WO2009150196A1

WO2009150196A1 - N-thiazolyl-1, 2, 3, 4-tetrahydro-6-isoquinolinecarboxamide derivatives as inhibitors of stearoyl coenzyme a desaturase

Info

Publication number: WO2009150196A1
Application number: PCT/EP2009/057227
Authority: WO
Inventors: Alain Claude-Marie Daugan; Anthony William Dean; Martin Christian Fillmore
Original assignee: Smithkline Beecham Corporation
Priority date: 2008-06-13
Filing date: 2009-06-11
Publication date: 2009-12-17
Also published as: GB0810913D0

Abstract

The present invention relates to substituted thiazole compounds of the formula (I) wherein Z represents (A), (B), (C) and (D) where * represents the point of attachment 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

N-THIAZOLYL-1 , 2 , 3 , ^TETRAHYDRO-e-ISOQUINOLINECARBOXAMIDE DERIVATIVES AS INHIBITORS OF STEAROYL COENZYME A DESATURASE

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), 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).

WO2005/011657 describes certain piperazine derivatives useful for inhibiting SCD activity.

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

(I) wherein Z represents:

where ^* represents the point of attachment

when Z represents (A) or (B) then R¹ represents: (i) H or -C_1-6alkyl, (ii) -C₆-ioaryl (such as phenyl or napthyl) optionally substituted by one, two or three groups independently selected from:

(a) -C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C^ecycloalkyl, -C_1- ₆alkoxy (such as -OCH₃ or -OCH₂CH(CH₃)₂), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro), (b) -C₆-ioaryl (such as phenyl), -C_5-10heteroaryl or -Cs-ioheterocyclyl, wherein the -C_6-ioaryl, -C_5-ioheteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -Ci- ₆alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C^ecycloalkyl, -C_1- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

(iii) -C_5-1oheteroaryl or -Cs-ioheterocyclyl wherein the -C_5-10heteroaryl or -C_5- ioheterocyclyl is optionally substituted by one, two or three groups independently selected from:

(a) -C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C^ecycloalkyl, -C_1- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

(b) -C_6-ioaryl (such as phenyl), -C_5-10heteroaryl or -Cs-ioheterocyclyl wherein the -C_6-ioaryl, -C_5-ioheteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -Ci- ₆alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C^ecycloalkyl, -C_1- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

Y represents -(CH₂)_m- or -CONHCH₂-, R² represents H, -C_1-6alkyl (such as -CH₃, -C₂H₄ or -C₃H₇) or -Cs-ecycloalkyl, R³ represents -C_1-6haloalkyl (such as -CF₃) or -C_3-6CyClOaIkYl, and m represents 1 or 2,

when Z represents (C) or (D) then R¹ represents:

(i) -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_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -

OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro), (b) -C₆-ioaryl (such as phenyl), -C_5-10heteroaryl or -Cs-ioheterocyclyl, wherein the -C_6-ioaryl, -C_5-i₀heteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -Ci- ₆alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -C_1- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

(ii) -C_5-1oheteroaryl or -Cs-ioheterocyclyl wherein the -C_5-1oheteroaryl or -C_5- ioheterocyclyl is optionally substituted by one, two or three groups independently selected from:

(a) -C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -C_1- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

(b) -C_6-ioaryl (such as phenyl), -C_5-10heteroaryl or -Cs-ioheterocyclyl wherein the -C_6-ioaryl, -C_5-i₀heteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -Ci- ₆alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -C_1- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro), Y represents -(CH₂)_m-,

R² represents H, -C_1-6alkyl (such as -CH₃ or -C₂H₄) or -Cs-ecycloalkyl, R³ represents, -Ci_-6haloalkyl (such as -CF₃) or -Cs-ecycloalkyl, and m represents O, 1 or 2,

or a salt thereof.

The said compounds have been found to inhibit SCD activity and may therefore be useful in the treatment of SCD-mediated diseases, 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, non-alcoholic 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, when Z represents (A) or (B) R¹ represents:

(ii) -C₆-ioaryl (such as phenyl or napthyl) optionally substituted by one, two or three groups independently selected from: (a) -Ci_-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -Ci- ₆alkoxy (such as -OCH₃ or -OCH₂CH(CH₃)₂), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

(b) -C₆-ioaryl (such as phenyl), -C₅-ioheteroaryl or -C_5-ioheterocyclyl, wherein the -C_6-ioaryl, -C_5-10heteroaryl or -C_5-1oheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -Ci- ₆alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -Ci- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

(iii) -C₅-ioheteroaryl or -C₅-ioheterocyclyl wherein the -C_5-ioheteroaryl or -C_5- ioheterocyclyl is optionally substituted by one, two or three groups independently selected from:

(a) -Ci_-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -Ci- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro), (b) -C_6-ioaryl (such as phenyl), -C₅-ioheteroaryl or -Cs-ioheterocyclyl wherein the -C_6-ioaryl, -C_5-i₀heteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -Ci- ₆alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -Ci- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B): 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_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -Ci_-6alkoxy

(such as -OCH₃ or -OCH₂CH(CH₃)₂), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro), (b) -C_6-ioaryl (such as phenyl) optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as - CF₃), -Cs-ecycloalkyl, -Ci_-6alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B):

R¹ represents -C_6-ioaryl (such as phenyl or napthyl) optionally substituted by: one or two groups independently selected from:

(a) -Ci_-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -Ci_-6alkoxy (such as -OCH₃ or -OCH₂CH(CH₃)₂), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

(b) -C_6-ioaryl (such as phenyl) optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as - CF₃), -Cs-ecycloalkyl, -Ci_-6alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B): R¹ represents phenyl optionally substituted by: one, two or three groups independently selected from: (a) -Ci_-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -Ci_-6alkoxy

(such as -OCH₃ or -OCH₂CH(CH₃)₂), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro), (b) -C_6-ioaryl (such as phenyl) optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as - CF₃), -Cs-ecycloalkyl, -C_1-6alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen

(such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B): R¹ represents phenyl optionally substituted by: one or two groups independently selected from:

(a) -C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -C_1-6alkoxy (such as -OCH₃ or -OCH₂CH(CH₃)₂), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

(b) -C_6-ioaryl (such as phenyl) optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -

CF₃), -Cs-ecycloalkyl, Ci_-6alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B): R¹ represents phenyl optionally substituted by one, two or three groups independently selected from: -Ci_-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -Ci_-6alkoxy (such as -OCH₃ or -OCH₂CH(CH₃)₂), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro). In another aspect of the invention, when Z represents (A) or (B): R¹ represents phenyl optionally substituted by one or two groups independently selected from: -C_1-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -C_1-6alkoxy (such as -OCH₃ or -OCH₂CH(CH₃)₂), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B): R¹ represents phenyl optionally substituted by one, two or three groups independently selected from: -Ci_-3alkyl (such as -CH₃), -Ci_-3haloalkyl (such as -CF₃), -C_1-3alkoxy (such as -OCH₃), -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B): R¹ represents phenyl optionally substituted by one or two groups independently selected from: -C_1-3alkyl (such as -CH₃), -Ci_-3haloalkyl (such as -CF₃), -Ci_-3alkoxy (such as -OCH₃), -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B): R¹ represents phenyl optionally substituted by one or two groups independently selected from: -C_1-3haloalkyl (such as -CF₃), -C_1-3alkoxy (such as -OCH₃), -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B): R¹ represents phenyl optionally substituted by one, two or three groups independently selected from: -CH₃, -CF₃, -OCH₃, -OCH₂CH(CH₃)₂, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B): R¹ represents phenyl optionally substituted by one or two groups independently selected from: -CH₃, -CF₃, -OCH_3, -OCH₂CH(CH₃)₂, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B): R¹ represents phenyl optionally substituted by one or two groups independently selected from: -CF₃, -OCH₃, -OCH₂CH(CH₃)₂, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B), R¹ represents phenyl.

In one aspect of the invention, when Z represents (C) or (D) R¹ represents:

(ii) -C₆-ioaryl (such as phenyl or napthyl) optionally substituted by one, two or three groups independently selected from: (a) -C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C_3-6CyClOaIkYl, - OR³, -CN, -NO2 or halogen (such as chloro, bromo or fluoro),

(b) -C_6-ioaryl (such as phenyl), -C_5-i₀heteroaryl or -Cs-ioheterocyclyl, wherein the -C_6-ioaryl, -C_5-10heteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -Ci- ₆alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -Ci- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

(iii) -C₅-ioheteroaryl or -C₅-ioheterocyclyl wherein the -C_5-i₀heteroaryl or -C_5- ioheterocyclyl is optionally substituted by one, two or three groups independently selected from:

(a) -Ci_-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -Ci- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro), (b) -C_6-ioaryl (such as phenyl), -C_5-i₀heteroaryl or -Cs-ioheterocyclyl wherein the -C_6-ioaryl, -C_5-i₀heteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -Ci- ₆alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -Ci- ₆alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D): R¹ represents -Cβ-ioaryl (such as phenyl or napthyl) optionally substituted by: one, two or three groups independently selected from: (a) -Ci_-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -OR³, -CN,

-NO₂ or halogen (such as chloro, bromo or fluoro),

(b) -C_6-ioaryl (such as phenyl) optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as - CF₃), -Cs-ecycloalkyl, -Ci_-6alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D): R¹ represents -C_6-ioaryl (such as phenyl or napthyl) optionally substituted by: one or two groups independently selected from: (a) -Ci_-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -OR³, -CN,

-NO₂ or halogen (such as chloro, bromo or fluoro),

In another aspect of the invention, when Z represents (C) or (D): R¹ represents phenyl optionally substituted by: one, two or three groups independently selected from:

(a) -Ci_-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -C_3-6CyClOaIkVl, -OR³, -CN,

-NO₂ or halogen (such as chloro, bromo or fluoro), (b) -C_6-ioaryl (such as phenyl) optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -

CF₃), -Cs-ecycloalkyl, -C_1-6alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen

(such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D):

R¹ represents phenyl optionally substituted by: one or two groups independently selected from: (a) -C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -OR³, -

CN, -NO₂ or halogen (such as chloro, bromo or fluoro), (b) -C_6-ioaryl (such as phenyl) optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as - CF₃), -Cs-ecycloalkyl, Ci_-6alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D):

R¹ represents phenyl optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D):

R¹ represents phenyl optionally substituted by one or two groups independently selected from: -C_1-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D):

R¹ represents phenyl optionally substituted by one, two or three groups independently selected from: -Ci_-3alkyl (such as -CH₃), -Ci_-3haloalkyl (such as -CF₃), -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D):

R¹ represents phenyl optionally substituted by one or two groups independently selected from: -C_1-3alkyl (such as -CH₃), -C_1-3haloalkyl (such as -CF₃), -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D):

R¹ represents phenyl optionally substituted by one or two groups independently selected from: -Ci_-3haloalkyl (such as -CF₃), -NO₂ or halogen (such as chloro, bromo or fluoro). In another aspect of the invention, when Z represents (C) or (D): R¹ represents phenyl optionally substituted by one, two or three groups independently selected from: -CH₃, -CF₃, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D):

R¹ represents phenyl optionally substituted by one or two groups independently selected from: -CH₃, -CF₃, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D):

R¹ represents phenyl optionally substituted by one or two groups independently selected from: -CF₃, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D), R¹ represents phenyl.

In another aspect of the invention, when Z represents (A) or (B): R¹ represents naphthyl optionally substituted by: one, two or three groups independently selected from: (a) -Ci_-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -Cs-ecycloalkyl, -Ci_-6alkoxy

(such as -OCH₃ or -OCH₂CH(CH₃)₂), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro), (b) -C_6-ioaryl (such as phenyl) optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as - CF₃), -C_3-6CyClOaIkVl, C_1-6alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen

(such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B): R¹ represents naphthyl optionally substituted by: one, two or three groups independently selected from:

-C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -C_1-6alkoxy (such as -OCH₃ or -OCH₂CH(CH₃)₂), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (A) or (B), R¹ represents naphthyl.

In another aspect of the invention, when Z represents (C) or (D): In another aspect of the invention, R¹ represents naphthyl optionally substituted by: one, two or three groups independently selected from:

(a) -Ci-ealkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro), (b) -C_6-ioaryl (such as phenyl) optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as - CF₃), -Cs-ecycloalkyl, Ci_-6alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D):

R¹ represents naphthyl optionally substituted by: one, two or three groups independently selected from:

-Ci_-6alkyl (such as -CH₃), -Ci_-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -OR³, -CN, - NO₂ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D), R¹ represents naphthyl.

In another aspect of the invention, when Z represents (A) or (B):

R¹ represents -C_5-10heteroaryl or -Cs-ioheterocyclyl wherein the -C_5-10heteroaryl or -C_5- -_loheterocyclyl is optionally substituted by one, two or three groups independently selected from:

(a) -C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -C_1-6alkoxy (such as -OCH₃), -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

(b) -C_6-ioaryl (such as phenyl), -C_5-i₀heteroaryl or -Cs-ioheterocyclyl wherein the -C_6- ₁₀aryl, -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- ₆haloalkyl (such as -CF₃), -Ci_-6alkoxy (such as -OCH₃), -OR³, -CN or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, when Z represents (C) or (D): R¹ represents -C_5-10heteroaryl or -Cs-ioheterocyclyl wherein the -C_5-10heteroaryl or -C_5- -_loheterocyclyl is optionally substituted by one, two or three groups independently selected from:

(a) -C_1-6alkyl (such as -CH₃), -C_1-6haloalkyl (such as -CF₃), -C_3-6cycloalkyl, -OR³, -CN, -NO₂ or halogen (such as chloro, bromo or fluoro),

In one aspect of the invention, when Z represents (A) or (B), Y represents -CH₂- (methylene). In another aspect of the invention, when Z represents (A) or (B), Y represents -C₂H₄- (ethylene). In another aspect of the invention, when Z represents (A) or (B), Y represents -CONHCH₂-. In one aspect of the invention, when Z represents (C) or (D), Y represents -CH₂- (methylene). In another aspect of the invention, when Z represents (C) or (D), Y is absent.

In one aspect of the invention, when Z represents (A) or (B), m represents 1. In another aspect of the invention, when Z represents (A) or (B), m represents 2.

In one aspect of the invention, when Z represents (C) or (D), m represents 0. In another aspect of the invention, when Z represents (C) or (D), m represents 1.

In one aspect of the invention, when Z represents (A), (B), (C) or (D), R² represents hydrogen or -C_halky!. In another aspect of the invention, when Z represents (A), (B), (C) or (D), R² represents hydrogen or -C_1-3alkyl. In another aspect of the invention, when Z represents (A), (B), (C) or (D), R² represents hydrogen or methyl (-CH₃). In another aspect of the invention, when Z represents (A), (B), (C) or (D), R² represents hydrogen. In another aspect of the invention, when Z represents (A), (B), (C) or (D), R² represents -Ci_-3alkyl. In another aspect of the invention, when Z represents (A), (B), (C) or (D), R² represents methyl (-CH₃). In another aspect of the invention, when Z represents (A), (B), (C) or (D), R² represents ethyl (-C₂H₅). In another aspect of the invention, when Z represents (A), (B), (C) or (D), R² represents propyl (-C₃H₇). In another aspect of the invention, when Z represents (A), (B), (C) or (D), R² represents -C_3-6cycloalkyl.

In one aspect of the invention, when Z represents (A), (B), (C) or (D), R³ represents - C_1-6haloalkyl. In another aspect of the invention, when Z represents (A), (B), (C) or (D), R³ represents -C_3-6cycloalkyl.

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 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 Y represents -CH₂- and R² represents H.

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 10 carbon ring-atoms, such as 3 to 6 carbon ring-atoms. Examples include cyclopropyl, cyclopentyl and cyclohexyl.

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. benzothiophene. 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 'aryl' means an aromatic carbocyclic moiety. 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 naphthyl, and more specifically phenyl.

As used herein, the term "-C_5-ioheterocyclyl" 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, wherein said cyclic group is saturated, partially or fully unsaturated but, which is not aromatic. This definition includes bicyclic structures provided the moiety is non-aromatic.

Examples of heterocyclyl and heteroaromatic 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.

In one aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof.

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 in the blood, 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. 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 hydroxy 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).

Phosphonates and carbamates may be active in their own right and/or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt. A phosphonate is formed by reaction with phosphorous (phosphonic) acid, by methods well known in the art. For example, phosphonates may be derivatives such as RP(O)(OR)₂ and the like. A carbamate is an ester of carbamic acid.

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:

N-{5-[(4-chlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-[5-(phenylmethyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide,

N-[4-methyl-5-(phenylmethyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-{5-[(4-chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-{5-[(3-chlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, N-{5-[(3-chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride

N-(4-methyl-5-{[2-(methyloxy)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-(4-methyl-5-{[4-(methyloxy)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-(4-methyl-5-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-

6-isoquinolinecarboxamide,

N-(5-{[4-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, N-(4-methyl-5-{[4-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-

6-isoquinolinecarboxamide,

N-{5-[(3,4-dichlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, N-{5-[(2-chlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-{5-[(2_!5-dichlorophenyl)methyl]-1 _!3-thiazol-2-yl}-1 _!2_!3,4-tetrahydro-6- isoquinolinecarboxamide, N-{5-[(4-cyanophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-^i-naphthalenylmethyO-I .S-thiazol^-yO-I ^.S^-tetrahydro-θ- isoquinolinecarboxamide,

N-{5-[(3_!4-dichlorophenyl)methyl]-4-methyl-1 _!3-thiazol-2-yl}-1 _!2_!3,4-tetrahydro-6- isoquinolinecarboxamide,

N-(5-{[3-(trifluoromethyl)phenyl]methyl}-1 _!3-thiazol-2-yl)-1 _!2_!3,4-tetrahydro-6- isoquinolinecarboxamide,

N-[4-methyl-5-(1-naphthalenylmethyl)-1 _!3-thiazol-2-yl]-1 _!2_!3,4-tetrahydro-6- isoquinolinecarboxamide, N-{5-[(4-chlorophenyl)methyl]-4-ethyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-{5-[(4-chlorophenyl)methyl]-4-propyl-1 _!3-thiazol-2-yl}-1 _!2_!3,4-tetrahydro-6- isoquinolinecarboxamide,

N-[4-methyl-5-({2-[(2-methylpropyl)oxy]phenyl}methyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4- tetrahydro-6-isoquinolinecarboxamide,

N-[5-(2-phenylethyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide,

N-(5-methyl-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide,

N-{5-[(3-nitrophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, N-(4-methyl-5-{[(phenylmethyl)amino]carbonyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-(5-butyl-4-methyl-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide,

N-{2-[(4-chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-5-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, N-{4-[(3-nitrophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-(5-ethyl-4-phenyl-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide,

N-{4-[(3-chlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, N-(5-methyl-4-phenyl-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide,

N-(5-methyl-4-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-

6-isoquinolinecarboxamide,

N-{4-[(4-chlorophenyl)methyl]-5-methyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, N-(2-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-4-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, or

N-(4-methyl-5-{[(phenylmethyl)amino]carbonyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide. In another aspect of the invention there is provided a compound, selected from the group consisting of:

N-{5-[(4-chlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-[4-methyl-5-(phenylmethyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-{5-[(4-chlorophenyl)methyl]-4-methyl-1 _!3-thiazol-2-yl}-1 ,2_!3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-{5-[(3-chlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-{5-[(3-chlorophenyl)methyl]-4-methyl-1 _!3-thiazol-2-yl}-1 ,2_!3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride, N-(4-methyl-5-{[2-(methyloxy)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-(4-methyl-5-{[4-(methyloxy)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-(4-methyl-5-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro- 6-isoquinolinecarboxamide hydrochloride,

N-(5-{[4-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-(4-methyl-5-{[4-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-

6-isoquinolinecarboxamide hydrochloride, N-{5-[(3,4-dichlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-{5-[(2-chlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-{5-[(2,5-dichlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-{5-[(4-cyanophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-[5-(1-naphthalenylmethyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride, N-{5-[(3,4-dichlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-(5-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-[4-methyl-5-(1-naphthalenylmethyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-{5-[(4-chlorophenyl)methyl]-4-ethyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride, N-{5-[(4-chlorophenyl)methyl]-4-propyl-1 _!3-thiazol-2-yl}-1 _!2_!3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-[4-methyl-5-({2-[(2-methylpropyl)oxy]phenyl}methyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4- tetrahydro-6-isoquinolinecarboxamide hydrochloride, N-[5-(2-phenylethyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide hydrochloride,

N-(5-methyl-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide hydrochloride,

N-{5-[(3-nitrophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-(4-methyl-5-{[(phenylmethyl)amino]carbonyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-(5-butyl-4-methyl-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide hydrochloride, N-{2-[(4-chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-5-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-{4-[(3-nitrophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-(5-ethyl-4-phenyl-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide hydrochloride,

N-{4-[(3-chlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-(5-methyl-4-phenyl-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide hydrochloride, N-(5-methyl-4-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-

6-isoquinolinecarboxamide hydrochloride,

N-{4-[(4-chlorophenyl)methyl]-5-methyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride,

N-(2-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-4-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride, or

N-(4-methyl-5-{[(phenylmethyl)amino]carbonyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide.

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 a 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, R², R³, Z 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.

When Z is (A) compounds of formula (I) may be prepared by the following schemes:

In a general process, compounds of 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 in a suitable solvent such as 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

Compounds of formula (III), wherein Y represents -(CH₂)_m- and m represents 1 or 2, may be prepared according to reaction scheme 2 by reacting compounds of formula (V), 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 2

(V) (III)

Compounds of formula (V), wherein L¹ represents a halogen such as bromine and Y represents -(CH₂)_m- and m represents 1 or 2, may be prepared according to reaction scheme 3 by reacting compounds of formula (Vl) with a brominating agent such as pyridium tribromide in a suitable solvent such as THF suitably at 0⁰C to room temperature, or bromine in a suitable solvent such as chloroform suitably at room temperature.

Scheme 3

(Vl) (V) Compounds of formula (V), wherein L¹ represents a halogen such as chlorine and in which Y represents -(CH₂)_m- and m represents 1 , may also be prepared according to reaction scheme 4 by reacting compounds of formula (VII) with a compound of formula (VIII) in the presence of a copper salt such as CuCI₂ in a suitable solvent such as toluene (suitably at 10⁰C to 30⁰C).

Scheme 4

Compounds of formula (III) in which Y represents -(CH₂)_m- and m represents 1 , may also be prepared according to reaction scheme 5 by reacting compounds of formula (IX) with an aldehyde of formula (X) 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 (Xl) with triethylsilane and trifluoroacetic acid in a suitable solvent such as dichloromethane (suitably at room temperature).

Scheme 5

When Z is (B) compounds of formula (I) may be prepared by the following schemes:

In a general process, compounds of formula (Ib) may be prepared according to reaction scheme 6 by reacting compounds of formula (XIII) and compounds of formula (IV), wherein P¹ represents a suitable nitrogen protecting group such as Boc, to form a compound of formula (XII). The reaction is suitably carried out in the presence of a coupling reagent such as EDCI in a suitable solvent such as DCM

(suitably at room temperature), and is followed by deprotection of compound of formula (XII) under acidic conditions such as hydrochloric acid in a suitable solvent such as ethyl acetate at room temperature.

Scheme 6

Compounds of formula (XIII), may be prepared according to reaction scheme 7 by reacting compounds of formula (XIV) with DPPA in the presence of tert butanol suitably at reflux temperature, followed by deprotection of compound of formula (XV) under acidic conditions such as hydrochloric acid in a suitable solvent such as ethyl acetate at room temperature.

Scheme 7

Compounds of formula (XIV), may be prepared according to reaction scheme 8 by reacting compounds of formula (XVI) with ethyl 2-chloro-3-oxobutanoate in a suitable solvent such as ethanol suitably at reflux temperature, followed by saponification of compounds of formula (XVII) in the presence of sodium hydroxide in a suitable solvent such as ethanol at reflux temperature.

Scheme 8

When Z is (C) compounds of formula (I) may be prepared by the following schemes:

In a general process, compounds of formula (Ic) may be prepared according to reaction scheme 9 by reacting compounds of formula (XIX) and compounds of formula (IV), wherein P¹ represents a suitable nitrogen protecting group such as Boc, to form a compound of formula (XVIII). The reaction is suitably carried out in the presence of a coupling reagent such as EDCI in a suitable solvent such as DCM (suitably at room temperature), and is followed by deprotection of compound of formula (XVIII) under acidic conditions such as hydrochloric acid in a suitable solvent such as ethyl acetate at room temperature.

Scheme 9

Compounds of formula (XIX) may be prepared according to reaction scheme 10 by reacting compounds of formula (XX) with thiourea in a suitable solvent such as ethanol suitably at room temperature to 60⁰C.

Scheme 10

(XX)

When Z is (D) compounds of formula (I) may be prepared by the following schemes:

In a general process, compounds of formula (Id) may be prepared according to reaction scheme 1 1 by reacting compounds of formula (XXII) and compounds of formula (IV), wherein P¹ represents a suitable nitrogen protecting group such as Boc, to form a compound of formula (XXI). The reaction is suitably carried out in the presence of a coupling reagent such as EDCI in a suitable solvent such as DCM (suitably at room temperature), and is followed by deprotection of compound of formula (XXI) under acidic conditions such as hydrochloric acid in a suitable solvent such as ethyl acetate at room temperature. Scheme 11

Compounds of formula (XXII) may be prepared according to reaction scheme 12 by reacting compounds of formula (XXIII) with DPPA in the presence of tert butanol suitably at reflux temperature, followed by deprotection of compound of formula (XXIV) under acidic conditions such as hydrochloric acid in a suitable solvent such as ethyl acetate at room temperature.

Scheme 12

(XXlIl) (XXIV) (XXII)

When Z is (A) and Y represents -CONHCH₂- compounds of formula (I) may be prepared by the following scheme:

In a general process, compounds of formula (Ie) may be prepared according to reaction scheme 13 by reacting compounds of formula (XXV) and compounds of formula (IV), wherein P¹ represents a suitable nitrogen protecting group such as Boc, to form a compound of formula (XXVI). The reaction is suitably carried out in the presence of a coupling reagent such as HATU in a suitable solvent such as DMF (suitably at room temperature to 80⁰C), and is followed by hydrolysis of compound of formula (XXVI) under basic conditions such as sodium hydroxide in a suitable solvent such as ethanol to form a compound of formula (XXVII). Compound of formula (XXVIII) may be prepared by reacting compounds of formula (XXVII) and compounds of formula R₁-NH₂ in the presence of a coupling reagent such as HATU in a suitable solvent such as DMF (suitably at room temperature to 80⁰C), and is followed by deprotection of compound of formula (XXVIII) under acidic conditions such as hydrochloric acid or trifluoracetic acid (suitably at room temperature) to form compounds of formula (Ie).

Scheme 13

(Ie)

(XXVIII)

When Z is (B) and Y represents -CONHCH₂- compounds of formula (I) may be prepared by the following scheme using similar chemistry to that described for Scheme 13:

Scheme 14

(If) (XXXII)

Compounds of formula (IV), (Vl), (VII), (VIII), (IX), (XVI), (XX), (XXIII), (XXV) and XXIX 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 synthesis 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 solvates 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), (XII), (XVIII) and (XXI) constitute a further aspect of the present invention.

The compounds of formula (I) or pharmaceutically acceptable salt(s) 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, a bile acid sequestrant, 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, dispersions, lotions, creams, gels, pastes, powders, aerosol sprays, syrups or ointments on sponges or cotton applicators, and solutions or suspensions in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion, or water-in-oil liquid emulsion.

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 C₁₂-₁5 alkyl 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; aldehydes 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.

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 50-500 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)

DEFINITIONS

Boc tertbutyloxy carbonyl

CDCI₃ deuterated chloroform

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

NaCI sodium chloride

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, 100°C; 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.

The following non-limiting examples illustrate the present invention.

Intermediate 1 : 3-Bromo-4-[2-(methyloxy)phenyl1-2-butanone

To a solution of 4-[2-(methyloxy)phenyl]-2-butanone (1.08 g, 6.07 mmol) in THF was added pyridinium tribromide (1.94 g, 6.07 mmol) in THF dropwise at 0°C. The mixture was stirred at 0⁰C for 1 hour and at room temperature for 30 min. Dichloromethane and a mixture of saturated solution of NaCI / solution of Na₂S₂O₃ 0.1 M (300 ml.) were added. The organic phase was extracted with DCM, dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with cyclohexane / AcOEt : 95/5 to give the title compound as a yellow oil (1.05 g, 6 To). LC/MS: m/z 258 (M+H)+, Rt: 3.23 min.

The following Intermediates were similarly prepared by a method analogous to that described for Intermediate 1.

Table 1

Intermediate 4: 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, ) in toluene (50 ml_). The reaction mixture was stirred between 10⁰C to 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).

Intermediate 5: 3-Chloro-4-r4-(trifluoromethyl)phenyll-2-butanone

This compound was similarly prepared by a method analogous to that described for Intermediate 4, starting from 4-(trifluoromethyl)aniline, and was used in the next step without further purification.

Intermediate 6 : 3-Bromo-4-(4-chlorophenyl)-2-butanone

To a solution of 4-(4-chlorophenyl)-2-butanone (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 and the title compound was used in the next step without further purification.

The following Intermediates were similarly prepared by a method analogous to that described for 3-bromo-4-(4-chlorophenyl)-2-butanone (Intermediate 6).

Table 2

Intermediate 9: 4-Methyl-5-fr2-(methyloxy)phenyllmethyl}-1 ,3-thiazol-2-amine hydrochloride

To a solution of 3-bromo-4-[2-(methyloxy)phenyl]-2-butanone (Intermediate 1 ) (1.05 g, 4.08 mmol) in ethanol (15 ml.) was added thiourea (0.31 g, 4.08 mmol) and the mixture was stirred at 60⁰C for 3 hours. The volatiles were removed under reduced pressure and the residue was dissolved in DCM. The organic phase was washed with a saturated aqueous solution of NaHCO₃, dried over Na₂SO₄ filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/ MeOH: 95/5 to give a colourless oil. The oil was dissolved in acetonitrile and a solution of 1 N HCI in diethyl ether was added. The precipitate was filtered and washed with pentane to give the title compound as a white solid (0.6 g, 55%). LC/MS: m/z 235 (M+H)+, Rt: 2.75 min.

The following Intermediate was similarly prepared by a method analogous to that described for Intermediate 9.

Table 3

Intermediate 1 1 : 4-Methyl-5-(phenylmethyl)-1 ,3-thiazol-2-amine

To a solution of 3-bromo-4-phenyl-2-butanone (Intermediate 2) (2.2 g, 9.7 mmol) in ethanol (30 ml.) was added thiourea (0.81 g, 10.6 mmol) and the mixture was stirred at 60⁰C for 2 hours. The volatiles were removed under reduced pressure and water was added to the residue. The precipitate was filtered, washed with water and pentane to give the title compound as a yellow solid (1.3 g, 66%). LC/MS: m/z 205 (M+H)+, Rt: 2.62 min.

Intermediate 12: 4-Methyl-5-{[3-(trifluoromethyl)phenyl1methyl}-1 ,3-thiazol-2-amine

To a solution of 3-ohloro-4-[3-(trifluoromethyl)phenyl]-2-butanone (Intermediate 4) (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 CCU 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 12:

Table 4

Intermediate 17: 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 %).

The following intermediates were similarly prepared by a method analogous to that described for Intermediate 17.

Table 5

Intermediate 21 : 5-r(3,4-Dichlorophenyl)methyll-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 17) (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.

The following intermediates were similarly prepared by a method analogous to that described for Intermediate 21.

Table 6

Intermediate 25 : 1.1-Dimethylethyl 6-r({5-r(4-chloroDhenyl)methyll-1.3-thiazol-2- yl}amino)carbonyll-3,4-dihvdro-2(1 H)-isoquinolinecarboxylate

A solution of 2-{[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (0.68 g, 2.45 mmol), HATU (1 g, 2.64 mmol), DIPEA (0.76 ml_, 4.4 mmol ) and 5-[(4-chlorophenyl)methyl]-1 ,3-thiazol-2-amine (0.5 g, 2.2 mmol) in DMF (5 ml.) was stirred at room temperature for one week. 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 solid was triturated with acetonitrile and recrystallised from methanol/dichloromethane to give the title compound as a white solid (0.67 g, 63%). LC/MS: m/z 484 (M+H)⁺, Rt : 3.86 min.

The following intermediates were similarly prepared by a method analogous to that described for Intermediate 25.

Table 7

Intermediate 51 : Ethyl 2-[(4-chlorophenyl)methyl1-4-methyl-1 ,3-thiazole-5-carboxylate

To a solution of 2-(4-chlorophenyl)ethanethioamide (1.46 g, 7.89 mmol) in EtOH (20 ml.) was added ethyl 2-chloro-3-oxobutanoate (1.09 ml_, 7.89 mmol) and the mixture was stirred at reflux temperature for 4 hours. Solvent was removed under reduced pressure and the residue was purified by flash column chromatography eluting with DCM / EtOAc: 98 / 2 to give the title compound as a yellow oil (1.18 g, 51%). LC/MS: m/z 296 (M+H)⁺, Rt : 3.63 min.

Intermediate 52: 2-r(4-Chlorophenyl)methyll-4-methyl-1 ,3-thiazole-5-carboxylic acid

To a solution of ethyl 2-[(4-chlorophenyl)methyl]-4-methyl-1 ,3-thiazole-5-carboxylate (Intermediate 51 ) (1.18 g, 4 mmol) in EtOH (20 ml.) was added a 1 N solution of sodium hydroxide (20 ml_, 20 mmol) and the mixture was stirred at reflux temperature for 1 hour. The solvent was partially evaporated under reduced pressure and the precipitate was filtered, washed with water and pentane to give the title compound as a yellow solid (950 mg, 89%). LC/MS: m/z 268 (M+H)⁺, Rt : 2.11 min.

Intermediate 53: 1 ,1-Dimethylethyl {2-r(4-chlorophenyl)methyll-4-methyl-1 ,3-thiazol- 5-yl}carbamate

To a solution of 2-[(4-chlorophenyl)methyl]-4-methyl-1 ,3-thiazole-5-carboxylic acid (Intermediate 52) (300 mg, 1.12 mmol) in tert-butanol (5 ml.) was added triethylamine (170 μl_, 1.22 mmol) and phosphorazidic diphenyl ester (270 μl_, 1.22 mmol) and the reaction mixture was stirred at reflux temperature under an inert atmosphere for 3 hours. The mixture was evaporated to dryness and the residue was purified by flash column chromatography eluting with DCM / EtOAc : 95 / 5 to give the title compound as a colorless oil (280 mg, 74%). LC/MS: m/z 339 (M+H)⁺, Rt : 3.47 min.

Intermediate 54: 2-r(4-Chlorophenyl)methyll-4-methyl-1 ,3-thiazol-5-amine hydrochloride

To a suspension of 1 , 1 -dimethylethyl {2-[(4-chlorophenyl)methyl]-4-methyl-1 ,3- thiazol-5-yl}carbamate (Intermediate 53) (275 mg, 0.81 mmol) in EtOAc was bubbled HCI(g) and the reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered and washed with pentane to give the title compound as a pale yellow solid (185 mg, 83%). LC/MS: m/z 239 (M+H)⁺, Rt : 2.71 min.

Intermediate 55: 1 ,1-Dimethylethyl 6-[({2-[(4-chlorophenyl)methyl1-4-methyl-1 ,3- thiazol-5-yl}amino)carbonyll-3,4-dihvdro-2(1 H)-isoquinolinecarboxylate

To a solution of 2-{[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (0.1 1 g, 0.4 mmol), HOBt (55 mg, 0.4 mmol), EDCI (77 mg, 0.4 mmol) and triethylamine (140 μl, 1 mmol) in DCM (5 ml.) was added 2-[(4- chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-5-amine hydrochloride (80 mg, 0.33 mmol) and the resulting mixture was stirred at room temperature for 5 days. The organic phase was washed successively with a 1 N solution of hydrochloric acid, with a 1 N solution of sodium hydroxide, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM / EtOAc: 8 / 2 to give the title compound as a yellow oil (25 mg, 15%). LC/MS: m/z 498 (M+H)⁺, Rt : 3.83 min.

Intermediate 56: 4-[(3-Chlorophenyl)methyl1-1 ,3-thiazol-2-amine hydrochloride

To a solution of 1-bromo-3-(3-chlorophenyl)-2-propanone (3.3 g, 13.36 mmol) in EtOH (50 ml.) was added thiourea (1.02 g, 13.39 mmol) and the reaction mixture was stirred at 60⁰C for 4 hours. The solvent was removed under reduced pressure and a saturated solution of NaHCO₃ was added to the residue. The aqueous layer was extracted with DCM and the organic phase was then dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM / MeOH : 97/3. The oily residue was dissolved in acetonitrile and a 1 N solution of hydrochloric acid in diethyl ether was added. The precipitate obtained was filtered and washed with pentane to give the title compound as a white solid (2.48 g, 71 %). LC/MS: m/z 225 (M+H)⁺, Rt : 2.82 min.

The following intermediates were similarly prepared by a method analogous to that described for Intermediate 56.

Table 9

Intermediate 59: 1.1-Dimethylethyl-6-r({4-r(3-nitroDhenyl)methyll-1.3-thiazol-2- yl}amino)carbonyll-3,4-dihvdro-2(1 H)-isoquinolinecarboxylate

To a solution of 2-{[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (33 mg, 0.12 mmol), HOBt (19 mg, 0.14 mmol), EDCI (26 mg, 0.14 mmol) and triethylamine (14 mg, 14 mmol) in DCM (3 ml.) was added 4-[(3- nitrophenyl)methyl]-1 ,3-thiazol-2-amine (30 mg, 0.12 mmol) and the resulting mixture was stirred at room temperature for 2 days. The organic phase was washed successively with water, with a 1 N solution of sodium hydroxide, with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM / MeOH: 98 / 2 to give the title compound as a pale yellow oil (30 mg, 52%). LC/MS: m/z 495 (M+H)⁺, Rt : 3.68 min.

The following intermediates were similarly prepared by a method analogous to that described for Intermediate 59.

Table 10

Intermediate 65: 1 ,1-Dimethylethyl (2-{r3-(trifluoromethyl)phenyllmethyl}-1 ,3-thiazol- 4-yl)carbamate

To a solution of 2-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazole-4-carboxylic acid (400 mg, 1.39 mmol) in tert-butanol (15 ml.) was added triethylamine (215 μl_, 1.53 mmol) and phosphorazidic diphenyl ester (330 μl_, 1.53 mmol) and the reaction mixture was stirred at reflux temperature under an inert atmosphere for 3 hours. The mixture was evaporated to dryness and the residue was purified by flash column chromatography eluting with DCM / EtOAc : 95 / 5 to give the title compound as a colorless oil (250 mg, 50%). 1H NMR (CDCI₃) δ 7.5-7.1 (m, 5H), 7.0 (br s, 1 H), 4.2 (s, 2H), 1.45 (s, 9H).

Intermediate 66: 2-{[3-(Trifluoromethyl)phenyl1methyl}-1 ,3-thiazol-4-amine

To a solution of 1 ,1-dimethylethyl (2-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-4- yl)carbamate (Intermediate 65) (250 mg, 0.7 mmol) in EtOAc (5 ml.) was bubbled HCI(g) and the reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered and washed with pentane. The solid was treated with a 1 N solution of sodium hydroxide and extracted with DCM. The organic phase was dried over Na₂SO₄, filtered and evaporated under reduced pressure to give the title compound as a yellow oil (75 mg, 42%). LC/MS: m/z 259 (M+H)⁺, Rt : 3.01 min.

Intermediate 67: 1 ,1-Dimethylethyl 6-{r(2-{r3-(trifluoromethyl)phenyllmethyl}-1 ,3- thiazol-4-yl)amino1carbonyl}-3,4-dihvdro-2(1 /-/)-isoquinolinecarboxvlate

To a solution of 2-{[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (100 mg, 0.36 mmol), HOBt (50 mg, 0.37 mmol), EDCI (70 mg, 0.37 mmol) and triethylamine (80 μl_, 0.58 mmol) in DCM (5 ml.) was added Intermediate 66 (75 mg, 0.29 mmol) and the resulting mixture was stirred at room temperature for 1 week. The organic phase was washed successively with a 1 N solution of hydrochloric acid, with a 1 N solution of sodium hydroxide, with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM / MeOH: 95 / 5 to give the title compound as a yellow oil (25 mg, 17%). LC/MS: m/z 518 (M+H)⁺, Rt : 4.05 min.

Intermediate 68 : 2-fr(2-fr(1.1-Dimethylethvnoxylcarbonyl>-1.2.3.4-tetrahvdro-6- isoquinolinvDcarbonyllaminoM-methyl-I .S-thiazole-δ-carboxylic acid

A solution of 2-{[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (296 mg, 1.07 mmol), HATU (406 mg, 1.07 mmol), DIPEA (0.41 ml_, 2.36 mmol ) and ethyl 2-amino-4-methyl-1 ,3-thiazole-5-carboxylate (199 mg, 1.07 mmol) in DMF (5 ml.) was stirred at 50⁰C for 6 hours. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic phase was then washed with dilute HCI, with a solution of sodium bicarbonate, dried over MgSO₄, filtered and evaporated under reduced pressure. The residue was dissolved in a mixture of ethanol (1.5 ml.) and water (2 ml.) and sodium hydroxide was added (86 mg, 2.15 mmol) and the reaction mixture was heated at 50⁰C for 4 hours. The reaction was then cooled, acidified with dilute HCI and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried over MgSO₄, filtered and evaporated under reduced pressure. The residue obtained was used directly in the next step without further purification.

Example 1 : ΛH5-r(4-Chlorophenyl)methyll-1 ,3-thiazol-2-yl>-1 ,2.3.4-tetrahvdro-6- isoquinolinecarboxamide hydrochloride

To a solution of 1 ,1-dimethylethyl 6-[({5-[(4-chlorophenyl)methyl]-1 ,3-thiazol-2- yl}amino)carbonyl]-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (Intermediate 25) (0.67 g, 1.38 mmol) in EtOAc (15 ml.) was bubbled HCI(g) and the reaction mixture was stirred at room temperature for 3 hours. The resulting precipitate was filtered, washed with DCM, and recrystallized from EtOH / CH₃CN to give the title compound as a pale yellow solid (320 mg, 55%).

HRMS calculated for C₂₀H₁₈CIN₃OS (M+H)⁺ 384.0937, found: 384.0909, Rt: 2.50 min.

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

Table 1 1

Example No. R¹ R² From : Physical data

(tιϊfluoromethyl)phenyl]me methyl}-1 ,3-thiazol-2- Theo: 418.1201 thyl}-1 ,3-thiazol-2-yl)- yl)amino]carbonyl}-3,4- Found: 418.1183 1 ,2,3,4-tetrahydro-6- dihydro-2(1 H)- Rt: 2.61 min isoquinolinecarboxamide isoquinolinecarboxylate hydrochloride

(Intermediate 42)

1 ,1-dimethylethyl 6-({[4-

19 methyl-5-(1-

HRMS (M+H)⁺: naphthalenylmethyl)-

Λ/-[4-methyl-5-(1- calculated for

1 ,3-thiazol-2- naphthalenylmethyl)-1 ,3- C₂₅H₂₃N₃OS

Me yl]amino}carbonyl)-3,4- thiazol-2-yl]-1 , 2,3,4- Theo: 414.1640

dihydro-2(1 H)- tetrahydro-6- Found: 414.1625 isoquinolinecarboxylate isoquinolinecarboxamide Rt: 2.69 min hydrochloride

(Intermediate 43)

1 ,1-dimethylethyl 6-[({5-

20

[(4-

HRMS (M+H)⁺: chlorophenyl)methyl]-4-

Λ/-{5-[(4- calculated for ethyl-1 ,3-thiazol-2- chlorophenyl)methyl]-4- C₂₂H₂₂CIN₃OS

Et yl}amino)carbonyl]-3,4- ethyl-1 ,3-thiazol-2-yl}-

Theo: 412.1250 dihydro-2(1 H)-

1 ,2,3,4-tetrahydro-6- Found: 412.1240 isoquinolinecarboxylate isoquinolinecarboxamide Rt: 2.80 min hydrochloride

(Intermediate 44)

1 ,1-dimethylethyl 6-[({5-

21

[(4-

HRMS (M+H)⁺: chlorophenyl)methyl]-4-

Λ/-{5-[(4- calculated for propyl-1 ,3-thiazol-2- chlorophenyl)methyl]-4- C₂₃H₂₄CIN₃OS

Pr yl}amino)carbonyl]-3,4- propyl-1 ,3-thiazol-2-yl}-

Theo: 426.1407 dihydro-2(1 H)-

1 ,2,3,4-tetrahydro-6- Found: 426.1403 isoquinolinecarboxylate isoquinolinecarboxamide Rt: 2.96 min hydrochloride

(Intermediate 45)

1 ,1-dimethylethyl 6-({[4-

22 methyl-5-({2-[(2-

HRMS (M+H)⁺: methylpropyl)oxy]phenyl

Λ/-[4-methyl-5-({2-[(2- calculated for

}methyl)-1 ,3-thiazol-2- methylpropyl)oxy]phenyl} C₂sH₂gN₃O₂S

Me yl]amino}carbonyl)-3,4- methyl)-1 ,3-thiazol-2-yl]- Theo: 436.2059

dihydro-2(1 H)-

1,2,3,4-tetrahydro-6- Found: 436.2070 isoquinolinecarboxylate isoquinolinecarboxamide Rt: 2.92 min hydrochloride

(Intermediate 46)

Example 27: N-{2-r(4-Chlorophenyl)methyll-4-methyl-1 ,3-thiazol-5-yl>-1.2.3.4- tetrahydro-6-isoquinolinecarboxamide hydrochloride

To a solution of 1 ,1-dimethylethyl 6-[({2-[(4-chlorophenyl)methyl]-4-methyl-1 ,3- thiazol-5-yl}amino)carbonyl]-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (Intermediate 55) (25 mg, 0.05 mmol) in EtOAc (5 mL) was bubbled HCI(g) and the reaction mixture was stirred at room temperature for 4 hours. The resulting precipitate was filtered and washed with EtOAc to give the title compound as a pale yellow solid (1 1 mg, 55%).

HRMS calculated for C_2IH₂₀CIN₃OS (M+H)⁺ 398.1094, found: 398.1116, Rt: 2.41 min.

Example 28: N-{4-r(3-Nitrophenyl)methyll-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride

To a solution of 1 ,1-dimethylethyl-6-[({4-[(3-nitrophenyl)methyl]-1 ,3-thiazol-2- yl}amino)carbonyl]-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (Intermediate 59) (30 mg, 0.06 mmol) in EtOAc (5 mL) was bubbled HCI(g) and the reaction mixture was stirred at room temperature for 1 hour. The resulting precipitate was filtered and washed with diisopropyl ether to give the title compound as a white solid (20 mg, 77%).

HRMS calculated for C₂₀H₁₈N₄O₃S (M+H)⁺ 395.1178, found: 395.1180, Rt: 2.45 min. The following examples were similarly prepared by a method analogous to that described for Example 28.

Table 13

Example 34: N-(2-{r3-(Trifluoromethvnphenyllmethyl}-1.3-thiazol-4-yl)-1.2.3.4- tetrahydro-6-isoquinolinecarboxamide hydrochloride

To a solution of 1 ,1-dimethylethyl 6-{[(2-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3- thiazol-4-yl)amino]carbonyl}-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (Intermediate 67) (25 mg, 0.048 mmol) in EtOAc (5 ml.) was bubbled HCI (g) and the reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered and washed with EtOAc to give the title compound as a cream solid (11 mg, 50%).

HRMS calculated for C_2IH₁₈F₃N₃OS (M+H)⁺ 418.1201 , found: 418.1204, Rt: 2.64 min.

Example 35: /V-(4-Methyl-5-{r(phenylmethvnaminolcarbonyl}-1.3-thiazol-2-yl)-1.2.3.4- tetrahvdro-6-isoquinolinecarboxamide

A solution of 2-{[(2-{[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinyl)carbonyl]amino}-4-methyl-1 ^-thiazole-δ-carboxylic acid (Intermediate 68) (417 mg, 1 mmol), HATU (0.38 g, 1 mmol), DIPEA (0.19 ml_, 1.1 mmol) and benzylamine (107 mg, 1 mmol) in DMF (5 ml.) was stirred at room temperature for 5 hours. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic phase was then washed with a solution of sodium carbonate, with a dilute solution of hydrochloric acid, dried over MgSO₄, filtered and evaporated under reduced pressure. The residue was dissolved in dioxane (2 ml.) and a 4N solution of HCI in dioxane (2 ml.) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralised with an aqueous sodium hydroxide solution and extracted with EtOAc. The organic phase was dried over MgSO₄, filtered and evaporated under reduced pressure. The residue was recrystallized from ethanol to give the title compound (25 mg) as a yellow solid.

LC/MS: m/z 405 (M-H)⁺, Rt : 2.24 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 tested by the above described in vitro assay for SCD activity were found to exhibit an average pi C₅₀ value of greater than 5.

All of the synthetic Example compounds 1 to 35 tested by the above described in vitro assay for SCD activity were found to exhibit an average plC₅₀ value of greater than 5.5.

The following compounds were prepared according similar protocols to above described and when tested by the above described in vitro assay for SCD activity were found to exhibit an average plC₅o value in the range 5-5.5.

Structure Name

2-[(4-chlorophenyl)methyl]-4- methyl-Λ/-(1 ,2,3,4-tetrahydro-6- isoquinolinyl)-1 ,3-thiazole-5- carboxamide hydrochloride

The following compounds were also prepared and when tested by the above described in vitro assay for SCD activity were found to exhibit an average plC₅₀ value of less than 5.

Structure Name

2-[(4-chlorophenyl)methyl]-/V-

(1 ,2,3,4-tetrahydro-6-isoquinolinyl)-

1 ,3-thiazole-4-carboxamide

hydrochloride

Claims

1. A compound of formula (I):

(I) wherein Z represents:

(A) (B) (C) (D)

where ^* represents the point of attachment

when Z represents (A) or (B)

R¹ represents:

(i) H or -Ci.₆alkyl,

(ii) -C_6-ioaryl optionally substituted by one, two or three groups independently selected from:

(a) -Ci_-6alkyl, -d_-6haloalkyl, -Cs-ecycloalkyl, -Ci_-6alkoxy, -OR³, -CN, -NO₂ or halogen,

(b) -C_6-ioaryl, -C_5-1oheteroaryl or -Cs^oheterocyclyl, wherein the -C_6-ioaryl, -C_5- ioheteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -Ci_-6alkyl, -Ci_-6haloalkyl, -C_3- ₆cycloalkyl, -C_1-6alkoxy, -OR³, -CN, -NO₂ or halogen,

(iii) -C₅-ioheteroaryl or -Cs-ioheterocyclyl wherein the -C_5-ioheteroaryl or -C_5- ioheterocyclyl is optionally substituted by one, two or three groups independently selected from: (a) -Ci_-6alkyl, -Ci_-6haloalkyl, -Cs-ecycloalkyl, -Ci_-6alkoxy, -OR³, -CN, -NO₂ or halogen,

(b) -C₆-ioaryl, -C_5-1oheteroaryl or -C_5-1oheterocyclyl wherein the -C_6-ioaryl, -C_5- ioheteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -Ci_-6alkyl, -Ci_-6haloalkyl, -C_3- ecycloalkyl, -C_1-6alkoxy, -OR³, -CN, -NO₂ or halogen,

Y represents -(CH₂)_m- or -CONHCH₂-,

R² represents H, -C_1-6alkyl or -Cs-ecycloalkyl,

R³ represents -Ci_-6haloalkyl or -Cs-βcycloalkyl, and m represents 1 or 2,

when Z represents C or D R¹ represents: (i) -Cβ-ioaryl optionally substituted by one, two or three groups independently selected from:

(a) -C_1-6alkyl, -C_1-6haloalkyl, -C_3-6cycloalkyl, -OR³, -CN, -NO₂ or halogen,

(b) -C_6-ioaryl, -C_5-ioheteroaryl or -Cs-ioheterocyclyl, wherein the -C_6-ioaryl, -C_5- ioheteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl, -C_1-6haloalkyl, -C_3- ₆cycloalkyl, -Ci_-6alkoxy, -OR³, -CN, -NO₂ or halogen,

(iii) -C₅-ioheteroaryl or -Cs-ioheterocyclyl wherein the -C_5-i₀heteroaryl or -C_5- ₁₀heterocyclyl is optionally substituted by one, two or three groups independently selected from: (a) -Ci_-6alkyl, -Ci_-6haloalkyl, -Cs-ecycloalkyl, -Ci_-6alkoxy, -OR³, -CN, -NO₂ or halogen,

(b) -C₆-ioaryl, -C_5-ioheteroaryl or -Cs-ioheterocyclyl wherein the -C_6-ioaryl, -C_5- ioheteroaryl or -Cs-ioheterocyclyl ring is optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl, -C_1-6haloalkyl, -C_3- ecycloalkyl, -Ci_-6alkoxy, -OR³, -CN, -NO₂ or halogen,

Y represents -(CH₂)_m-, R² represents H, -Ci_-6alkyl or -Cs-βcycloalkyl, R³ represents -Ci_-6haloalkyl or -Cs-βcycloalkyl, and m represents O, 1 or 2, or a salt thereof.

2. A compound of formula (I) or a salt thereof according to claim 1 wherein when Z represents (A) or (B): R¹ represents -C₆-ioaryl optionally substituted by: one, two or three groups independently selected from:

(a) -Ci_-6alkyl, -Ci_-6haloalkyl, -C^ecycloalkyl, -Ci_-6alkoxy, -OR³, -CN, -NO₂ or halogen,

(b) -C_6-ioaryl optionally substituted by one, two or three groups independently selected from: -C_1-6alkyl, -C_1-6haloalkyl, -Cs-ecycloalkyl, -C_1-6alkoxy, -OR³, -CN, - NO₂ or halogen.

3. A compound of formula (I) or a salt thereof according to claim 1 or 2 wherein when Z represents (C) or (D):

R¹ represents -C₆-ioaryl optionally substituted by: one, two or three groups independently selected from:

(a) -Ci_-6alkyl, -Ci_-6haloalkyl, -Ca-ecycloalkyl, -OR³, -CN, -NO₂ or halogen, (b) -C_6-ioaryl optionally substituted by one, two or three groups independently sseelleecctteedd ffrroomm:: --Ci_-6alkyl, -Ci_-6haloalkyl, -C_3-6cycloalkyl, -Ci_-6alkoxy, -OR³, -CN, - NO₂ or halogen.

4. A compound of formula (I) or a salt thereof according to any one of claims 1 to 3 wherein when Z represents (A) or (B), Y represents -CH₂- (methylene).

5. A compound of formula (I) or a salt thereof according to any one of claims 1 to 4 wherein when Z represents (C) or (D), Y represents -CH₂- (methylene).

6. A compound of formula (I) or a salt thereof according to any one of claims 1 to 5 wherein when Z represents (A), (B), (C) or (D), R² represents hydrogen or -Ci- ₃alkyl.

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

N-{5-[(3-chlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, N-{5-[(3-chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

6-isoquinolinecarboxamide,

N-{5-[(3,4-dichlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-{5-[(2-chlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-{5-[(2,5-dichlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, N-{5-[(4-cyanophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-[5-(1-naphthalenylmethyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, N-{5-[(3,4-dichlorophenyl)methyl]-4-methyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-(5-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-[4-methyl-5-(1-naphthalenylmethyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-{5-[(4-chlorophenyl)methyl]-4-ethyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-{5-[(4-chlorophenyl)methyl]-4-propyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, N-[4-methyl-5-({2-[(2-methylpropyl)oxy]phenyl}methyl)-1 ,3-thiazol-2-yl]-1 ,2,3,4- tetrahydro-6-isoquinolinecarboxamide,

N-(5-methyl-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide,

N-{5-[(3-nitrophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-(4-methyl-5-{[(phenylmethyl)amino]carbonyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-{2-[(4-chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-5-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-{4-[(3-nitrophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-{4-[(3-chlorophenyl)methyl]-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-(5-methyl-4-phenyl-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide,

6-isoquinolinecarboxamide,

N-{4-[(4-chlorophenyl)methyl]-5-methyl-1 ,3-thiazol-2-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide,

N-(2-{[3-(trifluoromethyl)phenyl]methyl}-1 ,3-thiazol-4-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, and

N-(4-methyl-5-{[(phenylmethyl)amino]carbonyl}-1 ,3-thiazol-2-yl)-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide, or a salt thereof.

8. A compound of formula (I) or a salt thereof as claimed in any one of claims 1 to 7 wherein the salt is a pharmaceutically acceptable salt

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

10. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 for use in therapy.

11. Use of a compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 for the manufacture of a medicament for treating and/or preventing a disease or a condition susceptible to amelioration by an SCD inhibitor.

12. Use of a compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 1 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.

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

14. Use of a compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 1 for the manufacture of a medicament for treating and/or preventing acne.

15. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 for use in treating and/or preventing a disease or a condition susceptible to amelioration by an SCD inhibitor.

16. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 15 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.

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

18. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 15 for use in treating and/or preventing acne.

19. 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 for formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.

20. 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, 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 comprising administering to a subject a therapeutically effective amount of compound for formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.

21. A method of treating and/or preventing acne, psoriasis, skin ageing, 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 compound for formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.

22. A method of treating and/or preventing acne comprising administering to a subject a therapeutically effective amount of compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.

23. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 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, a bile acid sequestrant, 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.