1.92 (m, 4H), 2.54 (s, 3H), 2.76 - 3.03 (m, 9H), 3.57 - 3.71 (m, IH), 4.51 - 4.70 (m, IH), 7.34 (s, 4H), 7.58 (d, J= 7.9 Hz, IH), 7.70 (d, J = 6.2 Hz, IH), 8.02 (s, IH), m/z 396 (M+H) ⁺ . Step 4: 4-[l-(3-amino-4-methyl-benzoyl)-4-piperidyl]-N,N-dimethyl-be nzamide

A solution of N,N-dimethyl-4-[l-(4-methyl-3-nitro-benzoyl)-4-piperidyl] benzamide (Step 3) (1.74g) in MeOH (35 tnL) was treated with palladium-on-charcoal catalyst (122 mg of 10% Pd/C). The reaction mixture was stirred in an atmosphere of hydrogen at ambient temperature and pressure for 2 hours. The catalyst was removed by filtration and the filtrate concentrated to give the title compound as a colourless solid (1.5Ig), ¹ H NMR (300.073 MHz, dmso) δ 1.46 - 1.68 (m, 2H), 1.69 - 1.88 (m, 2H), 2.06 (s, 3H), 2.74 - 3.07 (m, 9H), 3.64 - 3.97 (m, IH), 4.43 - 4.70 (m, IH), 4.97 (s, 2H), 6.49 (d, J= 7.4 Hz, IH), 6.64 (s, IH), 6.95 (d, J= 7.5 Hz, IH), 7.32 (s, 4H), m/z 366 (M+H) ⁺ . Intermediate I 4-[l-(3-amino-4-methyl-benzoyl)-4-piperidyl]benzamide

Step 1:

4-[l-(4-methyl-3-nitro-benzoyl)-4-piperidyl]benzamide

The title compound was prepared from 4-[l-(4-methyl-3-nitro-benzoyl)-4-piperidyl] benzoic acid (Intermediate H, Step 2) using the procedure described in Heterocycles, 2006, 68 (6), 1149-1162, ¹ H NMR (300.073 MHz, dmso) δ 1.57 - 1.94 (m, 4H), 2.54 (s, 3H), 2.66 - 3.03 (m, 3H), 3.56 (s, 3H), 3.59 - 3.72 (m, IH), 4.50 - 4.71 (m, IH), 7.24 (s, IH), 7.35 (d, J= 8.1 Hz, 2H), 7.57 (d, J= 7.9 Hz, IH), 7.70 (d, J= 7.8 Hz, IH), 7.80 (d, J= 8.1 Hz, 2H), 7.87 (s, IH), 8.02 (s, IH), m/z 368 (M+H) ⁺ .

Step 2:

4-[ 1 -(3-amino-4-methyl-benzoyl)-4-piperidyl]benzamide

The title compound was prepared from 4-[l-(4-methyl-3-nitro-benzoyl)-4-piperidyl] benzamide (Step 1) using the hydrogenation procedure described in Intermediate H, Step 4, ¹ H NMR (300.073 MHz, dmso) δ 1.47 - 1.67 (m, 2H), 1.70 - 1.88 (m, 2H), 2.06 (s, 3H), 2.69 - 2.98 (m, 3H), 3.66 - 3.98 (m, IH), 4.37 - 4.74 (m, IH), 4.97 (s, 2H), 6.49 (d, J = 7.5 Hz, IH), 6.64 (s, IH), 6.95 (d, J= 7.5 Hz, IH), 7.24 (s, IH), 7.33 (d, J= 8.2 Hz, 2H), 7.80 (d, J= 8.1 Hz, 2H), 7.87 (s, IH), m/z 368 (M+H) ⁺ .