WO2009056556A1 - Substitute 1, 6-naphthyridines for use as scd inhibitors - Google Patents

Abstract

The present invention relates to substituted tetrahydronaphthyridine (THN) compounds of the formula (I) and salts thereof, to pharmaceutical compositions containing them and their use in medicine. In particular, the invention relates to compounds for inhibiting SCD activity.

Description

SUBSTITUTE 1, 6-NAPHTHYRIDINES FOR USE AS SCD

INHIBITORS

FIELD OF THE INVENTION

The present invention relates to a novel class of compounds believed to be inhibitors of stearoyl-CoA desaturase (SCD), compositions comprising said compounds, methods of synthesis and uses for such compounds in treating and/or preventing various diseases, including those mediated by SCD enzyme, such as diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome, skin disorders such as acne, diseases or conditions related to cancer and the treatment of symptoms linked to the production of the amyloid plaque-forming Aβ42 peptide such as Alzheimer's disease and the like.

BACKGROUND OF THE INVENTION

Acyl desaturase enzymes catalyze the formation of double bonds in fatty acids derived from either dietary sources or de novo synthesis in the liver. Mammals synthesise at least three fatty acid desaturases of differing chain length that specifically catalyze the addition of double bonds at the delta-9, delta-6, and delta-5 positions. Stearoyl-CoA desaturases (SCDs) introduce a double bond in the C9-C10 position of saturated fatty acids. The preferred substrates for the enzymes are palmitoyl-CoA (16:0) and stearoyl-CoA (18:0), which are converted to palmitoleoyl-CoA (16:1 ) and oleoyl-CoA (18:1 ), respectively. The resulting mono-unsaturated fatty acids may then be employed in the preparation of phospholipids, triglycerides, and cholesteryl esters, in vivo.

A number of mammalian SCD genes have been cloned. For example, two genes have been cloned from rats (SCD1 , SCD2) and four SCD genes have been isolated from mice (SCD1 , 2, 3 and 4). While the basic biochemical roles of SCD has been known in rats and mice since the 1970's (Jeffcoat, R et al., Elsevier Science (1984), VoI 4, pp. 85-1 12; de Antueno, RJ, Lipids (1993), Vol. 28, No. 4, pp. 285-290), it has only recently been directly implicated in human diseases processes.

A single SCD gene, SCD1 , has been characterized in humans. SCD1 is described in Brownlie et al, WO 01/62954. A second human SCD isoform has been identified, and because it bears little sequence homology to known mouse or rat isoforms it has been named human SCD5 or hSCD5 (WO 02/26944).

Whilst not wishing to be bound by theory, it is thought that inhibition of the activity of SCD in vivo can be used to ameliorate and/or treat one or more diseases such as dyslipidemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, atherosclerosis, obesity, Type I diabetes, Type Il diabetes, insulin resistance, hyperinsulinaemia, metabolic syndrome; other cardiovascular diseases e.g. peripheral vascular disease, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, thrombosis; hepatic steatosis, non-alcoholic steatohepatitis (NASH) and other diseases related to accumulation of lipids in the liver.

An SCD-mediated disease or condition also includes a disorder of polyunsaturated fatty acid (PUFA) disorder, or a skin disorder, including but not limited to eczema, acne, psoriasis, skin ageing, keloid scar formation or prevention, diseases related to production or secretions from mucous membranes, such as monounsaturated fatty acids, wax esters, and the like (US2006/0205713A1 , WO2007/046868, WO2007/046867). SCD has been shown to play a physiological role in cholesterol homeostasis and the de novo biosynthesis of cholesterol esters, triglycerides and wax esters required for normal skin and eyelid function and therefore may be useful in the treatment of acne and other skin conditions (Makoto et al. J of Nutrition (2001 ), 131 (9), 2260-2268, Harrison et al. J of Investigative Dermatology (2007) 127(6), 1309-1317).

An SCD-mediated disease or condition also includes but is not limited to a disease or condition which is, or is related to cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like (US2006/0205713A1 , WO2007/046868, WO2007/046867). Recently, SCD- 1 has been identified as playing a role in human tumor cell survival and therefore has potential as an anticancer target (Morgan-Lappe et al. 2007 Cancer Res. 67(9) 4390-4398).

It has been shown that overexpression of Steroyl-CoA desaturase (SCD) in human cells in culture leads to a specific increase in the production of the amyloid plaque-forming Aβ42 peptide, and conversely, that reductions in SCD activity in human cells in culture leads to a specific decrease in the production of Aβ42. Therefore, SCD inhibitors may also be useful for treating, delaying the onset of symptoms, or slowing the progression of symptoms of mild cognitive impairment (MCI), Alzheimer's Disease (AD), cerebral amyloid angiopathy (CAA) or dementia associated with Down Syndrome (DS) and other neurodegenerative diseases characterized by the formation or accumulation of amyloid plaques comprising Aβ42 (US2007/0087363A1 ; Myriad Genetics).

WO2005/01 1657 describes certain piperazine derivatives useful for inhibiting SCD activity.

The present invention provides a compound of formula (I) for inhibiting SCD activity:

(I)

wherein: X represents -CONH- or -NHCO-;

R¹ represents:

(i) a substituent selected from: H, -Ci_-6alkyl, -C_3-6CyClOaIkYl or -Cs-ecycloalkenyl; (N) -C_6-ioaryl (such as phenyl or napthyl) optionally substituted by one, two or three groups independently selected from: (a) -Ci_-6alkyl (such as -CH₃), -Ci_-6alkoxy (such as -OCH₃ or -OC₄H₉), -Ci_-6haloalkyl (such as -

CF₃), -Cs-ecycloalkyl, -OC_1-6haloalkyl (such as -OCF₃), -CN, or halogen (such as chloro, bromo or fluoro); (b) -C_6-ioaryl (such as phenyl), -C_5-i₀heteroaryl or -Cs-ioheterocyclyl, wherein the -C₆-ioaryl

(such as phenyl), -C_5-1oheteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -Ci_-6alkoxy

(such as -OCH₃), -Ci_-6haloalkyl (such as -CF₃) or halogen (such as chloro, bromo or fluoro);

Y represents -CH₂- or -OCH₂-; and

W represents a -C_5-ioheteroaryl optionally substituted by one, two or three -Ci_-6alkyl (such as -CH₃) groups;

or a pharmaceutically acceptable salt thereof.

The said compounds have been found to inhibit SCD activity and may therefore be useful in the treatment of SCD-mediated diseases such as diseases or conditions caused by or associated with an abnormal plasma lipid profile including dyslipidemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, atherosclerosis, obesity, Type I diabetes, Type Il diabetes, insulin resistance, hyperinsulinaemia and metabolic syndrome; other cardiovascular diseases e.g. peripheral vascular disease, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, thrombosis, hepatic steatosis, nonalcoholic steatoheptatis (NASH) and other diseases related to accumulation of lipids in the liver; skin disorders e.g. eczema, acne, psoriasis, skin ageing, keloid scar formation or prevention, and diseases related to production or secretions from mucous membranes; cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like; mild cognitive impairment (MCI), Alzheimer's Disease (AD), cerebral amyloid angiopathy (CAA) or dementia associated with Down Syndrome (DS) and other neurodegenerative diseases characterized by the formation or accumulation of amyloid plaques comprising Aβ42.

In one aspect of the invention, X represents -CONH-. In another aspect of the invention, X represents -NHCO-. In one aspect of the invention, R¹ represents: -C_6-ioaryl (such as phenyl or napthyl) optionally substituted by one, two or three groups independently selected from:

(a) -Ci_-6alkyl (such as -CH₃), -Ci_-6alkoxy (such as -OCH₃ or -OC₄H₉), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -OCi_-6haloalkyl (such as -OCF₃), -CN or halogen (such as chloro, bromo or fluoro),

(b) -C₆-ioaryl (such as phenyl) optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -Ci_-6alkoxy (such as -OCH₃), -Ci- ₆haloalkyl (such as -CF₃) or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionally substituted by one, two or three groups independently selected from:

(a) -Ci_-6alkyl (such as -CH₃), -Ci_-6alkoxy (such as -OCH₃ or -OC₄H₉), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -OCi_-6haloalkyl (such as -OCF₃), -CN or halogen (such as chloro, bromo or fluoro), (b) phenyl optionally substituted by one, two or three groups independently selected from:

-Ci_-6alkyl (such as -CH₃), -Ci_-6alkoxy (such as -OCH₃), -Ci_-6haloalkyl (such as -CF₃) or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents -C₆-ioaryl (such as phenyl) optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as - CH₃), -Ci_-6alkoxy (such as -OCH₃ or -OC₄H₉), -Ci_-6haloalkyl (such as -CF₃), -C_{3- 6}cycloalkyl, -OCi_-6haloalkyl (such as -OCF₃), -CN or halogen.

In another aspect of the invention, R¹ represents phenyl optionally substituted by one, two or three groups independently selected from: -Ci_-6alkyl (such as -CH₃), -Ci_-6alkoxy (such as -OCH₃ or -OC₄H₉), -Ci_-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -OCi_-6haloalkyl (such as -OCF₃), -CN or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionally substituted by one or two groups independently selected from: -C_1-6alkyl (such as -CH₃), -C_1-6alkoxy (such as - OCH₃ or -OC₄H₉), -C_1-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -OC_1-6haloalkyl (such as - OCF₃), -CN or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionally substituted by one, two or three groups independently selected from: -Ci_-6alkoxy (such as -OCH₃ or -OC₄H₉), -Ci- ₆haloalkyl (such as -CF₃) or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionally substituted by one, two or three groups independently selected from: -Ci_-6alkoxy (such as -OCH₃ or -OC₄H₉), -Ci- ₃haloalkyl (such as -CF₃) or halogen (such as chloro, bromo or fluoro). In another aspect of the invention, R¹ represents phenyl optionally substituted by one or two groups independently selected from: -C_1-6alkoxy (such as -OCH₃ or -OC₄H₉), -C_{1- 6}haloalkyl (such as -CF₃) or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionally substituted by one or two groups independently selected from: -Ci_-6alkoxy (such as -OCH₃ or -OC₄H₉), -Ci- ₃haloalkyl (such as -CF₃) or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionally substituted by one, two or three groups independently selected from: -CF₃, -OCH₂CH(CH₃)₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionally substituted by one or two groups independently selected from: -CF₃, -OCH₂CH(CH₃)₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ is phenyl substituted in the meta position, that is in the 3 position, and the para position, that is in the 4 position, by halogen e.g chloro i.e.

In one aspect of the invention, Y represents -CH₂-. In another aspect of the invention, Y represents -OCH₂-.

In one aspect of the invention, W represents a -C_5-6heteroaryl optionally substituted by one, two or three -Ci_-6alkyl (such as -CH₃) groups.

In another aspect of the invention, W represents a -C_5-6heteroaryl optionally substituted by one or two -Ci_-6alkyl (such as -CH₃) groups.

In another aspect of the invention, W represents a -C_5-6heteroaryl optionally substituted by -Ci_-6alkyl (such as -CH₃).

In another aspect of the invention, W represents a -C_5-6heteroaryl optionally substituted by one, two or three -Ci_-3alkyl (such as -CH₃) groups.

In another aspect of the invention, W represents a -C_5-6heteroaryl optionally substituted by one or two -Ci_-3alkyl (such as -CH₃) groups.

In another aspect of the invention, W represents a -C_5-6heteroaryl optionally substituted by -Ci_-3alkyl (such as -CH₃). In another aspect of the invention, W represents a -C_5-6heteroaryl optionally substituted by -CH₃.

In another aspect of the invention, W represents a -C₅heteroaryl optionally substituted by - C_1-3alkyl (such as -CH₃).

In another aspect of the invention, W represents a -C₅heteroaryl optionally substituted by - CH₃.

In another aspect of the invention, W represents thiadiazole, triazole, pyrazole or thiazole optionally substituted by one, two or three -C_1-6alkyl (such as -CH₃) groups.

In another aspect of the invention, W represents thiadiazole, triazole, pyrazole or thiazole optionally substituted by one, two or three -C_1-3alkyl (such as -CH₃) groups.

In another aspect of the invention, W represents thiadiazole, triazole, pyrazole or thiazole optionally substituted by -CH₃.

Each of the aspects of the invention are independent unless stated otherwise. Nevertheless the skilled person will understand that all the permutations of the aspects of described are within the scope of the invention. Thus it is to be understood that the present invention covers all combinations of suitable, convenient and exemplified groups described herein. For example, in one aspect the invention provides a compound of formula (I) wherein X represents -NHCO- and Y represents -CH₂-.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The invention also extends to conformational isomers of compounds of formula (I) and any geometric {cis and/or trans) isomers of said compounds. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.

It will be appreciated that racemic compounds of formula (I) may be optionally resolved into their individual enantiomers. Such resolutions may conveniently be accomplished by standard methods known in the art. For example, a racemic compound of formula (I) may be resolved by chiral preparative HPLC.

It will also be appreciated that compounds of the invention which exist as polymorphs, and mixtures thereof, are within the scope of the present invention. As used herein, the term "alkyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C_1-6alkyl means a straight or branched alkyl containing at least 1 , and at most 6, carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl, isobutyl, isopropyl, t-butyl and 1 ,1-dimethylpropyl. However, when a moiety is defined such that alkyl bears a substituent it will be clear to the skilled person from the context that alkyl may include alkylene, for example methylene (-CH₂-), ethylene (- CH₂CH₂-) and propylene (-CH₂CH₂CH₂-).

As used herein, the term "alkoxy" refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, C_1-6alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 6, carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2- oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy. The point of attachment may be on the oxygen or carbon atom.

As used herein, the term "halogen" or "halo" refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) atom.

As used herein, the term "haloalkyl" refers to an alkyl group having one or more carbon atoms and wherein at least one hydrogen atom is replaced with a halogen atom, for example a trifluoromethyl group and the like.

As used herein, the term "cycloalkyl" refers to a saturated cyclic group containing 3 to 6 carbon ring-atoms. Examples include cyclopropyl, cyclopentyl and cyclohexyl.

As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic group containing 3 to 6 carbon ring-atoms. Examples include cyclobutenyl, cyclopentenyl, and cyclohexenyl.

As used herein, the term "C_5-1oheteroaryl" refers to an aromatic cyclic group containing 5 to 10 ring-atoms 1 , 2, 3 or 4 of which are hetero-atoms independently selected from nitrogen, oxygen and sulphur and the remaining ring-atoms are carbon, e.g. benzothiophenyl, indolyl or thienyl. This definition includes both monocyclic and bicyclic ring systems and bicyclic structures at least a portion of which is aromatic and the other part is saturated, partially or fully unsaturated.

As used herein, the term 'C_6-ioaryr means an aromatic carbocyclic moiety containing 6 to 10 carbon atoms. The definition includes both monocyclic and bicyclic ring systems and bicyclic structures at least a portion of which is aromatic and the other part is saturated, partially or fully unsaturated. Examples of aromatic, aryl groups include naphthyl, anthryl, phenanthryl, indanyl, indenyl, azulenyl, azulanyl, fluorenyl, phenyl and napthyl, and more specifically phenyl. As used herein, the term "C_5-1oheterocyclyr refers to a cyclic group containing 5 to 10 ring- atoms 1 , 2, 3 or 4 of which are hetero-atoms independently selected from nitrogen, oxygen and sulphur and the remaining ring-atoms are carbon,, and, wherein said cyclic group is saturated, partially or fully unsaturated but, which is not aromatic e.g. tetrahydrofuran, dihydrofuran, 1 ,4-dioxane, morpholine, 1 ,4-dithiane, piperazine, piperidine, 1 ,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, 1 ,3-dioxane, 1 ,3-dithiane, oxathiane or thiomorpholine. This definition includes bicyclic structures provided the moiety is non- aromatic.

Examples of heterocyclyl and heteroaryl groups include: furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, homopiperazinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and thiazolinyl, benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, benzothiophenyl oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl.

As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.

For the avoidance of doubt, the term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical use.

Salts of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable. However, salts having non- pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, malic, mandelic, acetic, fumaric, glutamic, lactic, citric, tartaric, benzoic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, ethanesulfonic or naphthalenesulfonic acid. Other non-pharmaceutically acceptable salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Reference is made to Berge et al. J. Pharm. ScL, 1977, 66, 1-19.

Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms thereof.

Solvates of the compounds of formula (I) and solvates of the salts of the compounds of formula (I) are included within the scope of the present invention.

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Most preferably the solvent used is water and the solvate may also be referred to as a hydrate.

Solvates of compounds of formula (I) which are suitable for use in medicine are those wherein the solvent is pharmaceutically acceptable. However, solvates having non- pharmaceutically acceptable solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.

Prodrugs of the compounds of formula (I) are included within the scope of the present invention.

As used herein, the term "prodrug" means a compound which is converted within the body, e.g. by hydrolysis, into its active form that has medical effects. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 and in D. Fleishner, S. Ramon and H. Barba "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 1 15-130, each of which are incorporated herein by reference. Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved in vivo yielding the parent compound. Prodrugs may include, for example, compounds of this invention wherein hydroxyl or amine groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy or amine groups. Thus, representative examples of prodrugs include (but are not limited to) phosphonate, carbamate, acetate, formate and benzoate derivatives of hydroxy and amine functional groups of the compounds of formula (I)-

In one aspect of the invention there is provided a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

Λ/-{1-[(3,4-dichlorophenyl)methyl]-1 H-pyrazol-4-yl}-5,6,7,8-tetrahydro-1 ,6-naphthyridine-2- carboxamide,

Λ/-{5-[(4-chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-yl}-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide, Λ/-(4-methyl-5-{[4-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide,

Λ/-(4-methyl-5-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide,

Λ/-(5-{[4-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide,

Λ/-(5-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide,

Λ/-(5-{[(2-chlorophenyl)oxy]methyl}-1 ,3,4-thiadiazol-2-yl)-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide, Λ/-[1 -({5-chloro-2-[(2-methylpropyl)oxy]phenyl}methyl)-5-methyl-1 H-pyrazol-3-yl]-5,6,7,8- tetrahydro-1 ,6-naphthyridine-2-carboxamide,

Λ/^i-p^-dichlorophenyOmethyO-S-methyl-I H-I ^.S-triazoM-ylϊ-S.ΘJ.δ-tetrahydro-i .θ- naphthyridine-2-carboxamide,

1-[(3,4-dichlorophenyl)methyl]-5-methyl-/V-(5,6J,8-tetrahydro-1 ,6-naphthyridin-2-yl)-1 H- 1 ,2,3-triazole-4-carboxamide,

1-[(3_!4-dichlorophenyl)methyl]-Λ/-(5_!6_!7_!8-tetrahydro-1 ,6-naphthyridin-2-yl)-1 H-pyrazole-4- carboxamide, or

Λ/-{5-[(3,4-dichlorophenyl)methyl]-4-methyl-1 _!3-thiazol-2-yl}-5_!6_!7_!8-tetrahydro-1 ,6- naphthyridine-2-carboxamide.

In another aspect of the invention there is provided a compound, selected from the group consisting of:

^-{^[(S^-dichlorophenyOmethyll-I H-pyrazol^-yll-S.ΘJ.δ-tetrahydro-i .θ-naphthyridine^- carboxamide hydrochloride, Λ/-{5-[(4-chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-yl}-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide hydrochloride,

Λ/-(4-methyl-5-{[4-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide hydrochloride,

Λ/-(4-methyl-5-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide hydrochloride,

Λ/-(5-{[4-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide hydrochloride, Λ/-(5-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide hydrochloride,

Λ/-(5-{[(2-chlorophenyl)oxy]methyl}-1 _!3_!4-thiadiazol-2-yl)-5_!6_!7_!8-tetrahydro-1 ,6- naphthyridine-2-carboxamide hydrochloride, Λ/-[1 -({5-chloro-2-[(2-methylpropyl)oxy]phenyl}methyl)-5-methyl-1 H-pyrazol-3-yl]-5,6,7,8- tetrahydro-1 ,6-naphthyridine-2-carboxamide hydrochloride,

Λ/-{1-[(3,4-dichlorophenyl)methyl]-5-methyl-1 H-1 ,2,3-triazol-4-yl}-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide hydrochloride,

1-[(3,4-dichlorophenyl)methyl]-5-methyl-Λ/-(5,6,7,8-tetrahydro-1 ,6-naphthyridin-2-yl)-1 H- 1 ,2,3-triazole-4-carboxamide hydrochloride,

1-[(3,4-dichlorophenyl)methyl]-Λ/-(5,6,7,8-tetrahydro-1 ,6-naphthyridin-2-yl)-1 H-pyrazole-4- carboxamide hydrochloride, or

Λ/-{5-[(3,4-dichlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-yl}-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide hydrochloride.

The compounds of the invention have been found to inhibit SCD activity and may therefore be useful in regulating lipid levels, e.g. plasma lipid levels. Diseases or conditions caused by or associated with an abnormal plasma lipid profile and for the treatment of which the compounds of the invention may be useful include; dyslipidemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, atherosclerosis, obesity, Type I diabetes, Type Il diabetes, insulin resistance, hyperinsulinaemia and metabolic syndrome. Other cardiovascular diseases for which the compounds of the present invention are useful include peripheral vascular disease, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes and thrombosis. Other diseases or conditions include hepatic steatosis, non-alcoholic steatohepatitis (NASH) and other diseases related to accumulation of lipids in the liver.

The compounds of the invention may also be useful in the treatment of skin disorders e.g. eczema, acne, psoriasis, skin ageing, keloid scar formation or prevention, and diseases related to production or secretions from mucous membranes.

The compounds of the invention may also be useful in the treatment of cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like.

The compounds of the invention may also be useful in the treatment of mild cognitive impairment (MCI), Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA) or dementia associated with Down Syndrome (DS) and other neurodegenerative diseases characterized by the formation or accumulation of amyloid plaques comprising Aβ42. Within the context of the present invention, the terms describing the indications used herein are classified in the Merck Manual of Diagnosis and Therapy, 17^th Edition and/or the International Classification of Diseases 10^th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention.

In one aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy.

In one aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating and/or preventing a disease or a condition susceptible to amelioration by an SCD inhibitor.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating and/or preventing acne, psoriasis, skin ageing, cancer, dyslipidemia, hypertriglyceridemia, atherosclerosis, obesity, Type Il diabetes, insulin resistance, hyperinsulinaemia, hepatic steatosis and/or non-alcoholic steatohepatitis (NASH).

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating and/or preventing acne, psoriasis, skin ageing, cancer, dyslipidemia, atherosclerosis, insulin resistance, hyperinsulinaemia, Type Il diabetes and/or hepatic steatosis.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating and/or preventing acne.

In one aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating and/or preventing a disease or a condition susceptible to amelioration by an SCD inhibitor in a mammal, including human.

In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating and/or preventing acne, psoriasis, skin ageing, cancer, dyslipidemia, hypertriglyceridemia, atherosclerosis, obesity, Type Il diabetes, insulin resistance, hyperinsulinaemia, hepatic steatosis and/or non-alcoholic steatohepatitis (NASH).

In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating and/or preventing acne, psoriasis, skin ageing, cancer, dyslipidemia, atherosclerosis, insulin resistance, hyperinsulinaemia, Type Il diabetes and/or hepatic steatosis. In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating and/or preventing acne.

In one aspect, the invention provides a method for treating and/or preventing a disease or a condition susceptible to amelioration by an SCD inhibitor, which method comprises administering to a subject, for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method for treating and/or preventing acne, psoriasis, skin ageing, cancer, dyslipidemia, hypertriglyceridemia, atherosclerosis, obesity, Type Il diabetes, insulin resistance, hyperinsulinaemia, hepatic steatosis and/or non-alcoholic steatohepatitis (NASH), which method comprises administering to a subject, for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method for treating and/or preventing acne, psoriasis, skin ageing, cancer, dyslipidemia, atherosclerosis, insulin resistance, hyperinsulinaemia, Type Il diabetes and/or hepatic steatosis, which method comprises administering to a subject, for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method for treating and/or preventing acne, which method comprises administering to a subject, for example a mammal, including human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

It will be appreciated that reference to "treatment" and "therapy" includes acute treatment or prophylaxis as well as the alleviation of established symptoms.

Since the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of a compound of the invention.

Processes for the preparation of the compounds of formula (I) form further aspects of the invention. R¹, X, W and Y are as defined above unless otherwise specified. Throughout the specification, general formulae are designated by Roman numerals (I), (II), (III), (IV) etc.

In certain instances final compounds of formula (I) can be converted into other compounds of formula (I) by techniques known to those in the art, for example, carboxylic acid substituents can be converted to esters or amides by routine techniques.

In a general process, compounds of formula (I), wherein X represents -NHCO- (formula (Ia)), may be prepared according to reaction scheme 1 by reacting compounds of formula (III) and compounds of formula (IV), wherein P¹ represents a suitable nitrogen protecting group such as Boc, to form a compound of formula (II). The reaction is suitably carried out in the presence of a coupling reagent such as HATU, EDCI and/or HOBt, in a suitable solvent such as DCM (suitably at room temperature to reflux) or DMF (suitably at room temperature to 80⁰C), and is followed by deprotection of compound of formula (II) under acidic conditions such as hydrochloric acid or trifluoracetic acid (suitably at room temperature).

Scheme 1

deprotection

(H) (Ia) coupling reaction

(IV)

Accordingly, in one aspect the invention provides a process for the preparation of compounds of the formula (Ia) by reacting a compound of formula (III), wherein R¹, Y and W are defined above, with a compound of formula (IV) wherein P¹ represents a suitable nitrogen protecting group, followed by the deprotection of a compound of formula (II).

Compounds of formula (I), wherein X represents -CONH- (formula (Ib)), may be prepared according to reaction scheme 2 by reacting compounds of formula (Vl) and compounds of formula (VII), wherein P¹ represents a suitable nitrogen protecting group such as Boc, to form a compound of formula (V). The reaction is suitably carried out in the presence of a coupling reagent such as HATU, EDCI and/or HOBt, in a suitable solvent such as DCM (suitably at room temperature to reflux) or DMF (suitably at room temperature to 80⁰C), and is followed by deprotection of compound of formula (V) under acidic conditions such as hydrochloric acid or trifluoracetic acid (suitably at room temperature). Scheme 2

deprotection

(V) (Ib) coupling reaction

(VIl)

Accordingly, in another aspect the invention provides a process for the preparation of compounds of the formula (Ib) by reacting a compound of formula (Vl), wherein R¹, Y and W are defined above, with a compound of formula (VII) wherein P¹ represents a suitable nitrogen protecting group, followed by the deprotection of a compound of formula (V),

Compounds of formula (III), wherein Y represents -CH₂-, W represents a pyrazole ring substituted on position 1 with Y and on position 4 with NH₂ and R² and R³ represent H or C_1-6alkyl (formula (NIa)), may be prepared according to reaction scheme 3 by reacting compounds of formula (VIII) with compounds of formula (IX), wherein L¹ represents a suitable leaving group such as a halide, in the presence of a base such as potassium carbonate in a suitable solvent such as DMF (suitably at room temperature), followed by reduction of the nitro group of compound of formula (X) in the presence of a reducing agent such as SnCI₂.2H₂O in a suitable solvent such as ethanol (suitably at reflux temperature).

Scheme 3

(VIII) (X) (Ilia)

Compounds of formula (Vl), wherein Y represents -CH₂-, W represents a pyrazole ring substituted on position 1 with Y and on position 4 with CO₂H and R² and R³ represent H or Ci_-6alkyl (formula (VIa)), may be prepared according to reaction scheme 4 by reacting compounds of formula (Xl) with a compound of formula (IX), wherein L¹ represents a suitable leaving group such as a halide, in the presence of a base such as potassium carbonate in a suitable solvent such as DMF (suitably at room temperature), followed by saponification of compound of formula (XII) with a base such as sodium hydroxide in a suitable solvent such as ethanol (suitably at reflux temperature).

Scheme 4

(Xl) (XII) (Via)

Compounds of formula (III), wherein Y represents -CH₂-, W represents a pyrazole ring substituted on position 1 with Y and on position 3 with NH₂ and R² and R³ represent H or Ci_-6alkyl (formula (NIb)), may be prepared according to reaction scheme 5 by reacting compounds of formula (XIII) with hydrazine hydrate or NaOH (cone.) in a suitable solvent such as ethanol or methanol (suitably at reflux temperature).

Scheme 5

Compounds of formula (XIII) may be prepared according to reaction scheme 6 by reacting compounds of formula (XV) with phthalic anhydride in a suitable solvent such as dioxane, followed by alkylation of compounds of formula (XIV) with a compound of formula (IX), wherein L¹ represents a suitable leaving group such as halogen or tosylate, in the presence of a base such as potassium carbonate in a suitable solvent such as acetonitrile (suitably at reflux temperature).

Scheme 6

Compounds of formula (Vl), wherein Y represents -CH₂-, W represents a pyrazole ring substituted on position 1 with Y and on position 3 with CO₂H and R² and R³ represent H or Ci_-6alkyl (formula (VIb)), may be prepared according to reaction scheme 7 by reacting compounds of formula (XVII) with a compound of formula (IX), wherein L¹ represents a suitable leaving group such as halogen or tosylate, in the presence of a base such as potassium carbonate in a suitable solvent such as acetone (suitably at reflux temperature), followed by saponification of compound of formula (XVI) with a base such as sodium hydroxide in a suitable solvent such as ethanol (suitably at reflux temperature).

Scheme 7

(XVII) (XVI) (VIb)

Compounds of formula (XVI), wherein R³ represents hydrogen (formula (XVIa)), may be prepared according to reaction scheme 8 by deprotection of compound of formula (XVIII), wherein P² represents a suitable nitrogen protecting group such as Boc, with trifluoroacetic acid in a solvent such as dichloromethane suitably at room temperature, followed by condensation with a compound of formula (XIX) in a suitable solvent such as acetic acid (suitably at reflux temperature).

Scheme 8

Compounds of formula (XVIII), wherein P² represents a suitable nitrogen protecting group such as Boc, may be prepared according to reaction scheme 9 by reacting compounds of formula (IX), wherein L¹ represents a suitable leaving group such as halogen or tosylate, with tert-butyl carbazate in a suitable solvent such as ethanol or by reacting compound of formula (XX) with tert-butyl carbazate in the presence of a reducing agent such as sodium triacetoxyborohydride and acetic acid in a suitable solvent such as dichloromethane (suitably at room temperature to reflux temperature).

Scheme 9 (IX)

Compounds of formula (III), wherein W represents a thiadiazole ring substituted on position 5 with Y and on position 2 with NH₂ (formula (NIc)), may be prepared according to reaction scheme 10 by reacting compounds of formula (XXI) in the presence of methane sulfonic acid in a suitable solvent such as toluene suitably at reflux temperature or in presence of phosphorous tribromide (suitably at room temperature to 6O⁰C).

Scheme 10

(XXI) (MIc)

Compounds of formula (III), wherein W represents a thiadiazole ring substituted on position 5 with Y and on position 2 with NH₂ (formula (NIc)), may also be prepared according to reaction scheme 11 by reacting compounds of formula (XXII) in the presence of hydrazinecarbothioamide in a suitable solvent such as polyphosphoric acid (suitably at room temperature to 1 1O⁰C).

Scheme 1 1

(XXIi) p_PA r^rA (IMc)

Compounds of formula (III), wherein W represents a thiadiazole ring substituted on position 5 with Y and on position 2 with NH₂ (formula (NIc)), may also be prepared according to reaction scheme 12 by reacting compounds of formula (XXIII) in the presence of hydrazinecarbothioamide in a suitable solvent such as trifluoroacetic acid (suitably at reflux temperature). Compounds of formula (XXIII), wherein Y is -OCH₂-, may be prepared according to reaction scheme 12 by reacting compounds of formula (XXIV) with a reagent such as 2-chloroacetonitrile in the presence of a base such as potassium carbonate in a suitable solvent such as acetone (suitably at reflux temperature).

Scheme 12

(XXIV)

Compounds of formula (XXI) may be prepared according to reaction scheme 13 by reacting compounds of formula (XXII) with hydrazinecarbothioamide in the presence of a coupling reagent such as HATU, EDCI and/or HOBt, in a suitable solvent such as DMF (suitably at room temperature to 8O⁰C). Compounds of formula (XXI) may also be prepared according to reaction scheme 13 by reacting compounds of formula (XXV) with hydrazinecarbothioamide with a base such as pyridine in a suitable solvent such as DMF (suitably at room temperature to reflux). Compounds of formula (XXV) may be prepared by reacting compounds of formula (XXII) with a chlorinating agent such as oxalyl chloride or thionyl chloride in a suitable solvent such as dichloromethane (suitably at room temperature to reflux temperature).

Scheme 13

(XXII)

Compounds of formula (XXII), wherein Y represents -OCH₂- (formula (XXIIa)), may be prepared according to reaction scheme 14 by reacting compounds of formula (XXIV) with a reagent such as ethyl bromoacetate or ethyl chloroacetate in the presence of a base such as potassium carbonate in a suitable solvent such as acetone, followed by saponification of compound of formula (XXVI) with a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as ethanol or methanol (suitably at room temperature to reflux temperature). Scheme 14

Compounds of formula (XXII) may also be prepared according to reaction scheme 15 by reacting compounds of formula (XXIII) with a base such as sodium hydroxide in a suitable solvent such as water (suitably at room temperature to reflux temperature).

Scheme 15

(XXIII) _{(χχ| |)}

Compounds of formula (III), wherein wherein Y represents -CH₂-, W represents a triazole ring substituted on position 1 with Y and on position 4 with NH₂ and R² represents H or C_{1- 6}alkyl (formula (HId)), may be prepared according to reaction scheme 16 by reacting compounds of formula (XXVII) in the presence of bromine and a base such as potassium hydroxide in a suitable solvent such as water (suitably at 4O⁰C to 80⁰C).

Scheme 16

(XXVII) (Mid)

Compounds of formula (Vl), wherein wherein Y represents -CH₂-, W represents a triazole ring substituted on position 1 with Y and on position 4 with CO₂H and R² represents H or C_1-6alkyl (formula (VId)), may be prepared according to reaction scheme 17 by reacting compounds of formula (XXIX) and compounds of formula (XXX) in the presence of base such as potassium carbonate in a suitable solvent such as DMF or DMSO (suitably at 40⁰C to 8O⁰C), followed by saponification of compound (XXVIII) in basic conditions such as sodium hydroxide in a suitable solvent, such as ethanol or methanol (suitably at reflux temperature).

Scheme 17

(XXVIII) (VId)

Compounds of formula (Vl), wherein wherein Y represents -CH₂-, W represents a triazole ring substituted on position 1 with Y, on position 4 with CO₂H and on position 5 with hydrogen (formula (VId)), may also be prepared according to reaction scheme 18 by reacting compounds of formula (XXIX) and ethyl 2-propynoate in a suitable solvent such as ethanol (suitably at reflux temperature), followed by saponification of compound (XXVIIIa) in basic conditions.

Scheme 18

Saponification

Compounds of formula (XXVII) may be prepared according to reaction scheme 19, by reacting compounds of formula (VId) with thionyl chloride in chloroform at room temperature, followed by reaction with aqueous ammonia in acetonitrile (suitably at -5°C to 5⁰C).

Scheme 19

II)

Compounds of formula (III), wherein wherein Y represents -CH₂-, W represents a thiazole ring substituted on position 5 with Y and on position 2 with NH₂ and R² represents H or C_{1- 6}alkyl (formula (NIe)), may be prepared according to reaction scheme 20 by reacting compounds of formula (XXXI), wherein L¹ represents a suitable leaving group such as halogen in the presence of thiourea in a suitable solvent such as ethyl alcohol (suitably at room temperature to 60⁰C).

Scheme 20

(XXXI) cm^®: )

Compounds of formula (XXXI), wherein L¹ represents bromine (formula (XXXIa)), may be prepared according to reaction scheme 21 by reacting compounds of formula (XXXII) with a brominating agent such as pyridium bromide in a suitable solvent such as THF suitably at 0⁰C or Bromine in a suitable solvent such as chloroform suitably at room temperature.

Scheme 21

(XXXII) (XXXIa)

Compounds of formula (XXXI), wherein L¹ represents chlorine (formula (XXXIb)), may be prepared according to reaction scheme 22 by reacting compounds of formula (XXXIII) with a compound of formula (XXXIV) in the presence of a copper salt such as CuC^ in a suitable solvent such as toluene (suitably at 10⁰C to 30⁰C).

Scheme 22

Compounds of formula (IV), wherein P¹ represents a suitable nitrogen protecting group such as Boc (formula (IVa)), may be prepared according to reaction scheme 23. Starting from the hydrogenation of Isoxazole (XLIII) with hydrogen in the presence of a catalyst such as Raney nickel in a suitable solvent such as methyl alcohol, the resulting compound (XLII) may react with 1-(phenylmethyl)-4-piperidinone (XLI) in the presence of a salt such as piperidinium acetate in suitable solvent such as triethylamine. The resulting compound (XL) may be hydrogenated in the presence of a catalyst such as palladium in charcoal in a suitable solvent such as acetic acid to lead to compound (XXXIX). After protection of the nitrogen of compound (XXXIX) with tertbutyloxy carbonyl anhydride in the presence of a base such as sodium hydroxide in a suitable solvent such as toluene suitably at room temperature, the resulting compound (XXXVIII) may react with an oxidation agent such as meta chloroperbenzoic acid in a suitable solvent such as dichloromethane suitably at 0°C to lead to compound (XXXVII). The compound (XXXVII) may react with a cyanidation agent such as cyano trimethylsilane and dimethylcarbamic chloride in a suitable solvent such as dichloromethane suitably at room temperature to lead to compound (XXXVI). The cyano group of compound (XXXVI) may be hydrolysed with acid such as concentrated HCI in a suitable solvent such as methyl alcohol suitably at 100⁰C to lead to compound (XXXV). Compound of formula (IVa) may then be prepared from compound (XXXV) in the presence of tertbutyloxy carbonyl anhydride and a base such as sodium hydrogenocarbonate in a suitable solvent such as THF suitably at room temperature followed by reaction with aqueous base such as sodium hydroxide in a suitable solvent such as a mixture of THF and methyl alcohol suitably at reflux temperature.

Scheme 23

1 ) protection

2) hydrolysis

(XXXVI) (XXXV) (IVa)

(XXXIX)

J , Hydrogenolysis

Compound of formula (IV) wherein P¹ represents a suitable nitrogen protecting group such as Boc (formula (IVa)), may also be prepared according scheme 24. Starting from the reaction of 1 ,1-dimethylethyl 4-(1-pyrrolidinyl)-3,6-dihydro-1 (2H)-pyridinecarboxylate

(XLVII) with 2-propynamide (XLVIII) in a suitable solvent such as toluene suitably at reflux temperature, the resulting compound (XLVI) may react with triflic anhydride in a presence of a base such as pyridine in suitable solvent such as dichloromethane suitably at 0⁰C to give the compound (XLV). Compound (XLV) may react with carbon monoxide in the presence of a catalyst such as palladium diacetoxide, a ligand such as DPPP and a base such as diisopropylethylamine in a suitable solvent such as a mixture of methyl alcohol and THF (suitably at 70⁰C) to lead to compound (XLIV). Compound (IVa) may be prepared by reacting compound (XLIV) with a base such as sodium hydroxide in a suitable solvent such as methanol and water (suitably at room temperature to reflux temperature).

Scheme 24 hydrolysis

(IVa)

Compounds of formula (VII), wherein P¹ represents a suitable nitrogen protecting group such as Boc (formula (Vila)), may be prepared according scheme 25 by palladium- catalyzed amination of compounds of formula (XLV) with 1 ,1-diphenylmethanimine in the presence of a catalyst such as palladium acetate, a ligand such as BINAP and a base such as cesium carbonate in a suitable solvent such as toluene suitably at reflux temperature. This is followed by cleavage of the imine intermediate with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as methanol at room temperature.

Scheme 25

(^XLV) (Vila)

Compounds of formula (III), wherein wherein Y represents -CH₂-, W represents a thiazole ring substituted on position 5 with Y and on position 2 with NH₂ and R² represents H or Ci- ₆alkyl (formula (NIe)), may also be prepared according to reaction scheme 26 by reacting compounds of formula (XLIX) with an aldehyde of formula (XX) in the presence of a base such as butyl lithium in a suitable solvent such as THF (suitably at -78°C to room temperature), followed by reacting compound of formula (L) with triethylsilane and trifluoroacetic acid in a suitable solvent such as dichloromethane (suitably at room temperature).

Scheme 26

(XLIX) (L) (^{ll le}) Compounds of formula (VIII), (IX), (Xl), (XV), (XVII), (XIX), (XX), (XXIII), (XXIV), (XXIX), (XXX), (XXXII), (XXXIII), (XXXIV), (XLI), (XLIII), (XLVII), (XLVIII) and (XLIX) to the extent to which they are not described herein are commercially available or may be prepared by methods known in the literature or processes known to those skilled in the art.

Further details for the preparation of compounds of formula (I) are found in the examples section hereinafter.

The compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1 ,000 compounds, and more preferably 10 to 100 compounds. Libraries of compounds of the invention may be prepared by a combinatorial

'split and mix' approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus according to a further aspect there is provided a compound library comprising at least 2 compounds of the invention.

Those skilled in the art will appreciate that in the preparation of compounds of formula (I) and/or salts thereof it may be necessary and/or desirable to protect one or more sensitive groups in the molecule or the appropriate intermediate to prevent undesirable side reactions. Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis" by T.W. Greene and P. G. M. Wuts (John Wiley & sons 1991 ) or "Protecting Groups" by PJ. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl type protecting groups (e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g. benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl or aralkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).

Various intermediate compounds used in the above-mentioned process, including but not limited to certain compounds of formulae (II), (V), constitute a further aspect of the present invention.

The compounds of formula (I) or pharmaceutically acceptable salts thereof may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or pharmaceutically acceptable salt thereof together with one or more further therapeutic agent(s).

Compounds of the invention may be administered in combination with other therapeutic agents. Preferred therapeutic agents are selected from the list: an inhibitor of cholesteryl ester transferase (CETP inhibitors), a HMG-CoA reductase inhibitor, a microsomal triglyceride transfer protein, a peroxisome proliferator-activated receptor activator (PPAR), a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an inhibitor of AcylCoA: cholesterol acyltransferase (ACAT inhibitor), a cannabinoid 1 antagonist and a bile acid sequestrant. Other preferred therapeutic agents are selected from the list: a corticosteroid, a vitamin D3 derivative, a retinoid, an immunomodulator, an anti androgen, a keratolytic agent, an anti-microbial, a platinum chemotherapeutic, an antimetabolite, hydroxyurea, a taxane, a mitotic disrupter, an anthracycline, dactinomycin, an alkylating agent and a cholinesterase inhibitor

When the compound of formula (I) or pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with at least one pharmaceutically acceptable carrier and/or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.

When administration is sequential, either the SCD inhibitor or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

The invention also includes a pharmaceutical composition comprising one or more compounds of formula (I) or pharmaceutically acceptable salt(s) in combination with one or more excipients.

The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.

Creams, lotions, or ointments, may be prepared as rinse-off or leave-on products, as well as two stage treatment products for use with other skin cleansing or managing compositions. The compositions can be administered as a rinse-off product in a higher concentration form, such as a gel, and then a leave-on product in a lower concentration to avoid irritation of the skin. Each of these forms is well understood by those of ordinary skill in the art, such that dosages may be easily prepared to incorporate the pharmaceutical composition of the invention.

Ointments are hydrocarbon-based semisolid formulations containing dissolved or suspended drugs. Creams and lotions are semi-solid emulsion systems and the term is applied both to water/oil or oil/water. Gel formulations are semi-solid systems in which a liquid phase is trapped in a polymeric matrix.

By way of non-limiting example, the ointments may contain one or more hydrophobic carriers selected from, for example, white soft paraffin or other mineral waxes, liquid paraffin, non-mineral waxes, long chain alcohols, long chain acids and silicones. The ointment may contain in addition to the hydrophobic carriers some hydrophillic carriers selected from, for example, propylene glycol and polyethylene glycol in combination with an appropriate surfactant/co-surfactant system. The carrier compositions of the creams or lotions are typically based on water, white soft paraffin and an appropriate surfactant/co- surfactant system, in combination with other carriers/components selected from, for example, propylene glycol, butylene glycol glycerinemonostearate, PEG- glycerinemonostearate, esters such as Ci₂-i5alkyl benzoate, liquid paraffin, non-mineral waxes, long chain alcohols, long chain acids silicones, non-silicone polymers. The gels may by way of example be formulated using isopropyl alcohol or ethyl alcohol, propylene glycol and water with a gelling agent such as hydroxyethyl cellulose, suitably in combination with minor components, for example one or more of butylene glycol and a wetting agent such as a poloxamer.

An ointment, cream, lotion, gel, and the like, can further comprise a moisturizing agent. The moisturizing agent can be a hydrophobic moisturizing agent such as ceramide, borage oil, tocopherol, tocopherol linoleate, dimethicone or a mixture thereof or a hydrophilic moisturizing agent such as glycerine, hyaluronic acid, sodium peroxylinecarbolic acid, wheat protein, hair keratin amino acids, or a mixture thereof.

The compositions according to the invention may also comprise conventional additives and adjuvants for dermatological applications, such as preservatives, acids or bases used as pH buffer excipients and antioxidants.

The present invention encompasses administration via a transdermal patch or other forms of transdermal administration. Suitable formulations for transdermal administration are known in the art, and may be employed in the methods of the present invention. For example, suitable transdermal patch formulations for the administration of a pharmaceutical compound are described in, for example, U.S. Pat. No. 4, 460,372 to

Campbell et al., U.S. Pat. No. 4,573,996 to Kwiatek et al., U. S. Pat. No. 4,624,665 to Nuwayser, U.S. Pat. No. 4,722,941 to Eckert et al., and U.S. Pat. No. 5, 223,261 to

Nelson et al.

One suitable type of transdermal patch for use in the methods of the present invention encompasses a suitable transdermal patch includes a backing layer which is non- permeable, a permeable surface layer, an adhesive layer substantially continuously coating the permeable surface layer, and a reservoir located or sandwiched between the backing layer and the permeable surface layer such that the backing layer extends around the sides of the reservoir and is joined to the permeable surface layer at the edges of the permeable surface layer. The reservoir contains a compound of formula (I) or pharmaceutically acceptable salt thereof, alone or in combination, and is in fluid contact with the permeable surface layer. The transdermal patch is adhered to the skin by the adhesive layer on the permeable surface layer, such that the permeable surface layer is in substantially continuous contact with the skin when the transdermal patch is adhered to the skin. While the transdermal patch is adhered to the skin of the subject, the compound of formula (I) or pharmaceutically acceptable salt thereof contained in the reservoir of the transdermal patch is transferred via the permeable surface layer, from the reservoir, through the adhesive layer, and to the skin of the patient. The transdermal patch may optionally also include one or more penetration-enhancing agents in the reservoir that enhance the penetration of the compound of formula (I) or pharmaceutically acceptable salt thereof through the skin.

Examples of suitable materials which may comprise the backing layer are well known in the art of transdermal patch delivery, and any conventional backing layer material may be employed in the transdermal patch of the instant invention.

Suitable penetration-enhancing agents are well known in the art as well. Examples of conventional penetration-enhancing agents include alkanols such as ethanol, hexanol, cyclohexanol, and the like, hydrocarbons such as hexane, cyclohexaue, isopropylbenzene; aldebydes and ketones such as cyclohexanone, acetamide, N, N- di(lower alkyl)acetamides such as N,N-diethylacetamide, N,N-dimethyl acetamide, N-(2- hydroxyethyl) acetamide, esters such as N,N-di-lower alkyl sulfoxides; essential oils such as propylene glycol, glycerine, glycerol monolaurate, isopropyl myristate, and ethyl oleate, salicylates, and mixtures of any of the above.

The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Preparations for oral administration may be suitably formulated to give controlled/extended release of the active compound.

Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active ingredient, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50 to 500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

The invention also extends to novel intermediates disclosed herein, used in the preparation of compounds of formula (I) or salts thereof.

ABBREVIATIONS

BINAP 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl

Boc tertbutyloxy carbonyl

DIPEA diisopropylethylamine DCM dichloromethane

DMF dimethylformamide

DMSO dimethyl sulfoxide

EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EtOAc ethyl acetate EtOH ethanol

HATU O-(7-Azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate

HOBt N-Hydroxybenzotriazole MeOH methanol

NaOH sodium hydroxide

Na₂SO₄ sodium sulphate

NEt₃ triethylamine

THF tetrahydrofuran

TLC thin-layer chromatography

Regardless of how the preparation of compounds are represented in the present specification no inference can be drawn that particular batches (or mixtures of two or more batches) of intermediates were used in the next stage of the preparation. The examples and intermediates are intended to illustrate the synthetic routes suitable for preparation of the same, to assist the skilled persons understanding of the present invention.

Where reference is made to the use of a "similar" procedure, as will be appreciated by those skilled in the art, such a procedure may involve minor variation, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions.

Analytical methods LC-MS

Analytical HPLC was conducted on a X-terra MS C18 column (2.5 μm 3 x 30 mm id) eluting with 0.01 M ammonium acetate in water (solvent A) and 100% acetonitrile using the following elution gradient: 0 to 4 minutes, 5 to 100%B; 4 to 5 minutes, 100%B at a flow- rate of 1.1 mL/min with a temperature of 40⁰C.

The mass spectra (MS) were recorded on a micromass ZQ-LC mass spectrometer using electrospray positive ionisation [ES+ve to give MH⁺ molecular ion] or electrospray negative ionisation [ES-ve to give (M-H)^" molecular ion] modes.

Analytical methods LC-HRMS

Analytical HPLC was conducted on an Uptisphere-hsc column (3 μm 30 x 3 mm id) eluting with 0,01 M ammonium acetate in water (solvent A) and 100% acetonitrile (solvent B) using the following elution gradient: 0 to 0.5 minutes, 5%B; 0.5 to 3.5 minutes, 5 to 100%B; 3.5 to 4 minutes, 100%B; 4 to 4.5 minutes, 100 to 5%B; 4.5 to 5.5 minutes, 5%B at a flow-rate of 1.3 mL/min with a temperature of 40⁰C.

The mass spectra (MS) were recorded on a micromass LCT, mass spectrometer using electrospray positive ionisation [ES+ve to give MH⁺ molecular ion] or electrospray negative ionisation [ES-ve to give (M-H)^" molecular ion] modes.

Analytical method GC-MS Analytical GC was conducted on a DB-1 ms column (Agilent Technologies), 0.1 μm 10m x 0.1 mm id) eluting with an Helium flow of 0.5ml/min and pressure at 3.4 bar and with a gradient temperature: 0 to 0.35 min, 100⁰C; 0.35min to 6min, 100⁰C to 250°C (ramp of 80°C/min).

The mass spectra (MS) were recorded on a Agilent Technologies G5973 mass spectrometer using electronic impact ionisation.

Supporting Examples and Intermediates

The following non-limiting Examples illustrate the present invention.

Intermediate 1 : 1-r(3,4-Dichlorophenyl)methyll-4-nitro-1 H-pyrazole

To a solution of 4-nitro-1H-pyrazole (0.618 g, 5.5 mmol) and potassium carbonate (0.906 g, 6.56 mmol) in DMF (10 ml.) was added dropwise a solution of 1 ,2-dichloro-4- (chloromethyl)benzene (1.07 g, 5.5 mmol) in DMF (5 ml.) and the reaction mixture was stirred at room temperature for 2 hours. After evaporation of the solvent under reduced pressure, the residue was diluted with water and extracted with DCM. The combined extracts were washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/MeOH: 99/1 to give the title compound as a white solid (1.3 g, 88%). LC/MS: m/z 272 (M+H)⁺, Rt: 3.27 min.

Intermediate 2: 1-r(3,4-Dichlorophenyl)methyll-1 H-pyrazol-4-amine

To a solution of 1-[(3,4-dichlorophenyl)methyl]-4-nitro-1 H-pyrazole (Intermediate 1 ) (1.3 g, 4.79 mmol) in EtOH (35 ml.) was added SnCI₂.2H₂O (5.39 g, 23.98 mmol) and the mixture was stirred at reflux overnight. After cooling at room temperature, the mixture was poured into water and basified with a saturated solution of NaHCO₃. The aqueous phase was extracted with EtOAc and the organic phase was washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCIWMeOH: 95/5 to give the title compound as a colorless oil (0.46 g, 40%). LC/MS: m/z 242 (IVH-H)⁺, Rt : 2.53 min.

Intermediate 3: 2-(5-Methyl-1 H-pyrazol-3-ylV1 H-isoindole-1 ,3(2HVdione

To a solution of 5-methyl-1 H-pyrazol-3-amine (50 g, 515 mmol) in dioxane (800 ml.) was added phthalic anhydride (76.2 g, 515 mmol) and the reaction mixture was stirred at reflux for 24 hours. The resulting precipitate was filtered and the filtrate was concentrated to 150 ml. leading to the crystallization of a second crop. The combined solids were then triturated in a mixture of EtOH/diisopropyl ether and filtered to give the title compound as a pale yellow solid (100 g, 86%). LC/MS: m/z 228 (M+H)⁺, Rt: 2.19 min.

Intermediate 4: 4-Chloro-2-methyl-1-r(2-methylpropyl)oxylbenzene

To a solution of 4-chloro-2-methylphenol (50 g, 0.35 mol) in acetonitrile (500 ml.) was added cesium carbonate (228 g, 0.70 mol) and 1-bromo-2-methylpropane (57 ml_, 1.5 eq.) The reaction mixture was stirred at reflux for 5 hours. After cooling, the salts were removed by filtration and the filtrate was evaporated under reduced pressure. The title compound was obtained as a yellow oil (47 g, 68%). GC/MS: m/z 198 (M⁺), Rt: 1.59 min.

Intermediate 5: 2-(Bromomethyl)-4-chloro-1-r(2-methylpropyl)oxylbenzene

To a solution of 4-chloro-2-methyl-1-[(2-methylpropyl)oxy]benzene (Intermediate 4) (47 g, 0.24 mol) in carbon tetrachloride (800 ml.) were added N-bromo succinimide (46.5 g, 0.261 mol) and a small quantity of dibenzoyl peroxyde. The reaction was stirred to reflux for 24 hours. After cooling, water was added to the reaction mixture and the organic phase was decanted and filtered on a bed of silica, to give the title compound as a yellow oil (65 g, 100%). GC/MS: m/z 277 (M⁺), Rt: 2.08 min.

Intermediate 6: 2-ri-({5-Chloro-2-r(2-methylpropyl)oxylphenyl)methyl)-5-methyl-1 H- pyrazol-3-yll-i H-isoindole-1 ,3(2H)-dione

To a solution of 2-(5-methyl-1 H-pyrazol-3-yl)-1 H-isoindole-1 ,3(2H)-dione (Intermediate 3) (13.3 g, 58.5 mmol) in acetone (300 ml.) was added potassium carbonate (16.2 g, 117 mmol) followed by 2-(bromomethyl)-4-chloro-1-[(2-methylpropyl)oxy]benzene (Intermediate 5) (32.5 g, 127 mmol) and the reaction mixture was refluxed for 24 hours. A second portion of potassium carbonate (4.05 g, 29.3 mmol) and acetone (300 ml.) were added and the reaction mixture was refluxed for 2 days. A third portion of potassium carbonate (4.05 g, 29.3 mmol) and acetone (300 ml.) were added and the reaction mixture was refluxed overnight. After cooling the salts were removed by filtration and the filtrate was evaporated under reduced pressure. The residue was poured in a mixture of cyclohexane/EtOAc: 80/20 and the resulting solid was filtered to give after drying the title compound as a light yellow solid (7.6 g, 30.6%). LC/MS: m/z 424 (M+H)⁺, Rt: 3.96 min.

Intermediate 7: 1-({5-Chloro-2-r(2-methylpropyl)oxylphenyl)methyl)-5-methyl-1 H-pyrazol- 3-amine

To a suspension of 2-[1-({5-chloro-2-[(2-methylpropyl)oxy]phenyl}methyl)-5-methyl-1 H- pyrazol-3-yl]-1 H-isoindole-1 , 3(2H)-dione (Intermediate 6) (1.9 g, 4.5 mmol) in methyl alcohol was added hydrazine hydrate (0.5 ml_, 9 mmol) and the reaction mixture was stirred at reflux for 1 hour. After cooling the precipitate was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was diluted with acetone and the insoluble material was removed by filtration. After concentration of the filtrate, the residue was purified by flash column chromatography eluting with DCIWEtOAc: 95/5 to give the title compound as a yellow solid (1.2 g, 91%). LC/MS: m/z 294 (M+H)⁺, Rt: 3.31 min.

Intermediate 8: 2-{r(2-Chlorophenyl)oxylacetyl)hvdrazinecarbothioamide

Three coupling reactions were carried out simultaneously on 10 g scale. A solution of 2- chlorophenoxyacetic acid (10 g, 54 mmol), HATU (22.4 g, 59 mmol) and NEt₃ (11.1 ml_, 80 mmol) in DMF was stirred at room temperature for 1 hour. Hydrazinecarbothioamide (5.9 g, 64 mmol) was added, and the reaction mixture was stirred at room temperature for two days. After evaporation of the solvent under reduced pressure of the three combined mixtures, the residue was diluted with water and the formed precipitate was filtered and dried to give the title compound as a pale yellow powder (36.6 g, 87%). LC/MS: m/z 260 (M+H)⁺, Rt: 2.09 min.

Intermediate 9: 5-{r(2-Chlorophenyl)oxylmethyl)-1 ,3,4-thiadiazol-2-amine

To a solution of 2-{[(2-chlorophenyl)oxy]acetyl}hydrazinecarbothioamide (Intermediate 8) (36.6 g, 0.14 mol) in toluene (250 ml.) was added dropwise methane sulfonic acid (13.7 ml_, 0.21 mol) and the reaction mixture was stirred at reflux temperature for 2 hours. The solvent was evaporated under reduce pressure and the residue was diluted with water and basified until pH=9 with an ammonium hydroxide solution. The formed precipitated was filtered and dried to give the title compound as a pale yellow solid (20.3 g, 60%). LC/MS: m/z 242 (M+H)⁺, Rt: 2.57 min.

Intermediate 10: (3,4-Dichlorophenyl)methyl azide

A mixture of 3,4-dichlorobenzyl chloride (10 g, 0.05 mol), sodium azide (5 g, 0.08 mol) in

DMSO (100 mL) was stirred at room temperature overnight. The mixture was poured into water (150 mL). The water layer was extracted with EtOAc (100 mL, 3x). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by distillation to give the title compound as an oil (14 g, quantitative yield). LC/MS: m/z 203 (IVH-H)⁺, Rt: 2.26 min.

Intermediate 11 : Methyl 1-r(3,4-dichlorophenyl)methyll-5-methyl-1 H-1 ,2,3-triazole-4- carboxylate

To a suspension of milled potassium carbonate (38.7 g, 0.28 mol) in DMSO (100 ml.) was added (3,4-dichlorophenyl)methyl azide (Intermediate 10) (14 g, 0.07 mol) and methyl acetoacetate (12.1 g, 0.1 mol) and the reaction mixture was stirred at 40⁰C for 2 days.

The mixture was poured into a mixture of ice and water (100 ml.) and extracted with

EtOAc (100 ml_, 2x).The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by distillation and the title compound was obtained as a white solid (14 g, 67%). LC/MS: m/z 301

(M+H)⁺, Rt: 1.97 min.

Intermediate 12: 1-r(3,4-Dichlorophenyl)methyll-5-methyl-1H-1 ,2,3-triazole-4-carboxylic acid

To a solution of methyl 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1 H-1 ,2,3-triazole-4- carboxylate (Intermediate 1 1 ) (9 g, 0.03 mol) in methanol (200 ml.) was added NaOH (2.4 g, 0.06 mol) in water (20 ml.) and the reaction mixture was stirred at room temperature overnight. Water was added and the solvent was evaporated under reduced pressure. The aqueous phase was extracted with DCM, and then acidified at pH=2 with a 2N hydrochloric acid solution. The solid which formed, was filtered and dried to give the title compound as a white solid (7.29 g, 84%). LC/MS: m/z 287 (M+H)⁺, Rt: 2.52 min.

Intermediate 13: 1-r(3,4-Dichlorophenyl)methyll-5-methyl-1 H-1 ,2,3-triazole-4-carboxamide

To a solution of ^[(S^-dichloropheny^methyO-S-methyl-I H-i ^^-triazole^-carboxylic acid (Intermediate 12) (14 g, 48.93 mmol) in chloroform (200 ml.) was added thionyl chloride (30 ml.) at room temperature and the reaction mixture was stirred at reflux temperature for 4 hours. The reaction mixture was then evaporated to dryness and the residue was dissolved in acetonitrile (50 ml_). Aqueous ammonia (50 ml.) was added at 0⁰C and the reaction mixture was stirred for 30 min. The resulting solid was filtered and dried to give the title compound as a white solid (12.7 g, 91.1%). LC/MS: m/z 285 (IvRH)⁺, Rt: 2.53 min.

Intermediate 14: 1-r(3,4-Dichlorophenyl)methyll-5-methyl-1 H-1 ,2,3-triazol-4-amine

To a solution of potassium hydroxide (10.96 g, 0.195 mol) in water (50 ml_), cooled in an ice-salt bath, was added bromine (6.3 g, 0.0396 mol) and at 0⁰C, 1-[(3,4- dichlorophenyl)methyl]-5-methyl-1 H-1 ,2,3-triazole-4-carboxamide (Intermediate 13) (9.3 g,

32.63 mmol) was added for 4 hours under vigorous stirring. The reaction mixture was then warmed at 80⁰C for 2 days and stirred at room temperature for 12 hours. The resulting solid was filtered and purified by HPLC to give the title compound (3.45 g, 41.14%). LC/MS: m/z 257 (M+H)⁺, Rt: 2.25 min.

Intermediate 15: 4-(4-Chlorophenyl)-2-butanone

A solution of 4-chlorobenzyl chloride (16.10 g, 100 mmol), 2,4-pentanedione (10.4 mL, 100 mmol) and K₂CO₃ (13.8 g, 100 mmol) in anhydrous ethanol (100 mL) was heated to reflux for 16 hours. The mixture was cooled to room temperature and ethanol was removed under reduced pressure. Water was added and the mixture was extracted with diethyl ether. The organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by distillation (78-80⁰C) to give the title compound as a colourless oil (8.9 g, 49%). ¹H NMR (300 MHz, CDCI₃, ppm), δ : 7.22 (d, 2H), 7.11 (d, 2H), 2.86 (t, 2H), 2.75 (t, 2H), 2.1 (s, 3H).

Intermediate 16: 5-[(4-Chlorophenyl)methyl1-4-methyl-1 ,3-thiazol-2-amine

To a solution of 4-(4-chlorophenyl)-2-butanone (Intermediate 15) (8.9 g, 48.9 mmol) in chloroform (70 ml.) was added dropwise bromine (2.4 ml_, 47.4 mmol) and the reaction mixture was stirred for 2 hours at room temperature. The solution was concentrated under reduced pressure. The residue was dissolved in ethyl alcohol (30 ml.) and thiourea (3.71 g, 48.9 mmol) was added. The mixture was stirred under reflux overnight. The volatiles were removed under reduced pressure and diethyl ether was added to the residue. After stirring for 20 minutes, the solid material was removed and treated again with diethyl ether. The solid material was then poured into water (50 ml.) and aqueous ammonia was added to basic pH. The pale yellow solid was filtered and recrystallized in dichloromethane to give the title compound as a white solid (1.35 g, 11.6%). Mp: 1 12- 113°C.

Intermediate 17: 3-Chloro-4-[3-(trifluoromethyl)phenyl1-2-butanone

A cooled solution of 3-(trifluoromethyl)benzenediazonium chloride prepared by diazotation of 3-(trifluoromethyl)aniline (32.2 g, 0.2 mol) was added dropwise with stirring to a mixture of methyl vinyl ketone (14 g, 0.2 mol) and CuCI₂.2H₂O (10 g, 0.06 mol) in toluene (50 ml_). The reaction mixture was stirred at 10-30⁰C overnight. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic extracts were combined, dried over Na₂SO₄ and evaporated. The residue was purified by distillation to give the title compound as an oil (22 g, 44%). ¹H NMR (300 MHz, CDCI₃, ppm) δ : 7.5 (m, 4H), 4.45 (t, 1 H), 3.4 (dd, 1 H), 3.1 (dd, 1 H), 2.4 (s, 3H).

The following compound was similarly prepared by a method analogous to that described for Intermediate 17:

Table 1

Intermediate 19: 4-Methyl-5-{[3-(trifluoromethyl)phenyl1methyl)-1 ,3-thiazol-2-amine

To a solution of 3-chloro-4-[3-(trifluoromethyl)phenyl]-2-butanone (Intermediate 17) (10 g, 46.3 mmol) in ethanol (30 ml.) was added thiourea (3.52 g, 46.3 mmol) and the mixture was stirred under reflux overnight. The volatiles were removed under reduced pressure and diethyl ether was added to the residue. After stirring for 10 minutes, the solid material was removed and treated again with diethyl ether. The solid material was then poured in water (50 ml.) and aqueous ammonia was added to basic pH. The solid material was filtered then recrystallized in CCI₄ to give the title compound as a white solid (1.67 g, 13%). Mp: 79-80⁰C.

The following compound was similarly prepared by a method analogous to that described for Intermediate 19:

Table 2

Intermediate 21 : 2-Chloro-3-r4-(trifluoromethyl)phenyllpropanal

To a mixture of concentrated hydrochloric acid (42 ml.) and glacial acetic acid (12.5 ml.) was added 4-(trifluoromethyl)benzenamine (20 g, 0.124 mol). After cooling of the suspension at -15°C, a solution of sodium nitrite (9.43 g, 0.136 mol) in water (15 ml.) was added dropwise without exceed a temperature superior to -5°C. The mixture was stirred for 45 minutes at -10 to -5°C. The cooled solution of 4-(trifluoromethyl)benzene diazonium chloride was then added dropwise with stirring to a mixture of acrolein (8.37 ml_, 0.124 mol) and CuCI₂.2H₂O (6.2 g, 0.124 mol ) in toluene (40 ml.) at -10 to -5°C. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic extracts were combined, dried over Na₂SO₄ and evaporated. The residue was purified by distillation to give the title compound as a yellow oil (1 1.4 g, 39%). ¹H NMR (300 MHz, CDCI₃, ppm) δ : 9.56 (s, 1 H), 7.59 (d, 2H), 7.36 (d, 2H), 4.40 (m, 1 H), 3.45 (m, 1 H), 3.12 (m, 1 H).

Intermediate 22: 5-{[4-(Trifluoromethyl)phenyl1methyl)-1 ,3-thiazol-2-amine

To a solution of 2-chloro-3-[4-(trifluoromethyl)phenyl]propanal (Intermediate 21 ) (5 g, 22 mmol) in ethanol (20 ml.) was added thiourea (1.69 g, 22 mmol) and the mixture was stirred under reflux overnight. After cooling of the mixture, water (100 ml.) was added and aqueous ammonia was added to basic pH. The solid material was filtered to give the title compound as a white solid (4.6 g, 84%). LC/MS: m/z 259.1 (M+H)⁺ _, Rt: 3.57 min.

Intermediate 23: 3-Amino-2-propenal

² ^^ XHO

To a solution of isoxazole (60 g, 0.87 mol) in anhydrous methyl alcohol (1.2 L) were added Raney nickel (12 g) and the mixture was hydrogenated under 40 psi of hydrogen. The mixture was stirred overnight at room temperature then filtered and evaporated under reduced pressure to give the title compound as a yellow solid (64 g, quantitative yield). ¹H NMR (300 MHz, DMSO, ppm) δ : 8.90 (d, 1 H), 7.26-7.06 (m, 3H), 5.10 (m, 1 H).

Intermediate 24: 6-(Phenylmethyl)-5,6,7,8-tetrahydro-1 ,6-naphthyridine

A mixture of 3-amino-2-propenal (Intermediate 23) (64 g, 0.87 mol), 1-(phenylmethyl)-4- piperidinone (113.6 g, 0.6 mol), triethylamine (50 ml.) and piperidinium acetate (1.5 g, 0.01 mol) was heated at 120⁰C for 24 hours. After return to room temperature, the mixture was dissolved in 3N hydrochloric acid solution and washed with chloroform. The aqueous layer was then treated with a saturated aqueous solution of Na₂CC>3 and extracted with CHCI₃. After concentration under vacuum of the organic layer, the red oily residue was purified by column chromatography to give the title compound as a yellow solid (57 g, 34%). LC/MS: m/z 225 (M+H)⁺, Rt: 0.83 min.

Intermediate 25: 1 ,1-Dimethylethyl 7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxylate

To a solution of 6-(phenylmethyl)-5,6,7,8-tetrahydro-1 ,6-naphthyridine (Intermediate 24) (36 g, 0.16 mol) in acetic acid (500 ml.) was added 10% Pd/C (6 g) and the mixture was hydrogenated under 1 atmosphere of hydrogen for 2 hours at 50 to 60⁰C. After return to room temperature, the mixture was filtered and evaporated under reduced pressure to give crude 5,6,7,8-tetrahydro-1 ,6-naphthyridine (12.8 g, 60%). The crude 5,6,7,8- tetrahydro-1 ,6-naphthyridine (24 g, 0.18 mol) was added to a solution of NaOH (216 g, 5.4 mol) in water. Toluene (1 L) was added then tertbutyloxy carbonyl anhydride (47 g, 0.2 mol). The biphasic mixture was strongly stirred for 20 minutes then the organic layer was separated and washed with water (500 ml.) and the aqueous layer was extracted with toluene. The combined organic layers were then washed with water and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the title compound as a white solid (23 g, 55%). ¹H NMR (300 MHz, CDCI₃, ppm) δ : 8.40 (d, 1 H), 7.38 (d, 1 H), 7.10 (m, 1 H), 4.57 (s, 2H), 3.73 (t, 2H), 2.98 (t, 2H), 1.47 (s, 9H).

Intermediate 26: 1 ,1-Dimethylethyl 7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxylate 1- oxide

To a solution of 1 ,1-dimethylethyl 7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxylate (Intermediate 25) (23 g, 0.1 mol) in DCM (500 ml.) was added m-chloroperbenzoic acid (48.5 g, 0.285 mol) at 0°C. The reaction mixture was stirred for 1 hour then Na₂SO₃ (37.8 g, 0.3 mol) was added. After stirring for 1 hour, saturated aqueous solution of NaHCO₃ was added. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the title compound as a white solid (19 g, 76%). ¹H NMR (300 MHz, CDCI₃, ppm) δ 8.19 (d, 1 H), 7.15-7.02 (m, 2H), 4.58 (s, 2H), 3.74 (t, 2H), 3.05 (t, 2H), 1.47 (s, 9H).

Intermediate 27: 1 ,1-Dimethylethyl 2-cvano-7,8-dihvdro-1 ,6-naphthyridine-6(5H)- carboxylate

To a solution of 1 ,1-dimethylethyl 7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxylate 1 -oxide (Intermediate 26) (19 g, 0.08 mol) in dichloromethane (300 ml.) was added trimethylsilyl cyanide (16 ml_, 0.12 mol). After stirring for 20 minutes at room temperature, N, N- dimethylcarbamyl chloride (11 ml_, 0.12 mol) was added. The mixture was stirred for 41 hours at room temperature and then quenched with a saturated aqueous solution of

NaHCO₃. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the title compound (12 g, 59%). ¹H NMR (300 MHz,

CDCI₃, ppm) δ : 7.53 (s, 2H), 4.65 (s, 2H), 3.75 (t, 2H), 3.02 (t, 2H), 1.48 (s, 9H).

Intermediate 28: 6-(1 ,1-Dimethylethyl) 2-methyl 7,8-dihvdro-1 ,6-naphthyridine-2,6(5H)- dicarboxylate

To a solution of 1 ,1-dimethylethyl 2-cyano-7,8-dihydro-1 ,6-naphthyridine-6(5H)- carboxylate (Intermediate 27) (6 g, 0.023 mol) in methyl alcohol (192 ml.) was added concentrated HCI (192 ml_). After stirring for 3 hours at 100⁰C, the mixture was cooled to room temperature and poured in a mixture of THF (1.2 L) and water (1.2 L) containing

NaHCO₃ (192 g, 2.28 mol). To the biphasic mixture was added tertbutyloxy carbonyl anhydride (7.58 g, 0.034 mol). The mixture was stirred for 30 minutes at room temperature and after decantation the aqueous layer was extracted with ethyl acetate.

The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with

DCM/EtOAc: 1/1 to give the title compound as a white solid (3.7 g, 55%). LC/MS: m/z 293

(M+H)⁺, Rt: 2.41 min.

Intermediate 29: 6-{[(1 ,1-Dimethylethyl)oxylcarbonyl)-5,6,7,8-tetrahvdro-1 ,6- naphthyridine-2-carboxylic acid

To a solution of 6-(1 ,1 -dimethylethyl) 2-methyl 7,8-dihydro-1 ,6-naphthyridine-2,6(5H)- dicarboxylate (Intermediate 28) (6.4 g, 0.022 mol) in a mixture of THF (60 ml.) and methyl alcohol (60 ml.) was added 1 N sodium hydroxide solution (31 ml_). After reflux for 3 hours, the mixture was cooled to room temperature and concentrated under vacuum. The residue was poured in a mixture of 0.05 N hydrochloric acid solution (620 ml.) and EtOAc

(1 L). The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the title compound as a white solid (4.5 g, 73%). LC/MS: m/z 279 (M+H)⁺, Rt: 1.91 min.

Intermediate 30: 2-Propynamide

To a solution of liquid NH₃ (50 ml.) at -78°C was added dropwise ethyl 2-propynoate (1 1 g, 0.11 mol). The mixture was stirred at -78°C for 2 hours, then for 3 hours at room temperature. The remaining residue was concentrated under vacuum to give the title compound which was used in the next step without further purification (8 g, quantitative yield).

Intermediate 31 : 1 ,1-Dimethylethyl 4-(1-pyrrolidinyl)-3,6-dihvdro-1 (2H)-pyridinecarboxvlate

A solution of 1 ,1 -dimethylethyl 4-oxo-1-piperidinecarboxylate (10 g, 0.05 mol) and pyrrolidine (5.33 g, 0.075 mol) in toluene (40 ml.) was heated under reflux with a Dean- stark apparatus for 6 hours. The mixture was then concentrated under vacuum to give the title compound which was used in the next step without further purification (13 g, quantitative yield).

Intermediate 32: 1 ,1-Dimethylethyl 2-oxo-1 ,5,7,8-tetrahvdro-1 ,6-naphthyridine-6(2H)- carboxylate

A solution of 1 ,1-dimethylethyl 4-(1-pyrrolidinyl)-3,6-dihydro-1 (2H)-pyridinecarboxylate (Intermediate 31 ) (6 g, 0.024 mol) in toluene (50 mL) was added 2-propynamide (Intermediate 30) (3.3 g, 0.048 mol). The reaction mixture was refluxed overnight then concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with DCIWMeOH: 100/2 to give the title compound (3.0 g, 50%). LC/MS: m/z 251 (IVH-H)⁺, Rt: 1.41 min.

Intermediate 33: 1.1-Dimethylethyl 2-fr(trifluoromethvnsulfonylloxy>-7.8-dihvdro-1.6- naphthyridine-6(5H)-carboxylate

To a solution of 1 ,1-dimethylethyl 2-oxo-1 ,5,7,8-tetrahydro-1 ,6-naphthyridine-6(2H)- carboxylate (Intermediate 32) (250 mg, 1 mmol) in dichloromethane (10 mL), containing pyridine (240 mg, 3 mmol) was added dropwise at 0°C, trifluoromethanesulfonic anhydride (330 mg, 1.2 mmol). The reaction mixture was stirred for 15 minutes and then concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound (200 mg, 52%). ¹H NMR (400 MHz, DMSO, ppm) δ : 7.93 (d, 1 H), 7.35 (d, 1 H), 4.55 (bs, 2H), 3.62 (t, 2H), 2.81 (t, 2H), 1.37 (s, 9H).

Intermediate 34: 1 ,1-Dimethylethyl 2-amino-7,8-dihvdro-1 ,6-naphthyridine-6(5H)- carboxylate

A mixture of 1 ,1-dimethylethyl 2-{[(trifluoromethyl)sulfonyl]oxy}-7,8-dihydro-1 ,6- naphthyridine-6(5H)-carboxylate (Intermediate 33) (38 g, 0.1 mol), palladium acetate (2.2 g, 0.01 mol), cesium carbonate (48 g, 0.15 mol) and BINAP (6.2 g , 0.01 mol) in anhydrous toluene (400 mL) under an atmosphere of nitrogen, was treated with 1 ,1- diphenylmethanimine (28 g, 0.15 mol) and the reaction mixture was refluxed overnight. After filtration and concentration under reduced pressure, the residue was dissolved in methanol (400 mL) and sodium acetate (17 g, 0.21 mol) and hydroxylamine hydrochloride (15 g, 0.21 mol) were added. The mixture was stirred at room temperature for 5 hours. After concentration the residue was purified by flash column chromatography to give the title compound (1 1.5 g, 46%). LC/MS: m/z 250 (IVH-H)⁺, Rt: 1.86 min.

Intermediate 35: 1 ,1-Dimethylethyl 2-r({1-r(3,4-dichlorophenyl)methyll-1 H-pyrazol-4- yl)amino)carbonyll-7,8-dihvdro-1 ,6-naphthyridine-6(5/-/)-carboxvlate

A solution of 6-{[(1 ,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydro-1 ,6-naphthyridine-2- carboxylic acid (Intermediate 29) (1.48 g, 5.32 mmol), HATU (2.2 g, 5.8 mmol), DIPEA (1.67 ml_, 9.7 mmol) and 1-[(3,4-dichlorophenyl)methyl]-1H-pyrazol-4-amine (Intermediate 2) (1.17 g, 4.85 mmol) in DMF (50 ml.) was stirred at room temperature for 4 days. The volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane. The organic phase was then washed with water, with a 1 N NaOH solution, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound as a cream solid (2.07 g, 86%). LC/MS: m/z 502 (M+H)⁺, Rt : 3.63 min.

Intermediate 36: 1.1-Dimethylethyl 2-r({5-r(4-chlorophenvnmethyll-4-methyl-1.3-thiazol-2- yl)amino)carbonyll-7,8-dihvdro-1 ,6-naphthyridine-6(5H)-carboxvlate

A solution of 6-{[(1 ,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydro-1 ,6-naphthyridine-2- carboxylic acid (Intermediate 29) (128 mg, 0.46 mmol), HATU (191 mg, 0.50 mmol), DIEA (145 μl_, 0.84 mmol) and 5-[(4-chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-amine (Intermediate 16) (100 mg, 0.42 mmol) in DMF (5 ml.) was stirred at room temperature for 2 days. The volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane. The organic phase was then washed with water, with a 1 N NaOH solution, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/MeOH: 96/4 to give the title compound as a white solid (1 10 mg, 53%) after recrystallization from diisopropyl ether. LC/MS: m/z 499 (M+H)⁺, Rt: 4.08 min. The following intermediates were similarly prepared by methods analogous to those described for Intermediates 35 and 36.

Table 3

Intermediate 44: 1.1-Dimethylethyl 2-rαi-r(3.4-dichloroDhenvnmethyll-5-methyl-1 H-1.2.3- triazol-4-yl)carbonyl)aminol-7,8-dihvdro-1 ,6-naphthyridine-6(5H)-carboxylate

A solution of 1 ,1-dimethylethyl 2-amino-7,8-dihydro-1 ,6-naphthyridine-6(5/-/)-carboxylate (Intermediate 34) (194 mg, 0.78 mmol), HATU (298 mg, 0.78 mmol), DIPEA (140 μL, 0.78 mmol) and 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1 H-1 ,2,3-triazole-4-carboxylic acid (Intermediate 12) (150 mg, 0.52 mmol) in DMF (5 mL) was stirred at 40⁰C for 7 days. The volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane. The organic phase was then washed with water and dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCIWEtOAc: 8/2 to give the title compound as a white solid (66 mg, 24%) after recrystallization from acetonitrile. LC/MS: m/z 517 (IvHH)⁺, Rt: 3.9 min.

Intermediate 45: Ethyl 1-[(3,4-dichlorophenyl)methyl1-1H-pyrazole-4-carboxylate

To a solution of ethyl 1 H-pyrazole-4-carboxylate (0.475 g, 3.39 mmol) and potassium carbonate (0.56 g, 4.05 mmol) in DMF (20 ml.) was added dropwise 1 ,2-dichloro-4-

(bromomethyl)benzene (0.98 g, 4.08 mmol) and the reaction mixture was stirred at room temperature overnight. After evaporation of the solvent under reduced pressure, the residue was diluted with water and extracted with DCM. The combined extracts were washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/EtOAc: 92/8 to give the title compound as a white solid (0.92 g, 91%). LC/MS: m/z 299 (M+H)⁺, Rt:

3.44 min.

Intermediate 46: 1-r(3,4-Dichlorophenyl)methyll-1 H-pyrazole-4-carboxylic acid

To a solution of Intermediate 2 (0.92 g, 3.09 mmol) in ethanol (20 ml.) was added a 1 N sodium hydroxide solution (12 ml_, 12 mmol) and the reaction mixture was stirred at reflux for 2 hours. Ethanol was evaporated under reduced pressure and the residue was treated with a 1 N hydrochloric acid solution. The precipitate obtained was filtered, washed with water and dried to give the title compound as a white solid (790 mg, 95%). LC/MS: m/z 269 (M-H)⁺ _, Rt: 2.17 min.

Intermediate 47: 1 ,1-Dimethylethyl {5-[(3,4-dichlorophenyl)(hvdroxy)methyl1-4-methyl-1 ,3- thiazol-2-yl)carbamate

A solution of butyl lithium in tetrahydrofuran (2.5 M, 105 mL, 262 mmol) was slowly added to a solution of 1 ,1-dimethylethyl (4-methyl-1 ,3-thiazol-2-yl)carbamate (1 1.3 g, 52 mmol) in anhydrous tetrahydrofuran (180 mL) at -78°C under a nitrogen atmosphere and the reaction mixture was stirred at the same temperature for 1 hour. A solution of 3,4- dichlorobenzaldehyde (13.8 g, 78.8 mmol) in tetrahydrofuran was then added drop-wise at -78°C. The mixture was warmed slowly to room temperature and stirred for 4 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography eluting with petroleum ether/ethyl acetate: 5/1 to give the title compound (4.78 g, 23.5%).

Intermediate 48: 5-[(3,4-Dichlorophenyl)methyl1-4-methyl-1 ,3-thiazol-2-amine

A mixture of 1 ,1-dimethylethyl {5-[(3,4-dichlorophenyl)(hydroxy)methyl]-4-methyl-1 ,3- thiazol-2-yl}carbamate (Intermediate 47) (4.78 g, 12.3 mmol), triethylsilane (1 1.4 g, 98.3 mmol) and trifluoroacetic acid (19 g, 166 mmol) in dichloromethane (70 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was treated with a saturated solution of NaHCO₃. The aqueous layer was extracted with dichloromethane and the combined organic extracts were dried over sodium sulphate, filtered and evaporated to dryness. The residue was purified by column chromatography eluting with petroleum ether/ethyl acetate: 4/1 to give the title compound (2.15 g, 65%). LC/MS: m/z 273 (M+H)⁺, Rt: 1.56 min.

Intermediate 49: 1.1-Dimethylethyl 2-r(l1-r(3.4-dichlorophenvnmethyll-1 H-pyrazol-4- yl)carbonyl)aminol-7,8-dihvdro-1 ,6-naphthyridine-6(5H)-carboxvlate

A solution of 1-[(3,4-dichlorophenyl)methyl]-1 H-pyrazole-4-carboxylic acid (Intermediate 46) (120 mg, 0.44 mmol), HATU (183 mg, 0.48 mmol), DIPEA (140 μL, 0.8 mmol) in DMF (5 mL) was stirred at room temperature for 45 min. 1 ,1-Dimethylethyl 2-amino-7,8-dihydro- 1 ,6-naphthyridine-6(5H)-carboxylate (Intermediate 34) (100 mg, 0.4 mmol) was then added and the reaction mixture was stirred at room temperature for 5 days and at 60⁰C for 5 days. The volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane. The organic phase was then washed with a 1 N sodium hydroxide solution, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCIWEtOAc: 3/7 to give the title compound a colorless oil (116 mg, 58%). LC/MS: m/z 502 (M+H)⁺, Rt : 3.54 min.

Intermediate 50: 1.1-Dimethylethyl 2-r({5-r(3.4-dichlorophenvnmethyll-4-methyl-1.3- thiazol-2-yl)amino)carbonyl1-7,8-dihvdro-1 ,6-naphthyridine-6(5H)-carboxylate

A solution of 6-{[(1 ,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydro-1 ,6-naphthyridine-2- carboxylic acid (Intermediate 29) (1 12 mg, 0.4 mmol), HATU (167 mg, 0.44 mmol), DIPEA (130 μl_, 0.73 mmol) in DMF (5 ml.) was stirred at room temperature for 45 min. 5-[(3,4- Dichlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-amine (Intermediate 48) (100 mg, 0.37 mmol) was then added and the reaction mixture was stirred at room temperature for 4 days. The volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane. The organic phase was then washed with a 1 N sodium hydroxide solution, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCIWMeOH: 98/2 to give the title compound as a yellow solid (139 mg, 70%). LC/MS: m/z 533 (M+H)⁺, Rt: 4.20 min.

Example 1 : N-{1-r(3,4-Dichlorophenyl)methyll-1 H-pyrazol-4-yl)-5,6,7,8-tetrahvdro-1 ,6- naphthyridine-2-carboxamide hydrochloride

1 ,1-Dimethylethyl 2-[({1-[(3,4-dichlorophenyl)methyl]-1H-pyrazol-4-yl}amino)carbonyl]-7,8- dihydro-1 ,6-naphthyridine-6(5H)-carboxylate (Intermediate 35) (2.07 g, 4.13 mmol) was dissolved in anhydrous ethyl acetate (50 ml.) and hydrogen chloride gas was passed through the solution. The mixture was stirred at room temperature for 24 hours and the resulting precipitate was collected by filtration and washed successively with ethyl acetate and pentane. The solid was then triturated with hot acetonitrile, cooled at 0⁰C and filtered to give the title compound as a pale yellow solid (1.76 g, 96%). ¹H NMR (400 MHz DMSO- d₆, ppm) δ : 10.73 (s, 1 H), 10.02 (br s, 2H), 8.28 (s, 1 H), 7.97 (d, 1 H, J = 8.08 Hz), 7.89 (d, 1 H, J = 8.08 Hz), 7.82 (s, 1 H), 7.61 (d, 1 H, J = 8.34 Hz), 7.51 (d, 1 H, J = 1.77 Hz), 7.22 (dd, 1 H, J = 8.34, 2.02 Hz), 5.35 (s, 2H), 4.38 (s, 2H), 3.5 (s, 2H), 3.25 (t, 2H, J = 6.06 Hz). HRMS calculated for Ci₉H₁₇CI₂N₅O (M+H)⁺ 402.0888, found: 402.0907, Rt: 2.41 min. Example 2: N-{5-r(4-Chlorophenvnmethyll-4-methyl-1.3-thiazol-2-yl}-5.6.7.8-tetrahvdro- 1 ,6-naphthyridine-2-carboxamide hydrochloride

1 ,1-Dimethylethyl 2-[({5-[(4-chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-yl}amino) carbonyl]-7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxylate (Intermediate 36) (1 10 mg, 0.22 mmol) was dissolved in anhydrous ethyl acetate (10 ml.) and hydrogen chloride gas was passed through the solution at 0⁰C. The mixture was stirred at room temperature for 2 hours and the resulting precipitate was collected by filtration and washed with ethyl acetate to give the title compound as a white solid (95 mg, 99%). HRMS calculated for C₂₀H₁₉CIN₄OS (M+H)⁺ 399.1046, found: 399.1021 , Rt: 2.67 min.

The following compounds were similarly prepared by a method analogous to that described for Example 1.

Table 4

carboxamide carboxylate hydrochloride

(Intermediate 42)

1 ,1-Dimethylethyl 2-

[({1-P.4- dichlorophenyl)methyl

N-{1-[(3,4- HRMS (M+H)⁺: ]-5-methyl-1 H-1 ,2,3- dichlorophenyl)methyl]- calculated for triazol-4-

5-methyl-1 H-1 ,2,3- Ci₉H₁₈CI₂N₆O yl}amino)carbonyl]- triazol-4-yl}-5,6,7,8- Theo: 417.0997

7,8-dihydro-1 ,6- tetrahydro-1 ,6-

Found: 417.0992 naphthyridine-6(5H)- naphthyridine-2- Rt: 2.43min carboxylate carboxamide hydrochloride

(Intermediate 43)

Example 10: 1-r(3.4-DichloroDhenyl)methyll-5-methyl-Λ/-(5.6.7.8-tetrahvdro-1.6- naphthyridin-2-yl)-1 H- 1 ,2,3-triazole-4-carboxamide hydrochloride

i .i-Dimethylethy^-^i-p^-dichlorophenyOmethyO-δ-methyl-I H-I ^.S-triazoM- yl}carbonyl)amino]-7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxylate (Intermediate 44) (66 mg, 0.13 mmol) was dissolved in anhydrous ethyl acetate (10 ml.) and hydrogen chloride gas was passed through the solution at 0⁰C. The mixture was stirred at room temperature overnight and the resulting precipitate was collected by filtration and washed with diethyl ether to give after recristallisation in methyl alcohol the title compound as a white solid (19 mg, 33%). HRMS calculated for C₁₉H₁₈CI₂N₆O (M+H)⁺ 417.0997, found: 417.0968, Rt: 2.5 min.

Example 11 : 1-r(3,4-Dichlorophenyl)methyll-Λ/-(5,6,7,8-tetrahvdro-1 ,6-naphthyridin-2-yl)- 1 H-pyrazole-4-carboxamide hydrochloride

1 ,1-Dimethylethyl 2-[({1-[(3,4-dichlorophenyl)methyl]-1H-pyrazol-4-yl}carbonyl)amino]-7,8- dihydro-1 ,6-naphthyridine-6(5H)-carboxylate (Intermediate 49) (116 mg, 0.23 mmol) was dissolved in anhydrous ethyl acetate (5 ml.) and hydrogen chloride gas was passed through the solution at 0⁰C. The mixture was stirred at room temperature overnight and the resulting precipitate was collected by filtration and recrystallized from ethanol to give the title compound as a cream solid (35 mg, 30%). HRMS calculated for Ci₉H₁₇CI₂N₅O (M+H)⁺ 402.0888, found: 402.0882, Rt: 2.38 min.

Example 12: : /V-{5-r(3.4-Dichlorophenvnmethyll-4-methyl-1.3-thiazol-2-yl}-5.6.7.8- tetrahvdro-1 ,6-naphthyridine-2-carboxamide hydrochloride

1 ,1-Dimethylethyl 2-[({5-[(3,4-dichlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-yl}amino) carbonyl]-7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxylate (Intermediate 50) (139 mg, 0.26 mmol) was dissolved in anhydrous ethyl acetate (10 ml.) and hydrogen chloride gas was passed through the solution at 0⁰C. The mixture was stirred at room temperature for 4 hours and the resulting precipitate was collected by filtration and washed successively with diisopropyl ether and ethanol to give the title compound as a cream solid (99 mg, 81 %). HRMS calculated for C₂₀H₁₈CI₂N₄OS (M+H)⁺ 433.0656, found: 433.0653, Rt: 2.77 min.

BIOLOGICAL ASSAY

The compounds of the present invention may be analysed in vitro for SCD activity using an assay based on the production of [³H]H₂O, which is released during the enzyme- catalyzed generation of the monounsaturated fatty acyl CoA product. The assay is performed in a 96-well filtration plates. The titrated substrate used in the assay is the [9,10-³H] stearoyl Coenzyme A. After incubation for 6 minutes of SCD-containing rat microsomes (2 μg protein) and substrate (1 μM), the labelled fatty acid acyl-CoA species and microsomes are absorbed with charcoal and separated from [³H]H₂O by centrifugation. The formation of [³H]H₂O is used as a measure of SCD activity. Compounds at concentrations starting at 10 μM to 0.1 nM or vehicle (DMSO) are preincubated for 5 minutes with the microsomes before addition of the substrate. The concentration-responses are fitted with sigmoidal curves to obtain IC₅₀ values.

All of the synthetic Example compounds 1-12 tested by the above described in vitro assay for SCD activity were found to exhibit an average pi C₅₀ value of greater than 5.5.

Claims

Claims

1. A compound of formula (I):

wherein:

X represents -CONH- or -NHCO-,

R¹ represents:

(i) a substituent selected from: H, -C_1-6alkyl, -C_3-6cycloalkyl or -Cs-ecycloalkenyl, (N) -C₆-ioaryl optionally substituted by one, two or three groups independently selected from: (a) -C_1-6alkyl, -C_1-6alkoxy, -C_1-6haloalkyl, -Cs-ecycloalkyl, -OC_1-6haloalkyl, -CN, or halogen,

(b) -C_6-ioaryl, -C_5-ioheteroaryl or -Cs-ioheterocyclyl, wherein the -C_6-ioaryl, -C_{5- 10}heteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -Ci_-6alkyl, -Ci_-6alkoxy, -Ci_-6haloalkyl or halogen,

Y represents -CH₂- or -OCH₂-, and

W represents a -C_5-ioheteroaryl optionally substituted by one, two or three -C_1-6alkyl groups,

or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 wherein X represents -NHCO-.

3. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 or claim 2 wherein R¹ represents -Cβ-ioaryl optionally substituted by: one, two or three groups independently selected from: -C_1-6alkyl, -C_1-6alkoxy, -C_1-6haloalkyl, -C_{3- 6}cycloalkyl, -OC_1-6haloalkyl, -CN or halogen.

4. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 wherein Y represents -CH₂-.

5. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 wherein W represents a -C₅heteroaryl optionally substituted by - Ci_-3alkyl.

6. A compound of formula (I) according to claim 1 selected from:

Λ/-{1-[(3,4-dichlorophenyl)methyl]-1 /-/-pyrazol-4-yl}-5,6,7,8-tetrahydro-1 ,6-naphthyridine-2- carboxamide,

Λ/-{5-[(4-chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-yl}-5_!6_!7_!8-tetrahydro-1 ,6- naphthyridine-2-carboxamide, Λ/-(4-methyl-5-{[4-(trifluoromethyl)phenyl]methyl}-1 _!3-thiazol-2-yl)-5_!6_!7_!8-tetrahydro-1 ,6- naphthyridine-2-carboxamide,

Λ/-(4-methyl-5-{[3-(trifluoromethyl)phenyl]methyl}-1 _!3-thiazol-2-yl)-5_!6_!7_!8-tetrahydro-1 ,6- naphthyridine-2-carboxamide,

Λ/-(5-{[4-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide,

Λ/-(5-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide,

Λ/-(5-{[(2-chlorophenyl)oxy]methyl}-1 ,3_!4-thiadiazol-2-yl)-5_!6_!7_!8-tetrahydro-1 ,6- naphthyridine-2-carboxamide, Λ/-[1 -({5-chloro-2-[(2-methylpropyl)oxy]phenyl}methyl)-5-methyl-1 /-/-pyrazol-3-yl]-5,6,7,8- tetrahydro-1 ,6-naphthyridine-2-carboxamide,

Λ/-{1-[(3,4-dichlorophenyl)methyl]-5-methyl-1 H-1 ,2,3-triazol-4-yl}-5,6,7,8-tetrahydro-1 ,6- naphthyridine-2-carboxamide,

1-[(3,4-dichlorophenyl)methyl]-5-methyl-Λ/-(5,6,7,8-tetrahydro-1 ,6-naphthyridin-2-yl)-1 H- 1 ,2,3-triazole-4-carboxamide,

1-[(3,4-dichlorophenyl)methyl]-Λ/-(5_!6_!7_!8-tetrahydro-1 ,6-naphthyridin-2-yl)-1 /-/-pyrazole-4- carboxamide, and

Λ/-{5-[(3,4-dichlorophenyl)methyl]-4-methyl-1 _!3-thiazol-2-yl}-5_!6_!7_!8-tetrahydro-1 ,6- naphthyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 together with at least one pharmaceutical carrier and/or excipient.

8. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for use in therapy.

9. Use of a compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for the manufacture of a medicament for treating and/or preventing a disease or a condition susceptible to amelioration by an SCD inhibitor.

10. Use of a compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 9 for the manufacture of a medicament for treating and/or preventing diseases or conditions caused by or associated with an abnormal plasma lipid profile including dyslipidemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, atherosclerosis, obesity, Type I diabetes, Type Il diabetes, insulin resistance, hyperinsulinaemia and metabolic syndrome; peripheral vascular disease, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, thrombosis, hepatic steatosis, non-alcoholic steatohepatitis (NASH) and other diseases related to accumulation of lipids in the liver; eczema, acne, psoriasis, skin ageing, keloid scar formation or prevention, and diseases related to production or secretions from mucous membranes; cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like; mild cognitive impairment (MCI), Alzheimer's Disease (AD), cerebral amyloid angiopathy (CAA) or dementia associated with Down Syndrome (DS) and other neurodegenerative diseases characterized by the formation or accumulation of amyloid plaques comprising Aβ42.

1 1. Use of a compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 9 for the manufacture of a medicament for treating and/or preventing acne, psoriasis, skin ageing, cancer, dyslipidemia, hypertriglyceridemia, atherosclerosis, obesity, Type Il diabetes, insulin resistance, hyperinsulinaemia, hepatic steatosis and/or non-alcoholic steatohepatitis (NASH).

12. Use of a compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 9 for the manufacture of a medicament for treating and/or preventing acne.

13. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for use in treating and/or preventing a disease or a condition susceptible to amelioration by an SCD inhibitor.

14. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 13 for use in treating and/or preventing diseases or conditions caused by or associated with an abnormal plasma lipid profile including dyslipidemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, atherosclerosis, obesity, Type I diabetes, Type Il diabetes, insulin resistance, hyperinsulinaemia and metabolic syndrome; peripheral vascular disease, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, thrombosis, hepatic steatosis, non-alcoholic steatohepatitis (NASH) and other diseases related to accumulation of lipids in the liver; eczema, acne, psoriasis, skin ageing, keloid scar formation or prevention, and diseases related to production or secretions from mucous membranes; cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like; mild cognitive impairment (MCI), Alzheimer's Disease (AD), cerebral amyloid angiopathy (CAA) or dementia associated with Down Syndrome (DS) and other neurodegenerative diseases characterized by the formation or accumulation of amyloid plaques comprising Aβ42.

15. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 13 for use in treating and/or preventing acne, psoriasis, skin ageing, cancer, dyslipidemia, hypertriglyceridemia, atherosclerosis, obesity, Type Il diabetes, insulin resistance, hyperinsulinaemia, hepatic steatosis and/or non-alcoholic steatohepatitis (NASH).

16. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 13 for use in treating and/or preventing acne.

17. A method of treating and/or preventing a disease or a condition susceptible to amelioration by an SCD comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

18. A method of treating and/or preventing diseases or conditions caused by or associated with an abnormal plasma lipid profile including dyslipidemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, atherosclerosis, obesity, Type I diabetes, Type Il diabetes, insulin resistance, hyperinsulinaemia and metabolic syndrome; peripheral vascular disease, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, thrombosis, hepatic steatosis, non-alcoholic steatohepatitis (NASH) and other diseases related to accumulation of lipids in the liver; eczema, acne, psoriasis, keloid scar formation or prevention, and diseases related to production or secretions from mucous membranes; cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like; mild cognitive impairment (MCI), Alzheimer's Disease (AD), cerebral amyloid angiopathy (CAA) or dementia associated with Down Syndrome (DS) and other neurodegenerative diseases characterized by the formation or accumulation of amyloid plaques comprising Aβ42 comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 17.

19. A method of treating and/or preventing acne, psoriasis, skin ageing, cancer, dyslipidemia, hypertriglyceridemia, atherosclerosis, obesity, Type Il diabetes, insulin resistance, hyperinsulinaemia, hepatic steatosis and/or non-alcoholic steatohepatitis (NASH) comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 17.

20. A method of treating and/or preventing acne comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 17.

21. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in combination with one or more active agent(s) selected from an inhibitor of cholesteryl ester transferase (CETP inhibitors), a HMG-CoA reductase inhibitor, a microsomal triglyceride transfer protein, a peroxisome proliferator-activated receptor activator (PPAR), a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an inhibitor of AcylCoA: cholesterol acyltransferase (ACAT inhibitor), a cannabinoid 1 antagonist, and a bile acid sequestrant,

22. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in combination with one or more active agent(s) selected from a corticosteroid, a vitamin D3 derivative, a retinoid, an immunomodulator, an anti androgen, a keratolytic agent, an anti-microbial, a platinum chemotherapeutic, an antimetabolite, hydroxyurea, a taxane, a mitotic disrupter, an anthracycline, dactinomycin, an alkylating agent and a cholinesterase inhibitor.