AU2003214442B2

AU2003214442B2 - Heteroaromatic urea derivatives as VR-1 receptor modulators for treating pain

Info

Publication number: AU2003214442B2
Application number: AU2003214442A
Authority: AU
Inventors: Rebecca Elizabeth Brown; Victoria Alexandra Doughty; Gregory John Hollingworth; A. Brian Jones; Matthew John Lindon; Christopher Richard Moyes; Lauren Rogers
Original assignee: Merck Sharp and Dohme Ltd
Current assignee: Organon Pharma UK Ltd
Priority date: 2002-03-22
Filing date: 2003-03-21
Publication date: 2009-02-12
Anticipated expiration: 2023-03-21

Description

HETEROROMATIC UREA DERIVATIVES AS VR-1 RECEPTOR MODULATORS FOR TREATING PAIN

The present invention is concerned with heteroaromatic ureas and 5 pharmaceutically acceptable salts and prodrugs thereof which are useful as therapeutic compounds, particularly in the treatment of pain and other conditions ameliorated by the modulation of the function of the vani loid-1 receptor (VR1).

The pharmacologically active ingredient of chilli peppers has been

10 recognised for some time to be the phenolic amide capsaicin. The application of capsaicin to mucous membranes or when injected intradermally, causes intense burning-like pain in humans. The beneficial effects of topical administration of capsaicin as an analgesic is also well established. However, understanding of the underlying molecular pharmacology mediating these responses to capsaicin has

15 been a more recent development.

The receptor for capsaicin, termed the vanilloid NRl receptor, was cloned by Caterina and colleagues at UCSF in 1997 (Nature, 398:816, 1997). VE1 receptors are cation channels that are found on sensory nerves that innervate the skin, viscera, peripheral tissues and spinal cord. Activation of NRl elicits action

20 potentials in sensory fibres that ultimately generate the sensation of pain.

Importantly NRl receptor is activated not only by capsaicin by also by acidic pH and by noxious heat stimuli and thus appears to be a polymodal integrator of painful stimuli.

The prototypical NRl antagonist is capsazepine (Walpole et al,

25 J. Med. Chem., 37:1942, 1994). This has only micromolar affinity for NRl and is non-specific in its action. A novel series of sub-micromolar antagonists has also been reported recently (Lee et al, Bioorg. Med. Chem., 9:1713, 2001), but these reports provide no evidence for in vivo efficacy. A much higher affinity antagonist has been derived from the 'ultra-potent' agonist resiniferatoxin.

30 Iodo-resiniferatoxin (Wahl et al, Mol. Pharmacol, 59:9, 2001) is a nanomolar antagonist of NRl but does not possess properties suitable for an oral pharmaceutical. This last is also true of the micromolar peptoid antagonists described by Garcia-Martinez (Proc. Natl. Acad. Sci., USA, 99:2374, 2002). Most recently International (PCT) patent publication No. WO 02/08221 has described a novel series of NRl antagonists, which are stated to show efficacy in a number of animal models. We herein describe another novel series of NRl modulators. These comprise predominantly NRl antagonists but encompass NRl partial antagonists and NRl partial agonists. Such compounds have been shown to be efficacious in animal models of pain.

Structurally related compounds are disclosed in EP-A-0418071, WO-A- 9104027, WO-A-9324458, US-A-5596001 and US-A-5362818 all in the name of Pfizer Inc., WO-A-0064888 and WO-A-0064876 in the name of Aventis Pharmaceutical Products Inc. and WO-A-9406280 in the name of The Regents of the University of California. None of the compounds disclosed are for treating pain.

The present invention provides compounds of formula (I):

(I) wherein

A, B, D and E are each C or N with the proviso that one or more are N; R¹ and R² are each independently hydrogen, halogen, hydroxy, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, haloCi-βalkyl, hydroxyCi-βalkyl, Ci-βalkoxy, haloCi-βalkoxy, hydroxyCi-βalkoxy, C3-7cycloalkyl, C3-5cycloalkylCι- alkyl, NR⁷R⁸, carboxy, esterified carboxy, Ci-βalkyl substituted with a group selected from NR⁷R⁸, carboxy and esterified carboxy, or Ci-βalkoxy substituted with a group selected from NR⁷R⁸, carboxy and esterified carboxy;

R⁸ and R⁴ are each independently hydrogen, Ci-βalkyl, C2-6alkenyl or C2-6alkynyl; R⁵ and R⁶ are, at each occurrence, independently hydrogen, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Ci-βalkoxy, Ci-βacyloxy, carboxy, esterified carboxy, CONR⁷R⁸, SO2R⁷, SO2NR⁷R⁸, aryl, heteroaryl, heterocyclyl, or Cι-6alkyl substituted with a group selected from hydroxy, Ci-βalkoxy, Ci-βacyloxy, carboxy, esterified carboxy, NR⁷R⁸, CONR⁷R⁸, SR⁷, SO2R⁷, SO₂NR⁷R⁸, aryl, heteroaryl and heterocyclyl; or R⁵ and R⁶ and the carbon atom to which they are attached together form a carbocyclic ring of 3 to 6 carbon atoms;

R⁷ and R⁸ are, at each occurrence, independently hydrogen, Ci-βalkyl, C2-6alkenyl,

C2-6alkynyl, C3-7cycloalkyl or fluoroCi-βalkyl; or R⁷ and R⁸ and the nitrogen atom to which they are attached together form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or Cι- alkoxy, which ring may optionally contain as one of the said ring atoms an oxygen or a sulfur atom, a group S(O) or S(O)₂, or a second nitrogen atom which will be part of a NH or NR^a moiety where R^a is Cι- alkyl optionally substituted by hydroxy or Cι- alkoxy;

X is an oxygen or sulfur atom or the group =NCN;

Y is an aryl, heteroaryl, carbocyclyl or fused-carbocyclyl group; and n is either zero or an integer from 1 to 3; or a pharmaceutically acceptable salt, N-oxide or a prodrug thereof. R¹ may be absent or one or two R¹ groups may be present, as a preferred embodiment. R¹ is thus preferably chosen independently from halogen, haloCi- βalkyl and Ci-ealkoxy, such as fluorine, chlorine, trifluoromethyl and methoxy. A preferred class of compound of formula (I) is that wherein R¹ is a hydrogen or halogen atom or a group selected from Ci-βalkyl and Ci-βalkoxy. More particularly, a preferred class of compound of formula (I) is that wherein R¹ is a hydrogen or a halogen atom, particularly a hydrogen or a fluorine atom, and most especially a hydrogen atom.

Where R¹ is other than hydrogen, preferably there is only one R¹ substituent. Generally R² is absent or one or two R² groups are present. Thus R² is preferably independently chosen from Ci-βalkoxy, halogen, di(Cι-6alkyl)amino,

Ci-βalkyl, hydroxy, Ci-βalkoxyearbonyl, carboxy, amino, haloCi-βalkyl, hydroxyCi-ealkyl and aminoCi-ealkyl. More preferably R² is independently chosen from halogen, hydroxy, carboxy, amino, Cι-3alkoxy, di(Cι-3alkyl)amino, Ci-aalkyl, Cι-3alkoxyearbonyl, haloCι-3alkyl, hydroxyCι-3alkyl and aminoCι-3alkyl. R² is particularly chosen independently from methoxy, methyl, ethyl, chlorine, dimethylamino, hydroxy, trifluoromethyl, methoxycarbonyl, carboxy, amino, hydroxymethyl and aminoethyl. Another preferred class of compound of formula (I) is that wherein R² is a hydrogen or halogen atom or a group selected from Ci-βalkyl, haloCi-ealkyl, Ci-ealkoxy, NR⁷R⁸, Ci-ealkyl substituted with NR⁷R⁸, and Ci-βalkoxy substituted with NR⁷R⁸, wherein R⁷ and R⁸ each independently preferably represent hydrogen atoms or Cι-4alkyl groups.

A further preferred class of compound of formula (I) is that wherein R² is a hydrogen or a halogen atom, or a group selected from Cι-₄alkyl, C1.4aIk.oxy and NR⁷R⁸, wherein R⁷ and R⁸ each independently preferably represent hydrogen atoms or Cι-₄alkyl groups. More particularly, R² preferably represents a hydrogen or chlorine atom or a group selected from methyl, methoxy and dimethylamino. Most preferably, R² is a hydrogen atom.

Where R² is other than hydrogen, preferably there is only one R² substituent. Thus quinoline, isoquinoline and cinnoline moieties included within the scope of the invention include isoquinolin-5-yl, isoquinolin-8-yl, quinolin-5-yl, 2-oxidoisoquinolin-5-yl, 3-methoxyisoquinolin-8-yl, cinnolin-5-yl, 3- methylisoquinohn-5-yl, l-chloroisoquinolin-5-yl, l-dimethylaminoisoquinolin-5-yl, 3-methylisoquinoHn-8-yl, 3-chloroisoquinolin-5-yl, 3-methylcinnolin-5-yl, 8- fl.uoroisoquinolin-5-yl, l-hydroxyisoquinoHn-5-yl, 3-trifluoromethylisoquinolin-5- yl, l-chloro-3-ethyHsoquinolin-5yl, l-methylisoquinolin-5-yl, 6,8-dϋluoro-3- methylisoquinolin-5-yl, 7-trifluoromethyl-3-methyhsoquinolin-5-yl, 3-methyl-8- fluoroisoquinohn-5-yl, 3-methyl-6-fluoroisoquinolin-5-yl, 7-methoxyisoquinolin-5- yl, l,3-dimethyHsoquinoUn-5-yl, 3-methyl-7-chloroisoquinolin-5-yl, 7- chloroisoquinohn-5-yl, 6-fluoroisoquinolin-5-yl, 7-fluoroisoquinolin-5-yl, 4- methylisoquinolin-5-yl, 8-trifl.uoromethylisoquinoUn-5-yl, 6- trifluoromethyUsoquinohn-5-yl, 7-trifluoromethyHsoquinolin-5-yl, l-methyl-6- fluoroisoquinolin-5-yl, l-chloroisoquinohn-5-yl, l-methoxycarbonyhsoquinolin-5- yl, l-carboxyisoquinolin-5-yl, l-aminoisoquinolin-5-yl, 1- hydroxymethyhsoquinoUn-5-yl, 3-methoxycarbonyhsoquinohn-5-yl, 3- carboxyisoquinolin-5-yl, 3-dimethylaminoisoquinohn-5-yl, 3-(2- aminoethyl)isoquinolin-5-yl and 8-methoxyisoquinolin-5-yl. A further preferred class of compound of formula (I) is that wherein R³ is a hydrogen atom or a Cι-₄alkyl group, particularly a hydrogen atom or a methyl group, and most especially a hydrogen atom.

A yet further preferred class of compound of formula (I) is that wherein R⁴ is a hydrogen atom or a Cι-₄alkyl group, particularly a hydrogen atom or a methyl group, and most especially a hydrogen atom.

Another preferred class of compound of formula (I) is that wherein R⁵ and R⁶ each independently represent a hydrogen atom or a group selected from Ci-βalkyl, Cι-6alkyl substituted by a group selected from hydroxy, Ci-βacyloxy, carboxy, esterified carboxy, NR⁷R⁸ and heterocyclyl, or an aryl group

More particularly, a preferred class of compound of formula (I) is that wherein R⁵ and R⁶ each independently represent a hydrogen atom or a Cι-4alkyl or phenyl group, particularly a hydrogen atom or a methyl group, and most especially a hydrogen atom. Thus -(CR⁵R⁶)n- can represent a bond, -CH2-, -(CEfeV, -(CH.2)3-,

-CH(C₆H5)CH₂CH2-, -CHCHs- and -CH(CH₂COOCH2CH3)-.

A further preferred class of compound of formula (I) is that wherein X is an oxygen atom. X may be sulphur or oxygen.

A yet further preferred class of compound of formula (I) is that wherein Y is an aryl group selected from unsubstituted phenyl or naphthyl and phenyl or naphthyl substituted by one or two substituents selected from halogen, Cι-₄alkyl, Cι-4alkoxy, haloCι.4alkyl, haloCι-4alkoxy, phenyl, cyano, nitro, pyrazolyl, di(Cι-6alkyl)amino, phenoxy, -OCH2O- and Ci-βalkylcarbonyl; or a heteroaryl group selected from pyridyl, thiazolyl, isoxazolyl, oxadiazolyl and pyrazolyl wherein each heteroaryl group is optionally substituted with one or two substituents selected from Cι-4alkyl, Cι-4alkoxy, haloCι-4alkyl, haloCι-4alkoxy, unsubstituted heteroaryl or phenyl which may be substituted by Ci-ealkyl or halogen; or a carbocyclyl group which is a C5-7cycloalkyl radical that is unsubstituted or substituted by a phenyl ring; or a fused-carbocyclyl group which is a Cδ-7cycloalkyl radical that is fused to a phenyl ring.

A yet further preferred class of compound of formula (I) is that wherein Y is an aryl group selected from unsubstituted phenyl and phenyl substituted by one or two substituents selected from halogen, Cι-₄alkyl, Cι.4a]koxy, haloCι-4alkyl, haloCι-4alkoxy, phenyl and pyrazolyl; or a heteroaryl group selected from pyridyl, thiazolyl, isoxazolyl, oxadiazolyl and pyrazolyl wherein each heteroaryl group is optionally substituted with one or two substituents selected from Cι-4alkyl, Cι-4alkoxy, haloCι.4alkyl, haloCι-4alkoxy, phenyl; or a carbocyclyl group which is a C5-7cycloalkyl radical that is unsubstituted or substituted by a phenyl ring; or a fused-carbocyclyl group which is a C5-7cycloalkyl radical that is fused to a phenyl ring.

Thus Y can be phenyl, biphen-4-yl, biphen-3-yl, l,2,3,4-tetrahydronaphthalen-2-yl, 4-chlorophenyl, 3,5-di(trifl.uoromethyl)phenyl, 3,4-dime hylphenyl, 4-tertbutylphenyl, 3-tertbutylphenyl, 3- trifluoromethylphenyl, 4-triQ.uoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 2, 3-dihydro- lH-inden-2-yl, 4-phenylcyclohexyl, 6, 7, 8, 9-tetrahydro-5H- benzo [a] [7] annulen-6-yl, 6, 7, 8, 9-tetrahydro-5H-benzo[a] [7] annulen- 7-yl, 3-trifLuoromethylpyridin-6-yl, 4-tertbutylpyridin-6-yl, 2-tertbutylpyridin-5-yl, 2-tertbutylpyridin-4-yl, 2-tertbutylpyridin-6-yl, 2-trifluoromethylpyridin-5-yl, 2-(pyrazol-l-yl)phenyl, 4-(pyrazol-l-yl)phenyl, 2-phenylthiazol-5-yl, 2-(thiophen- 2-yl)thiazol-3-yl, 3-phenylthiazol-2-yl, 5-phenyHsoxazol-3-yl, 3-phenylisoxazol-5- yl, 3-phenyloxadiazol-5-yl, 2-benzylthiazol-4-yl, l-(2-methylphenyl)pyrazol-4-yl, cyclohexyl, naphthalen-2-yl, 4-cyanophenyl, 4-nitrophenyl, 4-dimethylaminophenyl, 4-phenoxyphenyl, l,3-benzodioxol-5-yl, 4-methylcarbonylphenyl, isoquinolin-6-yl, 4-(morpholin-4-ylmethyl)phenyl and 2-(2-morpholin-4-ylethoxy)phenyl.

Another preferred class of compound of formula (I) is that wherein one of A, B, D and E is a nitrogen atom and the other three are carbon atoms, or A and B are nitrogen atoms and D and E are carbon atoms. It will be appreciated that the group R² is attached to any available carbon atom represented by A, B, D and E.

When present, R⁷ is preferably a hydrogen atom or a Cι-4alkyl group, and R⁸ is preferably a hydrogen atom or a Cι.4alkyl group, or the group NR⁷R⁸ represents a heteroaliphatic ring selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorphohnyl, piperazinyl or a piperazinyl group substituted on the nitrogen atom by Cι-4alkyl optionally substituted by hydroxy or Cι-₄alkoxy. More preferably, the group NR⁷R⁸ represents a group selected from -NH2- -NHCH3, -N(CH₃)₂, -NHCH2CH3, -N(CH)CH₂CH3 and -N(CH₂CH₃)2, and most especially, -N(CH-3)2. One favoured class of compound of the present invention is that of formula (la) and pharmaceutically acceptable salts, N-oxides and prodrugs thereof:

da)

With reference to formula (la), preferably E is a carbon atom. Also preferred are those compounds of formula (la) where E is a carbon atom, one of A, B and D is a nitrogen atom and the others are carbon atoms, or where A and B are nitrogen atoms and D and E are carbon atoms.

Another favoured class of compound of the present invention is that of formula (lb) and pharmaceutically acceptable salts, N-oxides and prodrugs thereof:

cn>)

With reference to formula (lb), preferably E is a carbon atom. Also preferred are those compounds of formula (lb) where E is a carbon atom, one of A, B and D is a nitrogen atom and the others are carbon atoms, or where A and B are nitrogen atoms and D and E are carbon atoms. With reference to compounds of formula (lb), preferably, A is a nitrogen atom and B, D and E are carbon atoms.

When any variable occurs more than one time in formula (I), formula (la) or formula (lb) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence. As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

As used herein, the term "hydroxyCi-ealkyl" means a Ci-βalkyl group in which one or more (in particular 1 to 3, and especially 1) hydrogen atoms have been replaced by hydroxy groups. Particularly preferred are hydroxyCι-3alkyl groups, for example, CH2OH, CH2CH2OH, CH(CH₃)OH or C(CH₃)2OH, and most especially CH2OH.

As used herein, the terms "haloCi-θalkyl" and "haloCi-βalkoxy" means a Ci-βalkyl or Ci-βalkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. Preferred are fluoroCi-βalkyl and fluoroCi-βalkoxy groups, in particular, fl.uoroCι-3alkyl and fl.uoroCι-3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3. OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF₃, OCF3 and OCH2CF3.

The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Suitable C3-7cycloalkylCι-4alkyl groups include, for example, cyclopropylmethyl and cyclohexylmethyl.

Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.

As used herein, the terms "alkenyl" and "alkynyl" as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is acetylene or propargyl.

When used herein, the term "halogen" means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated. When used herein, the term "carboxy" as a group or part of a group denotes CO2H.

When used herein, the term "esterified carboxy" denotes a Ci-ealkoxy or a haloCi-ealkoxy radical attached via the oxygen atom thereof to a carbonyl (C=O) radical thus forming a Ci-βalkoxycarbonyl or haloCi-βalkoxycarbonyl radical. Suitable examples of such esterified carboxy groups include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

When used herein, the term "acyloxy" denotes a Ci-βalkyl or a haloCi-ealkyl radical attached to a carbonyl (C=O) radical thus forming a Ci-βalkoyl or haloCi-βalkanoyl radical which is attached via the carbonyl (C=O) radical to an oxygen atom. Suitable examples of such esterified carboxy groups include, for example, acetoxy, propionyloxy, isopropionyloxy and trifluoroacetoxy.

As used herein, the term "aryl" as a group or part of a group means an aromatic radical such as phenyl, biphenyl or naphthyl, wherein said phenyl, biphenyl or naphthyl group may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci-βalkyl, Ci-βalkoxy, haloCi-ealkyl, haloCi-ealkoxy, NR⁷R⁸, benzyl, NO₂, cyano, SR^b, SOR , SO₂R^b, COR^b, CO₂R^b, CONR R^c, C2-6alkenyl, C^alkynyl, Cι-₄alkoxyCι-4alkyl, -O(CH2)mO- or a heteroaromatic group selected from furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyridyl substituted by a group selected from halogen, haloCi-ealkyl and haloCi-ealkoxy (where R^b and R^c each independently represent hydrogen, Cι-4alkyl, C3-scycloalkyl or fluoroCι.4alkyl or R^b and R^c, together with the nitrogen atom to which they are attached form a piperidine, piperazine or morpholine ring and m is 1 or 2).

As used herein, the term "aryl" as a group or part of a group means an aromatic radical such as phenyl, biphenyl or naphthyl, wherein said phenyl, biphenyl or naphthyl group may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci-βalkyl, Ci-βalkoxy, haloCi-ealkyl, haloCi-ealkoxy, NR⁷R⁸, benzyl, NO₂, cyano, SR , SOR^b, SO₂R^b, COR^b, CO₂R^b, CONR^bR^c, C₂.₆alkenyl, C₂-₆alkynyl, Cι-4alkoxyCι.₄alkyl, -O(CH2)mO- or a heteroaromatic group selected from furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyridyl substituted by a group selected from halogen, haloCi-ealkyl and haloCi-ealkoxy (where R^b and R^c each independently represent hydrogen, Cι-4alkyl, Cs-scycloalkyl or fluoroCι-4alkyl and m is 1 or 2).

Preferably said phenyl, biphenyl or naphthyl group is optionally substituted by one or two substituents, especially none or one. Particularly preferred substituents include fluorine, chlorine, Cι-4alkyl (especially methyl or t-butyl), Cι-4alkoxy (especially methoxy), trifluoromethyl or trifiuoromethoxy.

As used herein, the term "heteroaryl" as a group or part of a group means a 5 or 6-membered monocyclic heteroaromatic radical containing from 1 to 4 nitrogen atoms or an oxygen atom or a sulfur atom, or a combination thereof, or an 8- to 10-membered bicyclic heteroaromatic radical containing from 1 to 4 nitrogen atoms or an oxygen atom or a sulfur atom or a combination thereof. Suitable examples include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl and cinnolinyl, wherein said heteroaromatic radicals may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci-βalkyl, Ci-βalkoxy, haloCi-ealkyl, haloCi-ealkoxy, NR⁷R⁸, phenyl, phenyl substituted by a group selected from halogen, haloCi-ealkyl and haloCi-ealkoxy, benzyl, NO₂, cyano, SR^b, SOR^b, SO2 ^b, COR^b, CO₂R , CONR R^c, C^alkenyl, C^alkynyl, Cι.4alkoxyCι- alkyl, -O(CH₂)_mO- or an additional heteroaromatic group selected from furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyridyl substituted by a group selected from halogen, haloCi-ealkyl and haloCi-ealkoxy (where R^b, R^c and m are as previously defined). Preferably said heteroaromatic radical is optionally substituted by one or two substituents, especially none or one. Particularly preferred substituents include Cι-4alkyl (especially methyl or tert-butyl), Cι-₄alkoxy (especially methoxy), trifluoromethyl, trifiuoromethoxy, phenyl, phenyl substituted by halogen (especially fluorine) and Cι-4alkyl (especially methyl), benzyl, or thienyl.

As used herein, the term "carbocyclyl" as a group or part of a group means a 3 to 7-membered cycloalkyl radical such as cyclobutyl, cyclopentyl or cyclohexyl, wherein said cycloalkyl radical may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci-βalkyl, Ci-ealkoxy, haloCi-ealkyl, haloCi-ealkoxy, NR⁷R⁸, phenyl, phenyl substituted by a group selected from halogen, haloCi-ealkyl and haloCi-ealkoxy, benzyl, NO2, cyano, NR^bR^c, SR^b, SOR , SO₂R^b, COR , CO₂R^b, CONR R^c, C₂.₆alkenyl, C₂-₆alkynyl, Cι-4alkoxyCι-4alkyl, -O(CH.2)mO- or a heteroaromatic group selected from furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyridyl substituted by a group selected from halogen, haloCι-6alkyl and haloCi-ealkoxy (where R^b, R° and m are as previously defined). Preferably said carbocyclyl group is optionally substituted by one or two substituents, especially none or one. A particularly preferred substituent is phenyl.

As used herein, the term "fused-carbocyclyl" as a group or part of a group means a 3 to 7-membered cycloalkyl radical such as cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, wherein said cycloalkyl radical is fused to an aryl or heteroaryl group as herein defined. Preferably, said fused-carbocylyl group is attached to the remainder of the molecule via a carbon atom of the cycloalkyl radical. Preferably, said cycloalkyl radical is fused to a phenyl or pyridyl ring where said phenyl ring is optionally substituted by a group selected from halogen (especially fluorine) and fl.uoroCι.4alkyl (especially trifluoromethyl), furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, and said pyridyl ring is optionally substituted by a group selected from halogen (especially fluorine) and fl.uoroCι.4alkyl (especially trifluoromethyl). Preferably said cycloalkyl radical is fused to a phenyl ring. Particular compounds of the invention include:

N-benzyl-iV-isoquinoHn-5-ylurea

N-(l,l'-biphenyl-4-ylmethyl)-N¹-isoquinohn-5-ylurea

N-(l,r-biphenyl-3-ylmethyl)-N-isoquinoHn-5-ylurea

N-isoquinolin-5-yl-iV¹-(3-phenylpropyl)urea; N-isoqιύnolin-5-yl-N-(l,2,3,4-tetrahydronaphthalen-2-ylmethyl)urea;

N-[2-(4-chlorophenyl)ethyl]-N-isoquinohn-5-ylurea;

N-fS^-bis^rifluoromethy^benzylj-iV-isoquinolin-δ-ylurea;

N-[3-(3,4-dimethylphenyl)propyl]-iV^,-isoquinolin-5-ylurea;

N-(4-tert-butylbenzyl)-N-isoquinolin-8-ylurea; N-(4-tert-butylbenzyl)-N-isoquinolin-5-ylurea;

N-(4-tert-butylbenzyl)-N-quinolin-5-ylurea;

N-(3-tert-butylbenzyl)-N-isoquinolin-5-ylurea;

N-[2-(4-tert-butylphenyl)ethyl]-N-isoquinohn-5-ylurea;

N-isoquinolin-5-yl-N-[4-(trifluorometlιyl)benzyl]urea; N-isoquinohn-δ-yl-iV-fS-^riiluoromethy^benzyyurea;

N-isoquinolin-5-yl-iV¹-{2-[4-(trifluoromethyl)phenyl]ethyl}urea;

N-(2-oxidoisoquinolin-5-yl)-N¹-[4-(trifl.uoromethyl)benzyl]urea;

N-isoquinohn- 5 -γl-N- {2- [3-(trifl.uoromethyl)phenyl] ethyl}urea; N-isoquinohn- 5 -γl-N-{3 - [4- (trifluoromethyl)phenyl] propyl}urea;

N-isoquinolin-8-yl-IV¹- [4-(trifluoromethyl)benzyl] urea;

N-[3-fl.uoro-4-(trifi.uoromethyl)benzyl]-iV¹-isoquinoHn-5-ylurea;

N-[2-fl.uoro-4-(trifluoromethyl)benzyl]--Y-isoquinolin-5-ylurea;

N-isoquinolin-5-yl-iV¹-{3-[3-(trrfl.uoromethyl)phenyl]propyl}urea; N-isoqxύnolin-5-yl-iV^,-[4-(trifluoromethoxy)benzyl]urea;

N-{[6-(4-fluorophenyl)pyridin-3-yl]methyl}-N-isoquinolin-5-ylurea;

N-isoquinohn-8-yl-iV-{3-[4-(trifluoromethyl)phenyl]propyl}urea;

N-quinohn-δ-yl-N-lS-^-^rifluoromethy^phenyypropyllurea;

N-isoquinoHn-δ-yl-iV-fS-p-^rifluoromethy^phenyypropylJurea; N-quinohn-δ-yl-iV-lS-fS-^rifluoromethyyphenyljpropy^urea;

N-isoquinolin-8-yl-iV - [4- (trifluoromethoxy)benzyl] ure a;

N-quinoHn-δ-yl-.N-[4-(trifluoromethoxy)benzyl]urea;

N-(2, 3-dihydro- lH-inden-2-ylmethyl)-N-isoquinolin-5-ylurea;

N-isoquinoΗn-5-yl-N-(4-phenylcyclohexyl)urea; N-isoquinoΗn-δ-yl-N-(6,7,8,9-tetrahydro-δH-benzo[α][7]annulen-6-ylmethyl)urea;

N-isoquinoUn-δ-yl-iV¹-(6,7,8,9-tetrahyα^,ro-δH-benzo[α][7]annulen-7-ylmethyl)urea;

N-isoquinoΗn-δ-yl-iV^,-{[δ-(trifluoromethyl)pyridin-2-yl]methyl}urea;

N-[(4-tert-butylpyri(hn-2-yl)methyl]-iV¹-isoqvdnolin-δ-ylurea;

N- [(6-tert-butylpyridin-3-yl)methyl] -iV^-isoquinolin-δ-ylurea; N-[(2-ter^butylpyridin-4-yl)methyl]-iV^,-isoqvιinolin-δ-ylurea;

N-[(6-tert-butylpyridin-2-yl)methyl]-N-isoqvιinolin-δ-ylurea;

N-isoquinolin-δ-yl-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}urea;

N-isoquinohn-δ-yl-iV-lS-te-^rifluoromethy^pyridin-S-yllpropylJurea;

N-isoquinolin-δ-yl-N-[3-(lH-pyrazol-l-yl)benzyl]urea; N-isoquinoΗn-δ-yl-N-[4-(lH-pyrazol-l-yl)benzyl]urea;

N-isoquinolin-δ-yl-iV^t-[(2-phenyl-l,3-thiazol-δ-yl)methyl]urea;

N-isoquinoπn-δ-yl-N-[(2-thien-2-yl-l,3-thiazol-4-yl)methyl]urea;

N-isoquinoΗn-δ-yl-iV¹-[(4-phenyl-l,3-thiazol-2-yl)methyl]urea;

N-isoquinolin-δ-yl-iV- [(2-phenyl- 1, 3-thiazol-4-yl)methyl] urea; N-isoquinohn-δ-yl-iV¹- [2-(4-phenyl- 1, 3-thiazol-2-yl)ethyl]urea;

N-isoquinolin-δ-yl-Λ^-[(δ-phenyhsoxazol-3-yl)methyl]urea;

N-isoquinolin-δ-yl-iV-KS-phenyUsoxazol-δ-y^methyyurea;

^(δ-fluoroisoquinohn-δ-y^-N-^-^rifluoromethy^benzyyurea; δ N-isoquinolin-δ-yl-N-methyl-iV¹- [4-(trifluoromethyl)benzyl]urea;

N¹ -isoquinohn-δ -yl-N-methyl-N- [4- (trifluoromethyl)benzyl] urea;

N-isoquinoHn-δ-yl-N-ll-^-^rifluoromethy^phenyllethylJurea;

N- ( 1, 3 -diphenylpropyl) -N-isoquinolin- δ-ylurea;

N-isoquinolin-δ-yl-N-[(3-phenyl-l,2,4-oxadiazol-δ-yl)methyl]urea; 10 N- [(2-benzyl- 1, 3-thiazol-4-yl)methyl] -iV-isoqxiinolin-δ-ylurea;

N-isoquinoUn-δ-yl-iV¹-{[l-(2-methylphenyl)-lH-pyrazol-4-yl]methyl}urea;

^(S-methoxyisoquinohn-δ-y^-N'-^-^rifluoromethy^benzyyurea;

N-cinnoKn-δ-yl-N-[4-(trifluoromethyl)benzyl]urea;

N- (4- ter£-butylbenzyl) -N-cinnolin- δ -ylurea; lδ N-(3-cyclohexylpropyl)-N-isoquinoUn-δ-ylurea;

N-isoquinohn-δ-yl-iV¹-(6, 7, 8, 9-tetrahydro-δH-benzo [a] [7] annulen- 7-yl)urea;

N-isoquinolin-δ-yl-N-[4-(trifluoromethyl)benzyl]thiourea;

N-isoquinoΗn-6-yl-N-[4-(trifluoromethyl)benzyl]urea;

N-isoquinoHn-6-yl-N-[4-(trifluoromethoxy)benzyl]urea; 20 ^(S-methyHsoquinohn-δ-y^-N-^-^rifluoromethy^benzyllurea;

N-(l-chloroisoquinolin-5-yl)-N-[4-(trifluoromethyl)benzyl]urea;

N-[l-(dimethylamino)isoquinoHn-δ-yl]-iV-[4-(trifluoromethyl)benzyl]urea;

Λ -(3-methyhsoquinolin-δ-yl)-iV^,-[4-(trifluoromethoxy)benzyl]urea;

N-(3-methyHsoquinolin-8-yl)-N'-[4-(trifluoromethyl)benzyl]urea; 2δ N-(3-chloroisoquinoUn-5-yl)-N-[4-(trifluoromethyl)benzyl]urea;

N- (3-methylcinnolin- 5 -yl) -N- [4- (trifluoromethyl)benzyl] urea;

N-cinnohn-δ-yl-N-[4-(trifluoromethoxy)benzyl]urea;

^(l-hydroxyisoquinohn-δ-y^-iV-^-^rifluoromethy^benzyllurea;

N-^-^rifluoromethy^benzylj-N-tS-^rifluoromethy^isoquinohn-δ-yllurea; 30 N-(l-chloro-3-ethyHsoquinoHn-5-yl)---V-[4-(trifluoromethyl)benzyl]urea;

N-phenyl-N'- [quinolin- 6-yl] urea;

N-(2-naphthyl)-N'-[quinoMn-6-yl]urea;

N-(4-nitrophenyl)-N'-[quinohn-6-yl]urea;

N- [3, δ-bis(trifl.uoromethyl)phenyl] -N'- [quinolin-6-yl]urea; N-(4-phenoxyphenyl)-N'-[quinohn-6-yl]urea;

N-(4-acetylphenyl)-N'-[quinolin-6-yl]urea;

N-benzyl-N'- [quinohn-6-yl]urea;

N- [quinohn-6-yl] -N'- [4-(trifluoromethoxy)phenyl] urea; δ N-(4-cyanophenyl)-N'-[quinolin-6-yl]urea;

N-(l,l'-biphenyl-4-yl)-N'-[quinohn-6-yl]urea;

N- [4-(dimethylamino)phenyl] -N'- [quinohn-6-yl] urea;

N-(l,3-benzodioxol-δ-yl)-N'-[quinolin-6-yl]urea;

N-cyclohexyl-iV'- [quinohn- 6-yl] urea; 10 N- [(+/-)- 1-phenylethyl] -N'- [quinohn-6-yl]urea;

N-(l-methylisoquinoUn-δ-yl)-Λ^-[4-(triQ.uoromethyl)benzyl]urea;

N-(l-methyHsoquinoHn-5-yl)-Λ^?,-[4-(trifluoromethoxy)benzyl]urea;

^(βjδ-difluoro-S-methyHsoquinoHn-δ-y^-N-^-^rifluoromethy^benzyljurea;

N-[3-methyl-7-(trifluoromethyl)isoquinoUn-δ-yl]-iV¹-[4- lδ (trifluoromethyl)benzyl]urea;

^(S-fluoro-S-methyUsoquinolin-δ-y^-iV-^-^rifluoromethy^benzyyurea;

N-(6-fluoro-3-methyhsoquino-lin-δ-yl)-iv¹-[4-(trifluoromethyl)benzyl]urea;

N-(6-fl.uoro-3-methyHsoquinoUn-δ-yl)-iV¹-[4-(trifluoromethoxy)benzyl]urea;

N-(3-methylcinnohn-δ-yl)-N-[4-(trifluoromethoxy)benzyl]urea; 20 N-(7-methoxyisoquinoHn-δ-yl)-iV¹-[4-(trifluoromethyl)benzyl]urea;

N-(l,3-dimethylisoquinoUn-δ-yl)-N-[4-(trifluoromethyl)benzyl]urea;

N-(7-chloro-3-methyHsoquinolin-δ-yl)-iV^,-[4-(trifluoromethyl)benzyl]urea;

N-(7-chloroisoquinohn-δ-yl)-iV¹-[4-(trifluoromethyl)benzyl]urea;

N-(8-fluoro-3-metho-xyisoquinolin-δ-yl)-N-[4-(trifluoromethyl)benzyl]urea; 2δ N-(6-fluoroisoquinolin-δ-yl)-ΛT'-[4-(trifluoromethyl)benzyl]urea;

N-(6-fluoroisoquinohn-δ-yl)-N¹-[4-(trifluoromethoxy)benzyl]urea;

N-(7-fl.uoroisoquinolin-δ-yl)-N-[4-(trifluoiOmethyl)benzyl]urea;

N-(4-methyhsoquinoUn-δ-yl)-iV¹-[4-(trifluoromethyl)benzyl]urea;

N-tδ-^rifluoromethy^isoquinolin-δ-yll-N-^-^rifluoromethy^benzyyurea; 30 N-fβ-^rifluoromethy^isoquinolin-δ-yll-iV-^-^rifluoromethy^benzyyurea;

N-[7-(trifluoromethyl)isoquinohn-δ-yl]-iV¹-[4-(triιluoromethyl)benzyl]urea;

N-[7-(trifluoromethyl)isoquinolin-δ-yl]-iV¹-[4-(trifluoromethoxy)benzyl]urea;

N-(6-fl-uoro-l-methylisoquinolin-δ-yl)-N'-[4-(trifluoromethyl)benzyl]urea;

N-(l-cyanoisoquinolin-δ-yl)-N-[4-(trifluoromethyl)benzyl]urea; N-[l-(methoxycarbonyl)isoquinoHn-δ-yl]-N-[4-(triQ.uoromethyl)benzyl]urea;

N-(l-carboxyisoquinohn-δ-yl)-N-[4-(trifl.uoromethyl)benzyl]urea;

N-(l-aminoisoquinoHn-δ-yl)-Λ^-[4-(trifluoromethyl)benzyl]urea;

N-fl-diydroxymethy^isoquinohn-δ-yy-A^-^-^ri luoromethy^benzyyurea; 5 N- [3-(methoxycarbonyl)isoquinolin-δ-yl] -N'- [4-(trifl.uoromethyl)benzyl]urea;

N-(3-carboxyisoqxιinolin-δ-yl)-N-[4-(trifl.uoromethyl)benzyl]urea;

N-[3-(dimethylamino)isoquinoHn-δ-yl]-iV¹-[4-(trifluoromethyl)benzyl]urea;

N- [3-(2-aminoethyl)isoquinoUn-δ-yl] -N- [4-(trifl.uoromethyl)benzyl] urea;

^(S-methoxyisoquinohn-δ-y^-iV-^-^rifluoromethy^benzylJurea; 10 N-isoquinolin-7-yl-N'- [4-(trifhιoromethyl)benzyl]urea;

N-N-dϋsoquinolin-δ-ylurea;

N-isoquinoMn-δ-yl-N'-^-^rifluoromethy^phenyyurea;

N-isoquinoUn-δ-yl-N-{[2-(trifluoromethyl)pyrimidin-δ-yl]methyl}urea; ethyl 3-{[(isoquinohn-δ-ylamino)carbonyl] amino}-2- [4-(trifluoromethyl)benzyl] lδ propanoate;

3-{[(isoquinoUn-δ-ylamino)carbonyl]amino}-2-[4-(trifl.uoromethyl)benzyl]propanoic acid;

N-isoquinoUn-5-yl-iV¹-[4-(morpholin-4-ylmethyl)benzyl]urea; and

N-isoquinohn-5-yl-N-[2-(2-morpholin-4-ylethoxy)-4-(trifluoromethyl)benzyl]urea; 20 or a pharmaceutically acceptable salt or N-oxide thereof.

In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.

For use in medicine, the salts of the compounds of formula (I) will be 2δ non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound 30 according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p -toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry a acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or δ magnesium salts.

The salts may be formed by conventional means, such as by reacting the free base form of the compound of formula (I) with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by 10 exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.

The present invention also includes within its scope N-oxides of the compounds of formula (I) above. In general, such N-oxides may be formed on any available nitrogen atom, and preferably on any one of A, B, D or E where they lδ represent a nitrogen atom. The N-oxides may be formed by conventional means, such as reacting the compound of formula (I) with oxone in the presence of wet alumina.

The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of 20 the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 198δ.

A prodrug may be a pharmacologically inactive derivative of a biologically 25 active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecxile. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or 30 reduction or oxidation of a susceptible functionality.

The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention may have one or more asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, the compounds of formula (I) may also exist in tautomeric forms and the invention includes within its scope both mixtures and separate individual tautomers.

It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred classes of compound represented by formula (la) and formula (lb).

The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.

Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto- injector devices, suppositories, creams or gels; for oral, parenteral, intrathecal, intranasal, sublingual, rectal or topical administration, or for administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Favoured unit dosage forms contain from 1 to 500 mg, for example 1, 5, 10, 2δ, δO, 100, 300 or δOO mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric δ layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

10 The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or lδ suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of painful conditions such as those listed below, a suitable dosage level is about 1.0 mg to lδ g per day, preferably about δ.O mg to

20 δ g per day, and especially about 20 mg to 2 g day. The compounds may be administered on a regimen of 1 to 4 times per day.

It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the

2δ nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.

The invention further provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in treatment of the human or animal body. Preferably, said treatment is for a condition which is

30 susceptible to treatment by modulation (preferably antagonism) of VRl receptors. The compounds of the present invention will be of use in the prevention or treatment of diseases and conditions in which pain and/or inflammation predominates, including chronic and acute pain conditions. Such conditions include rheumatoid arthritis; osteoarthritis; post-surgical pain; musculo-skeletal pain, particularly after trauma; spinal pain; myofascial pain syndromes; headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain; ear pain; episiotomy pain; burns, and especially primary hyperalgesia associated 5 therewith; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, pain associated with cystitis and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions,

10 amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; itching conditions including pruritis, itch due to hemodialysis, and contact dermatitis; pain (as well as broncho-constriction and inflammation) due to exposure (e.g. via ingestion, inhalation, or eye contact) of mucous membranes to capsaicin and related irritants such as tear gas, hot lδ peppers or pepper spray; neuropathic pain conditions such as diabetic neuropathy, chemotherapy-induced neuropathy and post-herpetic neuralgia; "non-painful" neuropathies; complex regional pain syndromes; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage, low back pain, sciatica and

20 . ankylosing spondyHtis; gout; scar pain; irritable bowel syndrome; inflammatory bowel disease; urinary incontinence including bladder detrusor hyper-refl-exia and bladder hypersensitivity; respiratory diseases including chronic obstructive pulmonary disease (COPD), chronic bronchitis, cystic fibrosis and asthma; autoimmune diseases; and immunodeficiency disorders.

25 Thus, according to a further aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment or prevention of physiological disorders that may be amehorated by modulating VRl activity.

The present invention also provides a method for the treatment or

30 prevention of physiological disorders that may be amehorated by modulating VRl activity, which method comprises administration to a patient in need thereof of an effective amount of a compound of formxila (I) or a composition comprising a compound of formula (I). According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment or prevention of a disease or condition in which pain and/or inflammation predominates. 5 The present invention also provides a method for the treatment or prevention of a disease or condition in which pain and/or inflammation predominates, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) or a composition comprising a compound of forπmla (I).

10 According to a further aspect of the present invention, it may be desirable to treat any of the aforementioned conditions with a combination of a compound according to the present invention and one or more other pharmacologically active agents suitable for the treatment of the specific condition. The compound of formula (I) and the other pharmacologically active agent(s) may be lδ administered to a patient simultaneously, sequentially or in combination.

Thus, for example, for the treatment or prevention of pain and/or inflammation, a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs, including selective cyclooxygenase-2 (COX- 2) inhibitors, as well as opioid

20 analgesics, especially morphine, NR2B antagonists, bradykinin antagonists, anti-migraine agents, anticonvulsants such as oxcarbazepine and carbamazepine, antidepressants (such as TCAs, SSRIs, SNRIs, substance P antagonists, etc.), spinal blocks, gabapentin, pregabalin and asthma treatments (such as β2-adrenergic receptor agonists or leukotriene D4antagonists (e.g. montelukast).

2δ Specific anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, nabumetone, ketoprofen, naproxen, piroxicam and sulindac, etodolac, meloxicam, rofecoxib, celecoxib, etoricoxib, parecoxib, valdecoxib and tilicoxib. Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine,

30 hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof. Suitable anti-migraine agents of use in conjunction with a compound of the present invention include CGRP-antagonists, ergotamines or δ-HTi agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.

Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.

In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use

10 in the treatment or prevention of a disease or condition in which pain and/or inflammation predominates.

According to a general process (A), compounds of formula (I) may be prepared by the reaction of a compound of formula (II) with a compound of formula (III): lδ

(ID (III)

The reaction is conveniently effected at a temperature between 20°C and the reflux temperature of the solvent. Suitable solvents include a halogenated 20 hydrocarbon, for example, dichloromethane.

Similarly, according to a general process (B), compounds of formula (I) may also be prepared by the reaction of a compound of formula (IV) with a compound of formula (V):

(IV) (V)

The reaction is essentially effected in the same manner as general process

(A).

According to an alternative general process (C), compounds of formula (I), in which X is an oxygen atom, may be prepared by the reaction of a compound of formula (II) with a compound of formula (VI):

(VI)

The carboxylic acid is first reacted with diphenylphosphoryl azide and triethylamine which forms the corresponding isocyanate by a Curtius rearrangement. The isocyanate may then be reacted in situ with the amine of formula (II) by heating at reflux to give the desired compound of formula (I). The reactions are conveniently effected in a suitable solvent such as an aromatic hydrocarbon, for example, toluene.

Similarly, according to a general process (D), compounds of formula (I), in which X is an oxygen atom, may also be prepared by the reaction of a compound of formula (V) with a compound of formula (VII):

(VII)

The reaction is essentially effected in the same manner as general process (C). Further details of suitable procedures will be found in the accompanying

Examples. For instance, compounds of formula I can be converted into other compounds of formula I utilising synthetic methodology well known in the art. For example, when R² is a chlorine atom it can be converted to a cyano group using zinc chloride by heating, generally to about 80°C, in the presence of a catalyst such as triphenylphosphine palladium under an inert atmosphere for about three days. When R² is a carboxylic ester it can be hydrolysed in the presence of a basic catalyst to the carboxylic acid by known methods. This compound can be converted to an amine group utilising diphenylphosphoryl azide, generally in the presence of a base such as triethylamine, a solvent such as dioxane, under an inert atmosphere and with heating to about 100°C for about 90 minutes, followed by the addition of water, generally with further heating, for about an hour. The carboxylic ester can be selectively reduced to a hydroxymethyl group with lithium borohydride, generally in a solvent, such as a mixture of tetrahydrofuran and toluene, at 60°C for about lh. Compounds of formulae (III) and (IV) in which X is an oxygen atom may be prepared in situ, as described in general process (C), or they may be prepared from the corresponding carboxyUc acid of formulae (VT) and (VII), respectively, by first being converted into the corresponding acyl halide by reaction with, for example, oxalyl chloride. The acyl halide is then converted into the corresponding acyl azide by reaction with, for example, with sodium azide. The desired isocyanate is then obtained by a conventional Curtius rearrangement by heating the acyl azide at reflux. The reactions are conveniently effected in a suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane.

Compounds of formula (III) and (TV) in which X is a sulfur atom may be prepared from the corresponding amine of formula (IV) and (II), respectively 5 (wherein R⁸ and R⁴ are hydrogen), by reaction with l,l'-thiocarbonyl-2(lH)- pyridone. The reaction is conveniently effected at room temperature in a suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane.

Compounds of formulae (II) to (Nil) are either known compounds or may be prepared by conventional methodology well known to one of ordinary skill in 10 the art using, for instance, procedures described in the accompanying Examples, or by alternative procedures which will be readily apparent.

For example, compounds of formula II in which B is a nitrogen atom and A, D and E are carbon atoms, one group R² is present at the 3 -position and R³ is hydrogen, can be made by reacting a compound in which the amino group is lδ absent with a mixture of concentrated sulfuric acid and fuming nitric acid at about 0°C for about 30 minutes followed by reduction of the resultant nitro group for example using hydrogen and Lindlar catalyst, in a solvent such as methanol.

This compound can be made by reacting a compound of formula VIII:

20 (VIII)

in which R¹ is as defined above with ammonia, generally at about 80°C for about δ hours, at a pressure of about 3δ psi in a Parr apparatus.

The compound of formula VIII can be made by successively reacting a 2δ compound of formula IX:

in which R¹ is as defined above with a carbonylating agent such as dichloromethyl methylether in a solvent such as dichloromethane in the presence δ of a catalyst such as titanium tetrachloride at about room temperature for about an hour. The methoxy group is converted to a hydroxy group using a reagent such as borontribromide in a solvent such as dichloromethane at about room temperature for several hours. This compound is optionally activated, for example by forming the trifluoromethylsulfonate using trifluoromethanesulfonic 10 anhydride generally in the presence of a base such as triethylamine and a solvent such as dichloromethane for about one hour at room temperature. This compound is reacted with a solution of a compound of formula X:

R

(X) lδ in which R² is as defined above, which solvent is generally DMF, in the presence of a base such as triethylamine and preferably catalysts such as dichlorodi(triphenylphosphine)paIladium at about room temperature for two to four hours. An alternative activation can also occur by making the bromide in

20 place of the trifluoromethane sulfonate.

The carbonyl moiety in the compounds of formula VIII can also be produced by selectively reducing a carboxylic acid moiety using a reagent such as borane tetrahydrofuran complex in tetrahydrofuran, at about room temperature for about 4 hours, to the alcohol followed by selective oxidation to the aldehyde

2δ using, for example, oxalyl chloride in DMSO in a solvent such as dichloromethane at about room temperature for about an hour.

Compounds of formula II in which one group R² is present at the 3-position, B is nitrogen and A, D and E are carbon can also be made by reacting a compound of formula (XI):

(XI)

in which R¹ is as defined above, with the acetal of a compound of formula H2NCHR²CHO, in which R² is as defined above, generally at reflux for about 2 hours under Dean/Stark conditions followed by the addition of an acid such as concentrated sulfuric acid at a temperature of about 140°C for about 30 minutes.

Compounds of formula II in which an alkyl group is present at the 1- position can be made by the following sequence. A compound of formula (XII):

in which R¹ and R² are as defined above, is reacted with an alkylating agent, such as the appropriate Grignard reagent, generally in a solvent such as tetrahydrofuran for several hours at about room temperature followed by ehmination of water under acidic conditions, to produce the corresponding indene. This is converted to the corresponding epoxide, for example using ozone at a temperature of about -78°C for about 9% hours. This is followed by reacting with ammonium hydroxide at about room temperature for about 2 days to produce the isoquinoline which is then nitrated and reduced to produce the amine.

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The following non-limiting Examples serve to illustrate the preparation of compounds of the present invention:

The structures of the products of the following Descriptions and Examples were in most cases confirmed by Η NMR.

Description 1

2- Cyano- δ -(trifluoromethvDp yridine

To an ice-cooled solution of δ-(trifluoromethyl)pyridin-2-ol (10.24 g, 62.8 mmol) in anhydrous dichloromethane (200 ml) was added triethylamine (9.63 ml , 69 mmol), followed by dropwise addition of trifluoromethanesulfonic anhydride (12.68 ml , 7δ.4 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with water (600 ml) and the aqueous layer extracted with dichloromethane (2 x 100 ml). The combined organic layers were washed with water (2 x 300 ml), brine (lδO ml), then dried over Na2SO4, filtered through a 1 inch plug of silica gel and evaporated. The residue was dissolved in anhydrous N,N-dimethylformamide (150 ml) and zinc cyanide (3.98 g, 33.9 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (Pd(PPli3)4) (3.56 g, 3.09 mmol). The mixture was degassed and heated at 80 °C overnight. The cooled reaction mixture was diluted with water (600 ml) and extracted with ethyl acetate (3 x 150 ml). The combined organic layers were washed with water (2 x 250 ml), brine (150 ml), dried (Na2SO₄) and evaporated. The residue was purified by column chromatography on sihca eluting with a gradient rising from neat iso-hexanes to 10% Et2θ in iso-hexanes to give the title compound (8 g, 7δ%) as a white solid.

Description 2

2-Aminomethyl-5-(trifluoromethyl.pyridine

To a nitrogen flushed solution of 2-cyano-5-(trifluoromethyl)pyridine (Description

1; 8.0 g, 46.δmmol) in a mixture of ethanol (100 ml) and ammonium hydroxide (2δ ml) was added a spatula end of Raney Nickel and the resulting mixture hydrogenated at 60 psi overnight. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient rising from 2% MeOH in δ dichloromethane + 0.5% NH₄OH to 5% MeOH in dichloromethane + 0.5% NH₄OH to give the title compound (2.5 g, 30%) as a yellow oil.

Description 3 0 To a solution of 4-teri-butylpyridine (44.3 ml, 300 mmol) in glacial acetic acid (200 ml) was added hydrogen peroxide (37.1 ml of a 27.5 % aqueous solution, 300 mmol), and the resulting mixture heated at reflux overnight. The cooled mixture was evaporated to dryness. The residue was dissolved in dichloromethane (200 ml), and washed with brine (50 ml), then dried (Na SO ) 5 and evaporated to give the title compound (40 g, 88%) as a white solid.

Description 4

2- Cyano-4- tert-butylp yridine

To trimethylsilylcyanide (2δ.O ml, 187.δ mmol) was added a solution of 4-tert- 0 butylpyridine-N-oxide (Description 3; 22.68 g, lδO mmol) in anhydrous dichloromethane (200 ml). To this mixture was added dropwise a solution of dimethyl carbamoyl chloride (17.26 ml, 187.6 mmol) in anhydrous dichloromethane (δO ml). The reaction mixture was stirred at room temperature for 24 hours. A solution of 10% aqueous K2CO3 (200 ml) was added dropwise and δ the resulting mixture stirred for 10 minutes. The organic layer was separated and the aqueous layer extracted with 2 further portions of dichloromethane (100 ml). The combined organic layers were dried (Na2SO4) and evaporated to give the title compound (24 g, 100%).

0 Description 5

2-Aminomethyl-4-tert-butylpyridine

A solution of 2-cyano-4-tert-butylpyridine (Description 4; 24.0 g, lδO mmol) was hydrogenated according to the method of Description 2. Following removal of the catalyst, the residue was taken up in dichloromethane (300 ml) and washed with brine, dried over K2CO3, filtered and evaporated. The residue was purified by column chromatography on silica eluting with δ% MeOH in dichloromethane + 0.δ% NH4OH to give the title compound (12 g, 48%) as a pale yellow oil.

δ Description 6

2- |^"4-(Trifluoromethyl)phenyll ethylamine

A solution of [4-(trifluoromethyl)phenyl]acetonitrile (9.98 g, δ3.9mmol) was hydrogenated according to the method of Description 2. Following removal of the catalyst, the residue was purified by column chromatography on sihca eluting 0 with 4% MeOH in dichloromethane + 0.δ% NH4OH to give the title compound (6.δ g, 63%) as an orange oil.

Description 7

3-ter£-Butylphenyl trifluoromethane sulfonate 5 To an ice-cooled solution of 3-tert-butylphenol (10 g, 66.6 mmol) and triethylamine (13.92 ml, 99.9 mmol) in anhydrous dichloromethane (100 ml) under an atmosphere of nitrogen was added slowly trifluoromethanesulfonic anhydride (12.30 ml, 73.26 mmol), and the resulting mixture stirred at room temperature for 2 hours. The mixture was then washed with IN HCl (100 ml), 0 brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica eluting with iso-hexanes to give the title compound (16.38 g, 87%) as a clear oil.

Description 8

To a solution of 3-teri-butylphenyl trifluoromethane sulfonate (Description 7; 16.37 g, 58 mmol) in anhydrous N,N-dimethylformamide (200 ml) was added zinc cyanide (8.17 g, 69.6 mmol), and Pd(PPli3)4 (3.3δ g, 2.9 mmol) and the mixture was then degassed (N2) and heated at 80 °C overnight. The cooled reaction 0 mixture was poured into water (7δ0 ml), and extracted with ethyl acetate

(3 x 200 ml). The combined organic layers were washed with water (2 x 300 ml), brine (200 ml), dried (Na2SO₄), filtered through a 1 cm plug of silica and evaporated to give the title compound (7 g, 76%). Description 9

3-tert-Butylbenzylamine

A solution of 3-terf-butylbenzonitrile (Description 8; 7.0 g, 44 mmol) was hydrogenated according to the method of Description 2. Following removal of the δ catalyst, the residue was taken up in dichloromethane (100 ml), washed with brine, dried (Na2SO4), filtered through a short plug of sihca and evaporated to give the title compound (δ.2 g, 72%) as a red oil.

Description 10

10 2-tert-Butyl-δ-cvanopyridine

To a mixture of 3-cyanopyridine (10 g, 96 mmol), trimethylacetic acid (9.8 g, 96 mmol) and silver nitrate (1.63 g, 9.6 mmol) in 10% aqueous sulfuric acid (100 ml) at 70°C was added dropwise a solution of ammonium peroxodisulfate (21.9 g, 96 mmol) in water (120 ml). After complete addition the mixture was lδ stirred at 70°C for 2 hours. The mixture was cooled and basified by the addition of 33% aqueous NH4OH, and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine (100 ml), dried (Na2SO4) and evaporated to give the title compound (lδ.6 g, 100%).

20 Description 11

3-Aminomethyl-6-tert butylpyridine

A solution of 2-tert-butyl-δ-cyanopyridine (Description 10; lδ.δ g, 97 mmol) was hydrogenated according to the method of Description 2. Following removal of the catalyst, the residue was purified by column chromatography on sihca eluting 2δ with δ% MeOH in dichloromethane + 0.δ% NH4OH to give the title compound (10.5 g, 66%), as a pale yellow oil.

Description 12

2-tert-Butyl-4-cvanopyridine 30 A mixture of 4-cyanopyridine (10 g , 96 mmol), trimethylacetic acid (9.8 g,

96 mmol), and silver nitrate (1.63 g , 9.6 mmol) in 10% aqueous sulfuric acid (100 ml) at 70°C was treated with a solution of ammonium peroxodisulfate (21.9 g, 96 mmol) in water (120 ml) according to the method of Description 10. Purification by column chromatography on silica eluting with 10% Et₂O in iso-hexanes gave the title compound (6.δ g, 42%).

Description 13 δ 4- Aminomethyl- 2- tert-butylp yridine

A solution of 2-tert-butyl-4-cyanopyridine (Description 12; 6.δ0 g, 40.6 mmol) was hydrogenated according to the method of Description 2. Following removal of the catalyst, the residue was taken up in dichloromethane (100 ml), washed with brine, dried (Na2SO4), filtered through a short plug of silica and evaporated to 10 give the title compound (6.1 g, 91%) as a brown oil.

Description 14

2-Bromo-6-tert-butylpyridine

To potassium tert-butoxide (1.0M in tert butanol, 100 ml, 100 mmol) was added lδ 2,6-dibromopyridine (lδ.87 g, 67 mmol), and the resulting mixture heated at reflux for 3.δ hours. The mixture was evaporated and the residue quenched by the addition of water (150 ml). The mixture was extracted with ethyl acetate (3 x 80 ml) and the combined organic layers washed with brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography

20 on silica eluting with 2% Et₂O in iso-hexanes to give the title compound (9.9 g, 69%) as a clear oil.

Description 15

25 To a solution of 2-bromo-6-tert-butylpyridine (Description 14; 9.9 g, 46 mmol) in anhydrous N,N-dimethylformamide (130 ml) was added zinc cyanide (6.48 g, 5δ.2 mmol) and Pd(PPli3)4 (2.6δ g, 2.3 mmol). The mixture was degassed then heated at 80 °C overnight. The cooled reaction mixture was poured into water (δOO ml), and extracted with ethyl acetate (3 x lδO ml). The combined organic

30 layers were washed with water (2 x 300 ml), brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica eluting with δ% Et2θ in iso-hexanes to give the title compound (6.6 g, 89%). Description 16

2-Aminomethyl-6-tert-butylpyridine

A solution of 2-tert-butyl-6-cyanopyridine (Description lδ, 6.6 g, 41.2 mmol) was hydrogenated according to the method of Description 2. Following removal of the δ catalyst, the residue was taken up into dichloromethane (300 ml) and washed with brine, dried over K2CO3, filtered and evaporated. The residue was purified by column chromatography on silica eluting with δ% MeOH in dichloromethane + 0.δ% NH4OH to give the title compound (4.δ g, 66%) as a pale orange oil.

10 Description 17

(E/ )-3-r6-(Trifluoromethyl)pyridin-3-yllprop-2-enenitrile

To an ice-bath cooled suspension of sodium hydride (1.26 g of a 60% dispersion, 31.46 mmol) in anhydrous THF (7δ ml) was added dropwise a solution of diethyl cyanomethylphosphonate (δ.09 ml, 31.46 mmol) in THF (δO ml). After the lδ addition was complete the mixture was stirred for 10 minutes then a solution of 6-(trifluoromethyl)pyridine-3-carboxaldehyde (δ.00 g, 28.6 mmol) in THF (2δ ml) was added and the resulting mixture stirred at room temperature for 1 hour. Water (2δ0 ml) was added and the mixture extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with water (x2), brine,

20 dried (Na2SO₄) and evaporated. The residue was purified by column chromatography on silica eluting with a gradient rising from 10% ΕtOAc in isohexanes to 30% ΕtOAc in iso-hexanes to give the title compound - Ε and Z isomers were separated but then re-combined (δ.6 g, 100%).

2δ Description 18

3-r6-(Trifluoromethyl)pyridin-3-yllpropylamine

A solution of (E/Z)-3-[6-(trifluoromethyl)pyridin-3-yl]prop-2-enenitrile (Description 17; δ.60 g, 28.3mmol) was hydrogenated according to the method of Description 2. Following removal of the catalyst, the residue was purified by 30 column chromatography on silica eluting with δ% MeOH in dichloromethane + 0.6% NH4OH to give the title compound (3.δ g, δ7%). Description 19

1.2.3.4-Tetrahvdronaphthalene-2-carboxamide

To a suspension of l,2,3,4-tetrahydronaphthalene-2-carboxylic acid (6.08 g, 34. δ mmol) in anhydrous dichloromethane (60 ml) was added oxalyl chloride δ (4.δ2 ml, 51.8 mmol), followed by 2 drops of N,N-dimethylformamide and the resulting mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness, toluene (50 ml) was then added and the mixture evaporated to dryness again. The residue was dissolved in anhydrous dichloromethane (100 ml) and added in one portion to dichloromethane (150 ml)

10 which had been saturated with ammonia gas. The resulting mixture was stirred at room temperature for 48 hours. The mixture was evaporated to dryness and the residue partitioned between ethyl acetate (150 ml) and water (250 ml). The aqueous layer was further extracted with ethyl acetate (100 ml). The combined organic layers were washed with water (200 ml), brine (100 ml), then dried lδ (Na₂SO4) and evaporated to give the title compound (6 g, 99%) as a white solid.

Description 20

1.2.3.4-Tetrahydronaphthalen-2-ylmethylamine

To an ice-bath cooled solution of l,2,3,4-tetrahydronaphthalene-2-carboxamide

20 (Description 19; δ.99 g, 34.2 mmol) in anhydrous THF (lδO ml) was added in portions lithium aluminum hydride (2.6 g, 68.4 mmol). After complete addition, the mixture was heated to reflux for 3 hours then cooled in an ice bath and quenched carefully by the sequential addition of water (2.74 ml), 4N NaOH (2.74 ml) and water (8.2 ml). The resulting suspension was stirred for 10

2δ minutes, then filtered through Celite™ and the itrate evaporated to give the title compound (4.δ g, 81%).

Description 21

.2E/ )-3-r4-(Trifluoromethyl)phenyllprop-2-enenitrile 30 To a solution of 4-trifluoromethyhodobenzene (7.23 g, 26.6 mmol) in anhydrous acetonitrile (130 ml) was added triethylamine (3.74 ml, 26.6 mmol), acrylonitrile (1.77 ml, 26.6 mmol), palladium (II) acetate (60 mg, 0.26 mmol), and tri-o- tolylphosphine (324 mg, 1.06 mmol) and the resulting mixture heated at reflux overnight. The cooled reaction mixture was filtered through Celite™, and partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried (Na2SO₄) and evaporated. The residue was purified by column chromatography on silica eluting with δ% EtOAc in iso-hexanes to give the title compound (4.07 g, 78%). δ

Description 22 3-f4-(Trifluoromethyl)phenyllpropylamine

A solution of (2E/E)-3-[4-(trifluoromethyl)phenyl]prop-2-enenitrile (Description 21; 4.06 g, 20.6 mmol) was hydrogenated according to the method of 10 Description 2. Following removal of the catalyst, the residue was purified by column chromatography on silica eluting with 4% MeOH in dichloromethane + 0.δ% NH4OH to give the title compound (3.δ g, 83%) as an oil.

Description 23 lδ 3-[3-(Trifluoromethyl)phenyllpropylamine

To an ice-bath cooled suspension of sodium hydride (1.32 g of a 60% dispersion in oil, 33 mmol) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere was added dropwise a solution of diethyl cyanomethylphosphonate (δ.34 ml, 33 mmol) in tetrahydrofuran (40 ml) and the resulting mixture stirred

20 at 0 °C for lδ minutes. To this mixture was added a solution of

3-trifluoromethylbenzaldehyde (δ.22 g, 30 mmol) in anhydrous tetrahydrofuran (40 ml) and the resulting mixture stirred at room temperature for l.δ hours. Water (300 ml) was added and the mixture extracted with ethyl acetate (3 x lδO ml). The combined organic layers were washed with water (2 x 200 ml),

2δ brine (150 ml) then dried (Na2SO4) and evaporated. The residue was taken up in a mixture of ethanol (100 ml) and ammonium hydroxide (25 ml) and hydrogenated according to the method of Description 2. Purification by column chromatography on silica eluting with 5% MeOH in dichloromethane + 0.δ% NH4OH gave the title compound (l.δ g, 2δ%) as a yellow oil.

30

Description 24

6-(4-Fluorophenyl)nicotinamide

A mixture of 6-chloronicotinamide (δ.00 g, 31.9δ mmol), 4-fluorobenzene boronic acid (4.92 g, 3δ.l4 mmol), and Pd(PPh₃)₄ (1.10 g, 0.96 mmol) in a mixture of toluene (80 ml), ethanol (12 ml) and 2M sodium carbonate (36.74 ml, 73.48 mmol) was degassed (N2) and heated at 100 °C for 18 hours. The reaction mixture was cooled to room temperature and then filtered. The collected solid was washed with water and dried. The dried solid was taken up in methanol (100 ml) and δ heated to reflux for 20 minutes. The mixture was then cooled to room temperature, filtered and the solid dried to give the title compound (6.2δ g, 90%) as a pale grey sohd.

Description 25

10 f6-(4-Fluorophenyl)pyridin-3-yllmethylamine

To an ice-bath cooled solution of sodium borohydride (δ.47 g, 144.6 mmol) in anhydrous 1,4-dioxane (100 ml) was added slowly a solution of glacial acetic acid (8.27 ml, 144.δ mmol) in 1,4-dioxane (50 ml). To this mixture was added 6-(4-fluorophenyl)nicotinamide (Description 24; 6.25 g , 28.9 mmol) and the lδ resulting mixture heated at reflux for 4 hours. The cooled reaction mixture was evaporated and water (60 ml) added slowly. This mixture was extracted with dichloromethane, and the sohd which appeared between the layers was removed by filtration. This sohd was triturated with a mixture of dichloromethane and iso-hexanes, filtered and dried to give the title compound (δlO mg, 8%) as a pale

20 green sohd.

Description 26

6.7.8.9-Tetrahvdro-δH-benzorαir71annulen-6-ylmethylamine hydrochloride

To a nitrogen flushed solution of methyl 6,7-dihydro-5H-benzo[α][7]annulene-8-

2δ carboxylate [J. Org. Chem. 1991, 56, 6199-6206] (δ4.8 g, 271 mmol) in a mixture of ethyl acetate (2δ0 ml) and glacial acetic acid (δ ml) was added 10% palladium on carbon (10 g) and the mixture was hydrogenated at δδ psi for 16 hours. The catalyst was removed by filtration, and the filtrate evaporated to dryness. The residue was dissolved in ethanol (δδ ml) and 3M aqueous NaOΗ (165 ml,

30 495 mmol) was added, then the resulting mixture heated to reflux for 2 hours. The mixture was cooled and the ethanol removed by evaporation. The aqueous phase was washed with dichloromethane (x 3) then acidified to pΗ=l with 6M HCl and extracted with dichloromethane (x 3). The combined organic phases from the acidic extraction were dried over MgSO4, filtered and evaporated. The residue was triturated with tert-butyl methyl ether, filtered and dried to give 6,7,8,9-tetrahydro-δH-benzo[α][7]annulene-6-carboxylic acid (20.6 g, 40%). This material was dissolved in dichloromethane (100 ml) containing N,N-dimethylformamide (O.δ ml) and oxalyl chloride (9.68 ml, 111 mmol) δ dropwise at such a rate that the internal temperature did not rise above 10 °C. The mixture was stirred at δ °C for 30 minutes, then treated dropwise with 33% aqueous ammonium hydroxide (100 ml) whilst maintaining the temperature below lδ °C. The resulting slurry was then stirred at 10 °C for 30 minutes. The mixture was evaporated and the residue diluted with water and slurried at 0 °C

10 for lδ minutes. The resulting white solids were filtered, washed with more water, hexanes, and dried to give 6,7,8.9-tetrahydro-δH-benzo[α][7]annulene-6- carboxamide (11.6 g, δδ%). This material was dissolved in anhydrous TΗF and added dropwise over 60 minutes to a slurry of LiAlΗ4 (3.24 g, 8δ.4 mmol) in refluxing THF. The reaction was maintained at reflux for 2 hours then cooled to lδ 10 °C, diluted with tert-butyl methyl ether, and cautiously quenched by the addition of water while the temperature was maintained below 30 °C. The resulting gummy solid was removed by filtration and the phases were then separated. The aqueous phase was washed with teri-butyl methyl ether and the combined organic phases were dried over MgSO4, filtered and evaporated. The

20 residue was dissolved in isopropyl alcohol (30 ml), cooled to 0 °C and concentrated HCl was added dropwise causing a thick slurry to form. The slurry was concentrated and the residue reconstituted with tert-butyl methyl ether and stirred at 40 °C for lδ minutes. The mixture was cooled to 2δ °C, filtered and the resulting solids washed with tert-butyl methyl ether and dried to give the title

25 compound.

Description 27 7-(Nitromethyl)-6,7.8.9-tetrahvdro-5H-benzof ir71annulene A solution of 8,9-dihydro-5H-benzo[α][7]annulen-δ-one (323 g, 2 mol) in 30 nitromethane (620 ml) was treated with DBU (327 g, 2.1 mol) dropwise at such a rate that the temperature was maintained between 40 and δO °C. After GC analysis showed reaction completion, 3M ΗC1 (600 ml) was added and the resulting mixture was extracted with terf-butyl methyl ether (2 x 600 ml). The combined organic phases were treated with brine (600 ml), dried over MgSO4, filtered and evaporated to an oil (496 g, 90%). To 347.5g (1.58 mol) of this material dissolved in TFA (104δ ml) was added triethylsilane (583 ml, 3.65 mol) at such a rate that the temperature of the reaction mixture was maintained between 50 and 55 °C. After the addition was complete, the mixture was 5 maintained at δδ °C until GC analysis indicated reaction complete. The mixture was poured onto ice (lδOO g) and water (600 ml). The resulting slurry was filtered and washed with cold hexanes (2 x lδO ml) then dried to give the title compound (139 g, 42%).

10 Description 28

6.7.8.9-Tetrahvdro-δH-benzorαir71annulen-7-ylmethylamine hydrochloride A mixture of 7-(nitromethyl)-6,7,8,9-tetrahydro-δH-benzo[ ] [7]annulene (Description 27; 48.6 g , 0.24 mol) and Ra-Ni (δO g) in ethanol (600 ml) was hydrogenated at 60 psi for 12 hours. An additional charge of Ra-Ni (δO g) was lδ added and the mixture was hydrogenated until GC analysis indicated the reaction was complete. The resulting mixture was filtered over Celite™ and washed with ethanol (200 ml). The filtrate was treated with concentrated ΗC1 (3δ ml, 0.42 mol) and concentrated under reduced pressure. The product was then slurried in teri-butyl methyl ether (100 ml) and cooled between 0 and δ°C,

20 filtered and washed with terϊ-butyl methyl ether (100 ml) and dried to give the title compound (21 g, 42%).

Description 29

3-(lH-Pyrazol- l-yl)benzylamine hydrochloride

2δ To a suspension of 3-(lH-pyrazol-l-yl)-benzoic acid [see WO 00/219δl] (104 g, O.δδ mol) in anhydrous benzene (δOO ml) was added thionyl chloride (8δ g, 0.71δ mol) and DMF (O.δ ml). The mixture was heated at reflux for 3 hours, then evaporated under reduced pressure. The residue was dissolved in anhydrous TΗF (100ml) and evaporated. The residue was dissolved in anhydrous acetone

30 (600 ml), and treated with ammonium acetate (77 g, 1 mol). The mixture was heated at reflux for 12 hours, solvent was evaporated and the residue treated with cold water (2000 ml). The resulting precipitate was filtered, washed with cold water (200ml) and recrystallised from absolute ethanol (600 ml) to give 3-(lH-pyrazol-l-yl)benzamide (82 g, 80 %). A solution of this material (82 g, 0.44 mol) in THF was added dropwise to a solution of LiAffl (25 g, 0.66 mol) in anhydrous THF (800 ml). The mixture was heated at reflux for 4 hours, cooled and quenched by the sequential addition of water (25 ml), 15% aqueous NaOH (25 ml), and water (50 ml). The inorganic by-products were filtered off and δ washed several times with diethyl ether (overall volume 1000 ml). The combined filtrates were dried over Na2SO , filtered and evaporated. The residue was dissolved in methanol (400 ml), the solution was treated with activated carbon (10 g), and the mixture was re-fluxed for 40 minutes, then filtered and evaporated. The residue was treated with IN HCl in ether (1000 ml), and the precipitate 10 formed was filtered, washed with ether and dried to give the title compound (63 g, 70%).

Description 30

4-(lH-Pyrazol- l-yl)benzylamine hydrochloride lδ The title compound was prepared from 4-(lH-pyrazol-l-yl) -benzoic acid in an analogous procedure to that detailed in Description 29.

Description 31

N-Methyl-N- T4- (trifluor omethyDbenzyll amine

20 A mixture of 4-(trifluoromethyl)benzylamine (1.0 mL, 7.02 mmol) and di-tert- butyl carbonate (1.68 g, 7.72 mmol) in CΗ2CI2 (10 mL) was stirred for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution, extracted with CH2CI2 and the organic layers were combined, dried over MgSO4 and concentrated in vacuo to give a white crystalline sohd. To a solution

26 of the crude carbamate (1.00 g, 3.61 mmol) in THF (20 mL) in a room temperature water bath, was added LiAlH4 (0.69 g, 18.1 mmol) portion- wise over 10 minutes. The reaction was then heated at reflux for 4 hours. The reaction was cooled in ice and quenched by the addition of water (1.6 mL) and NaOH (2N, 1.3 mL). The grey slurry was filtered and washed with MeOH. The MeOH was

30 removed in vacuo and the crude product taken up in CH2CI2 and dried over

MgSO4 and concentrated in vacuo. Purification by flash column chromatography eluting with δ-10 % MeOH in CH₂Cl2plus 1 % NHs solution (2Nin MeOH) afforded the title compound. Description 32 l-[4-(Trifluoromethyl)phenyl]ethylamine

To a suspension of NaCNBH4 (0.48 g, 7.6 mmol) and 3A molecular sieves (4 g) in MeOH (lδ mL) was added NH₄OAc (6.16 g, 80 mmol) and 5 4- (trifluoromethyl) acetophenone (l.δ g, 8.0 mmol). The reaction was stirred at room temperature under nitrogen for 3 days. The reaction was concentrated in vacuo and the pH adjusted to pH 12 by the addition of aqueous NaOH (2N). The reaction was extracted with ethyl acetate and the organic layers combined, dried over MgSO4 and the solvent removed in vacuo. Purification by flash column 10 chromatography, eluting with 5 % MeOH in CH2CI2 afforded the title compound.

Description 33

1.3-Diphenylpropylamine

The title compound was prepared from 1,3-diphenylpropan-l-one in an analogous lδ procedure to that detailed in Description 32.

Description 34

(3-Phenyl-1.2.4-oxadiazol-5-yl)methylamine hydrochloride

A mixture of δ-chloromethyl-3-phenyl- 1,2, 4-oxadiazole [Synth. Commun. 1992,

20 22, 209] (90 g, O.δ mol) and potassium iodide (45 g) was added as one portion to a suspension of potassium phthalimide (90 g, 0.5 mol) in DMSO (400 ml) under intensive stirring. After self-heating ceased, the mixture was heated at 130 °C for lδ minutes, cooled, and poured into water (2.δ 1). The precipitate was filtered, washed with water, and dried in the air. Recrystallization from δ% DMSO in

25 ethanol (1 1) afforded 100 g of sohd. A suspension of this sohd (100 g, 0.33 mol) in ethanol (2 1) was treated with glyme (0.5 1), heated to 35-40 °C, treated with hydrazine hydrate (18 g, 0.35 mol), and heated to reflux for 2 hours. The mixture was diluted with concentrated hydrochloric acid (100 ml), and refluxed for 4 hours. After cooling the mixture was filtered, extracted with ether, and

30 evaporated. The residue was dissolved in the minimum volume of water, basified and taken up in ether (300 ml). The organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in the minimum volume of water, neutralized with hydrochloric acid and evaporated. The crude product was recrystalhzed twice from isopropanol and dried to give the title compound (21 g, 20%).

Description 35

(2-Benzyl- 1.3-thiazol-4-yl)methylamine

2-Benzyl-4-chloromethylthiazole [Pharmazie 1972, 27, 146] (223.7 g, 1 mol) was stirred with hquid ammonia (600 ml) in an autoclave for 24 hours. The ammonia was removed and the product was distilled in vacuo [bp (0.02 mmHg) 141-144°C] to give the title compound (102 g, 60%). 0

Description 36

[1 - (2-Methylphenyl) - lH-p yr azol-4- yll methylamine

A mixture of l-(2-tolyl)-pyrazole-4-carboxaldehyde [see US Patent No. 4,220,792]

(186 g, 1 mol), hydroxylamine hydrochloride (104.2 g, 1.5 mol), and sodium 5 acetate trihydrate (204 g) in ethanol (2 1) was refluxed for 1 hour. The mixture was cooled, diluted with water (8 1), and left overnight. The precipitate was filtered to give l-(2-tolyl)-pyrazole oxime (186 g , 92.5 %). Tolylpyrazole oxime (60.3 g, 0.25 mol) in methanol (600 ml) and ammonia (200 ml) was hydrogenated in an autoclave in the presence of Raney nickel (10 g of ethanolic suspension) at 0 50°C at 70 atm. The catalyst was filtered off and washed with methanol. The filtrate was evaporated, and the residue was distilled in vacuo to give the title compound (43 g, 92%).

Description 37 δ 3-Cvclohexylpropylamine hydrochloride

To a solution of 3-phenyl-l-propylamine (5.26 ml, 0.04 mol) in ethanol (100 ml) under nitrogen was added concentrated ΗC1 (3 ml) and platinum oxide (0.5 g, 0.002 mol). This was placed on a Parr apparatus and hydrogenated at 60 psi for δ days. Platinum oxide (O.δ g, 0.002 mol) was added and the mixture 0 hydrogenated for a further 5 days. The mixture was filtered and evaporated to give the title compound (6.4 g , 98%). Description 38

6.7.8.9-Tetrahvdro-5H-benzorαl [71annulene-7-carboxyhc acid A solution of 7-(nitromethyl)-6,7,8,9-tetrahydro-δH-benzo[ ][7]annulene (Description 27; 96 g, 0.47 mol) in TΗF (560 ml) was cooled to -18 °C and 5 potassium tert-butoxide (1.6M in TΗF, 263 ml, 0.42 mol) was added dropwise over 30 minutes while maintaining the temperature between -lδ and -δ°C. After stirring for 10 minutes a solution of KMnO4 (111 g, 0.7 mol) in water (900 ml) was added dropwise over 75 minutes while maintaining the temperature between -3 and 3 °C. The mixture was stirred at 0 °C until GC analysis indicated the 0 reaction was complete. terZ-Butyl methyl ether (500 ml) was added followed by saturated aqueous NaΗSOβ (1000 ml) and the resulting mixture was stirred for 30 minutes until a milky white slurry formed. This slurry was filtered, washed with a solution of 3N NaOΗ (50 ml) and water (100 ml) foUowed by tert-butyl methyl ether (100 ml). The pΗ of the filtrate was adjusted from 8.6 to 12.5 by the 5 addition of 3N NaOΗ (100 ml) and 6N NaOΗ (40 ml). The phases were separated and to the aqueous phase was added tert-butyl methyl ether (500 ml). The pΗ of the resulting mixture was adjusted to 2 with 6N ΗC1 (200 ml). The phases were again separated and the aqueous phase was extracted with terf-butyl methyl ether (2 x 300 ml). The organic phases were combined, dried over MgSO₄, filtered 0 and evaporated to give the title compound (73 g, 89%), as an off white sohd.

Description 39

2-Bromo-6-fluorobenzaldehvde

To a solution of diisopropylamine (lδ.7 ml 112 mmol) in anhydrous δ tetrahydrofuran (200 ml) cooled to 0 °C was added dropwise n-butylhthium (2.6M in hexanes, 44.8 ml, 112 mmol). After complete addition the mixture was cooled to -78 °C and 3-fluorobromobenzene (19.6 g, 112 mmol) added over 10 minutes. The mixture stirred at -78 °C for 1 hour then N,N dimethylformamide (9.72 ml, 125 mmol) was added dropwise over 5 minutes. The mixture was stirred for a 0 further 10 minutes, then acetic acid (10 ml) and water (360 ml) were added. The mixture was allowed to warm to room temperature and was extracted with Et2θ (250 +150 ml). The combined extracts were washed with water (x2) 0.2N ΗC1, brine, dried over Na₂SO4 and evaporated. The residue was purified by column chromatography on sihca eluting with 5% Et2θ in iso-hexanes to give the title compound (20 g, 88%) as a white sohd.

Description 40 2-Fluoro-6-[(trimethylsilyl)ethynyllbenzaldehvde

To a solution of 2-bromo-6-fluorobenzaldehyde (Description 39; 10.0 g, 49.3 mmol) and (trimethylsilyl) acetylene (13.94 ml, 98.6 mmol) in anhydrous N,N-dimethylformamide (260 ml) under an atmosphere of nitrogen was added triethylamine (10.25 ml, 73.95 mmol), copper (I) iodide (0.94 g, 4.93 mmol) and Pd(PPli3)2Cl2 (1.73 g, 2.47 mmol). The mixture was degassed and stirred at room temperature overnight. The mixtiire was poured into water (600 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic layers were washed with water (3 x 300 ml), brine (200 ml) then dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 5% Et2θ in iso-hexanes to give the title compound (10.38 g, 95%).

Description 41

8-Fluoroisoquinohne

2-Fluoro-6-[(trimethylsilyl)ethynyl]benzaldehyde (Description 40; 10.38 g, 47.1 mmol) was dissolved in 2M ammonia in methanol (235 ml, 471 mmol) in a Parr flask and the resulting mixture heated at 80 °C with shaking on a Parr apparatus (ca. 35 psi achieved). The reaction was cooled and the solvents evaporated. The residue was purified by column chromatography on silica eluting with a gradient from neat dichloromethane to 2% methanol in dichloromethane to give the title compound (4.0 g, 58 %).

Description 42

8-Fluoro-5-nitroisoquinohne

To a solution of 8-fluoroisoquinohne (Description 41; 1.24 g , 8.4mmol) in concentrated sulfuric acid (10 ml) cooled to between -5 °C and 0 °C was added slowly, over 10 minutes, a solution of potassium nitrate (0.93 g , 9.24 mmol) in concentrated sulfuric acid (5 ml). The mixture was stirred at 0 °C for 30 minutes after which time TLC indicated that reaction was complete. The mixture was poured onto ice (100 g) and basified by the careful addition of 33% aqueous ammonium hydroxide. The mixture was extracted with dichloromethane (3 x 150 ml) and the combined organic layers were washed with brine, dried over Na2SO4 and filtered through a 1 inch plug of silica gel. The sihca gel plug was further washed with 150 ml of a 1:1 mix of ethyl acetate and iso-hexanes. The combined organics were evaporated to give the title compound (1.33 g, 82%) as a brown sohd.

Description 43

8-Fluoroisoαuinohn-5-amine To a nitrogen flushed solution of 8-fluoro-5-nitroisoquinohne (Description 42; 1.33 g, 6.9 mmol) in methanol (100 ml) was added 10% paUadium on carbon (500 mg) and the resulting mixture stirred under a balloon of hydrogen for 3.5 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue was purified by MPLC (Biotage Flash™ 40) eluting with 2% MeOH in dichloromethane to give the title compound (450 mg, 40%) as a . yellow sohd.

Description 44

3-Methyl-5-nitroisoαuinoline 3-Methylisoquinoline (2.14 g, 14.9 mmol) was added portionwise to ice-cooled concentrated H2SO4 (10 ml) keeping the internal temperature below 10 °C. A nitrating mixture of concentrated H2SO4 (2 ml) and fuming nitric acid (2 ml) was then added dropwise keeping the internal temperature below 15 °C. After stirring for 30 minutes, TLC indicated reaction was complete. The acid was neutrahzed by adding the mixture to an excess of 4N aqueous NaOH (180 ml) with ice-cooling. The mixture was extracted with dichloromethane (2 x 150 ml), then dried (Na₂SO4) and evaporated to give the crude product (2.69 g) as a yellow sohd. Flash column chromatography using as eluant 5% methanol in dichloromethane gave a pure sample of the title compound (660 mg) and a further sample (1.95 g) containing ca. 10% of the isomer 3-methyl-8-nitroisoquinohne. Description 45

3-Methvhsoαuinohn-5-amine

3-Methyl-5-nitroisoquinoline (Description 44; 660 mg, 3.51 mmol) was dissolved in MeOH (30 ml) and Ptθ2 catalyst (120 mg) was added. The mixture was stirred for 1 hour 45 minutes under a balloon of hydrogen, then the catalyst was filtered off, washing with more methanol. The filtrate was evaporated and purified by flash column chromatography using as eluant 5% methanol in dichloromethane to give the title compound (250 mg).

Description 46

1-Chloroisoquinoline

A solution of isoquinoline-N-oxide (5.52 g, 38 mmol) in dichloromethane (60 ml) was added over 15 minutes to a solution of phosphorus oxychloride (40 ml) in dichloromethane (50 ml) at room temperature. The mixture was stirred for 1 hour, then heated to reflux for 2 hours. After coohng to room temperature, the mixture was poured into ice water (500 ml). The mixture was then extracted with dichloromethane (2 x 250 ml) and the combined organic layers were washed with 10% aqueous potassium carbonate solution (200 ml), brine (200 ml) then dried (Na2SO ) and evaporated to give the title compound (5.0 g).

Description 47 1-Chloro-δ-nitroisoquinoline

1-Chloroisoquinohne (Description 46; 4 g, 24.4 mmol) was nitrated according to the method of Description 44 to give the title compound (3.88 g).

Description 48 l-Chloroisoquinolin-5-amine

Copper (II) acetylacetonate (263 mg) was suspended in ethanol (10 ml) and sodium borohydride (366 mg) was added in one portion. The mixture was stirred for 5 minutes, by which time a black suspension had appeared. A suspension of 1-chloro-δ-nitroisoquinohne (Description 47; 1.01 g, 4.84 mmol) in ethanol (20 ml) was then added over 15 minutes whilst coohng in a water bath; the mixture effervesced. The mixture was stirred at room temperature for 1 hour, then more sodium borohydride (160 mg) was added and stirring continued for a further 1 hour. Water (100 ml) was added then the ethanol was evaporated and the mixture extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried (Na2SO4) and evaporated. Purification of the residue by flash column chromatography using 5% methanol-dichloromethane as eluant gave the title δ compound (210 mg).

Description 49

3 - Chloroisoquinoline

A mixture of 1,3-dichloroisoquinohne (9.94 g, 60.2 mmol) and hydrazine hydrate

10 (12.2 ml, 251 mmol) in ethanol (150 ml) was heated at reflux for 1.5 hours. The reaction was then cooled to room temperature and the ethanol evaporated. The residue was suspended in chloroform and manganese dioxide (20g) was added in portions over 30 minutes. Gas evolution was observed. After this had subsided, the mixture was heated to reflux for 2 hours, then filtered and evaporated. lδ Purification of the residue by flash column chromatography using dichloromethane as eluant gave the title compound (3.δ g).

Description 50

3-ChloroisoquinoHn-5-amine

20 3-Chloroisoquinoline (Description 49; 3.4 g, 20.7 mmol) was nitrated according to the method of Description 44 to give crude 3-chloro-δ-nitroisoquinohne (9 g). A sample (3.08 g) was added in portions over 15 minutes to a mixture of iron powder (4.2 g, 74 mmol) in water (50 ml) and 5M HCl (4 ml) at 50 °C. After the addition, the mixture was warmed to 85 °C for 2 hours, then filtered while still 5 warm to remove the iron. The filtrate was basified (4N NaOH, ca. 50 ml), then extracted with dichloromethane (3 x 150 ml). The combined organic layers were dried (Na2SO4) and evaporated to give the title compound (282 mg).

Description 51 0 6-Aminoisoquinoline

Benzophenone imine (445 μL, 2.64 mmol) was added to a mixture of 6-bromoisoquinohne (500 mg, 2.4 mmol), BINAP (60 mg, 0.1 mmol), palladium acetate (12 mg, 0.05 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in THF (10 ml) at room temperature. The mixture was degassed (N2 x 3) then heated at reflux under a nitrogen atmosphere for 16 hours. The reaction was then cooled to room temperature, partitioned between ethyl acetate (20 ml) and water (20 ml) and the aqueous phase extracted with ethyl acetate (20 ml). The combined organic phases were evaporated then re-dissolved in THF (lδ ml). Hydrochloric δ acid (2N, aqueous, 4 ml) was added, then after stirring for 1 hour the THF was evaporated. The mixture was partitioned between ethyl acetate (20 ml) and 3M HCl (50 ml) and the aqueous phase washed with ethyl acetate (20 ml). The aqueous phase was basified (12N NaOH) then extracted with dichloromethane (3 x 50 ml). The combined organic phases were dried (Na2SO4) and evaporated to 0 give the title compound (360 mg).

Description 52 iV- (2-BromobenzvD - 2.2-diethoxyacetamide

To a solution of ethyl diethoxyacetate (20.0g, 114 mmol) in ethanol (50 ml) was 5 added a solution of sodium hydroxide (4.56 g, 114 mmol) in water (25 ml), and the resulting mixture heated at reflux for 5 hours. The mixture was evaporated to dryness, and the residue dried in vacuo. The resulting sohd (22.76 g, 0.13 mol) was dissolved in dry ether (88 ml) and to this mixtvire was added thionyl chloride (13.3 g, 0.11 mol) with stirring for 10 minutes at 10 °C. The reaction mixture was 0 heated at reflux for 30 minutes and then allowed to cool. A solution of

2-bromobenzylamine (20.73 g, 0.11 mol) in toluene (57 ml) and pyridine (34 ml) was poured into this reaction mixture with vigorous stirring. This was heated at reflux for 30 minutes and then allowed to cool. The mixture was poured into ice water and extracted with toluene (x 3). The organic extracts were combined and δ washed firstly with 2% HCl and then water. The solvent was evaporated and the residue purified by flash chromatography on sihca gel (9: 1 hexane:ethyl acetate) to give the title compound (lδ.6 g, 44%).

Description 53 0 8-Bromoisoquinolin-3-ol

N-(2-Bromobenzyl)-2,2-diethoxyacetamide (Description 52; 15.6 g , 49 mmol) was carefully added to concentrated H2SO4 (78 ml) with stirring at 10-20°C. The reaction mixture was stirred at room temperatxire for 16 hours, poured into ice water and filtered. The filtrate was neutralised with 33% aqueous ammonium hydroxide and the resulting precipitate was filtered and dried to give the title compound (10.1 g, 91%).

Description 54 8-Bromo- 3 -methoxyisoquinohne

To a suspension of 8-bromoisoquinohn-3-ol (Description 53; 7.3 g, 0.03 mol) and silver carbonate (13.6 g, 0.05 mol) in dry DMF (380 ml) under nitrogen was added iodomethane (2.2δ ml, 0.04 mol). The mixture was stirred at 50 °C for 24 hours. Further iodomethane (1 ml, 0.015 mol) was added and the mixture heated for 64 hours at 50 °C. The mixture was cooled, water (300 ml) and ethyl acetate

(300 ml) were added and shaken well. The mixture was filtered through Celite™, the layers separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The organic layers were combined, evaporated to ~150 ml, washed twice with water and then brine. The organic extract was then evaporated to give the title compound (1.7 g, 22%).

Description 55

Methyl 3-methoxyisoquinohne-8-carboxylate

To a solution of 8-bromo-3-methoxyisoquinoline (Description 54; 1.6 g, 7.0 mmol) in anhydrous DMSO (12 ml) and methanol (8 ml) was added triethylamine (1.0 ml, 7.0 mmol), palladium acetate (30 mg, 0.1 mmol) and l,l'-bis(diphenylphosphine)ferrocene (7δ mg, 0.1 mmol). Carbon monoxide was bubbled through the mixture for 3 minutes and the reaction was then heated with stirring at 80 °C for 44 hours under a balloon of carbon monoxide. Palladium acetate (30 mg, 0.1 mmol), l,l'-bis(diphenylphosphine)ferrocene

(75 mg, 0.1 mmol), DMSO (4 ml) and methanol (6 ml) were added to the mixture and carbon monoxide was bubbled through for 3 minutes. The reaction was again heated at 80 °C under a carbon monoxide balloon for 5 hours. The mixture was aUowed to cool, brine (80 ml) was added and the mixture was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine (50 ml), dried over K2CO3 and evaporated. The residue was chromatographed on sihca gel (19:1 dichloromethane: methanol) to give the title compound (290 mg, 20%). Description 56

3-Methoxyisoquinohne-8-carboxyhc acid

To a solution of methyl-3-methoxyisoquinoline-8-carboxylate (Description 55; 280 mg, 1 mmol) in ethanol (10 ml) was added potassium hydroxide (145 mg, 3 mmol) in water (6 ml). This mixture was heated at reflux for 30 minutes, cooled and the ethanol removed by evaporation. The remaining aqueous mixture was acidified with IM HCl (3 ml) to pH δ. The sohd was collected by filtration and dried in a vacuum oven to give the title compound (23δ mg, 90%).

Description 57

Isoquinoline-8-carboxylic acid

THF (140 ml) was added to n-butylhthium (1.6M hexanes, 70 ml, 112 mmol) at -78 °C. A cold (-78 °C) solution of 8-bromoisoquinoline (19g, 91.3 mmol) was then added. The reaction was stirred for 15 minutes at -78 °C, then dry CO2 gas was bubbled through the solution for 30 minutes. The cooling was then removed and the mixture warmed to 0 °C over 1 hour. The THF was removed in vacuo, then aqueous NaOH (2N, 300 ml) was added. The mixture was washed with tert-butyl methyl ether (300 ml, then 2 x 100 ml) and the combined organic layers were back extracted with aqueous NaOH (2N, 50 ml). The combined aqueous phase was adjusted to pH 4.5 by the addition of 6N HCl. And the slurry cooled to 15 °C using an ice-bath. The precipitate was collected by filtration, washed with water (2 x 100 ml), isopropanol (100 ml), acetone (100 ml) and tert-butyl methyl ether (100 ml) to give the title compound (8.62 g).

Description 58

[4- (TrifluoromethyDbenzyll isocyanate

4-(Trifluoromethyl)phenylacetic acid (1.79 g, 8.77 mmol) was dissolved in dichloromethane (20 ml) at room temperature. Oxalyl chloride (0.92 ml, 10.5 mmol) was added foUowed by DMF (2 drops). The reaction was stirred for 4 hours, after which time effervescence had ceased. The dichloromethane and excess oxalyl chloride were then evaporated. The acid chloride was redissolved in DCM (20 ml) and poured in one go into a solution of sodium azide (0.63 g, 9.65 mmol) and tetrabutylammonium bromide (300 mg, 0.88 mmol) in water (15 ml). The mixture was stirred for 15 minutes, then the layers separated and the aqueous layer extracted with more dichloromethane (30 ml). The combined organic layers were dried (Na2SO ) and evaporated to give an oil which was purified by flash column (50% dichloromethane-hexane). The acyl azide (1.54 g) so produced was dissolved in dichloromethane (20 ml) and heated at reflux to quantitatively afford the title compound. The volume was adjusted to give a 0.33 M solution in dichloromethane for use in subsequent preparations.

Description 59

[4-(Trifluoromethoxy)benzyllisocvanate Prepared from 4-(trifluoromethoxy)phenylacetic acid according to the method of Description 68.

Synthesis of Ureas:

Ureas were synthesized, unless otherwise stated, using one of 2 methods. A convenient procedure starts with a carboxyhc acid which, on treatment with diphenylphosphoryl azide and triethylamine, undergoes a Curtius reaction. The isocyanate formed in situ is then trapped by addition of an amine all in one-pot. Alternatively ureas are synthesized by reacting an amine with a preformed isocyanate. Urea precursors not mentioned in Descriptions 1 to 58 are known compounds.

Description 60

Representative one-pot procedure for the synthesis of ureas from a carboxyhc acid and an amine A mixture of carboxyhc acid (0.30 mmol), diphenylphosphoryl azide (65 μl,

0.30 mmol) and triethylamine (42 μl, 0.30 mmol) in toluene (5 ml) was heated at reflux for 1 hour. To this mixture, the appropriate amine (0.30 mmol) was added and the reaction heated at reflux for 18 hours. The cooled reaction mixture was evaporated to dryness, then purified either by flash column chromatography, preparative thin layer chromatography or by mass-directed HPLC. For amine hydrochloride salts, an extra equivalent of triethylamine was added. Description 61

Representative one-pot procedure for the synthesis of ureas from an isocyanate and an amine

An amine (0.30 mmol) and an isocyanate (0.3δ mmol) were dissolved in dichloromethane (10 ml), then stirred at room temperature or at reflux if required until the starting amine had been consumed. The product was collected by filtration, washing with a httle dichloromethane. In cases where the product did not crystallise out, the solvent was evaporated and purification was effected either by flash column chromatography, preparative thin layer chromatography or by mass-directed HPLC.

Description 62

3 - (trifluoromethvDisoq uinohne l-Chloro-3-(trifluoromethyl)isoquinoline [see WO 01/92233 ] (2.0 g, 8.64 mmol) was dechlorinated according to the method of Description 49 to give the title compound (1.42 g).

Description 63

5-nitro-3-.trifluoromethyl)isoquinoline 3-(trifluoromethyl)isoquinoline (Description 62; 1 g, δ.O mmol) was nitrated according to the method of Description 44 to give the title compound (1.1 g).

Description 64

3-(trifluoromethyl)isoquinohn-5-amine 5-nitro-3-(trifluoromethyl)isoquinoline (Description 63; 1 g, 4.13 mmol) was hydrogenated according to the method of Description 43 to give the title compound (0.48 g).

Description 65 l-chloro-3-ethyl-5-nitroisoquinohne l-chloro-3-ethyhsoquinoline [see WO 01/92233] (2.0 g, 10.4 mmol) was nitrated according to the method of Description 42 to give the title compound (2.37 g, 96 %). Description 66 l-chloro-3-ethvhsoquinohn-5-amine l-chloro-3-ethyl-5-nitroisoquinohne (Description 65; 2.0 g, 8.4 mmol) was reduced according to the method of Description 50 to give the title compound (1.2 g, 69 %).

Description 67 l-Methyl-5-nitroisoquinohne

Prepared by nitration of 1-methyhsoquinohne according to the procedure of

Description 44.

Description 68 l-Methyhsoquinohn-5-amine

Prepared by reduction of l-methyl-5-nitroisoquinohne (Description 67) according to the procedure of Description 45.

Description 69

2.4-Difluoro-6-methoxybenzaldehvde

To a solution of 3.5-difluoroanisole (26 g; 176 mmol) in dichloromethane (150 ml) cooled at 0°C was added titanium tetrachloride (30.7 ml; 280 mmol). To this mixture was added dropwise over 10 minutes dichloromethyl methylether (15.8 ml; 175 mmol), and after complete addition the mixture was stirred at room temperature for 1 hour. The reaction was poured onto ice/water (600 ml) and extracted with DCM (3 x 300 ml). The combined DCM layers were washed with water (600 ml), saturated NaCl (200 ml), dried over Na2SO₄, filtered and evaporated. The residue was purified by column chromatography on sihca - eluting with a gradient rising from 15% Et2θ in isohexanes rising to 30% Et2θ in isohexanes to give the title compound (11.2 g, 37%) as a white sohd.

Description 70 2.4-Difluoro-6-hvdroxybenzaldehyde

To a solution of 2,4-difluoro-6-methoxybenzaldehyde (Description 69, 11.2 g; 77.8 mmol) in anhydrous dichloromethane (600 ml) cooled at -78°C was added boron tribromide (9.47 ml; 85.68 mmol) dropwise over 10 minutes. After complete addition the mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured onto ice/water (1 htre) and extracted with DCM (3 x 400 ml). The combined organic layers were washed with water (1 htre), saturated NaCl (500 ml), dried over Na₂SO₄, filtered and evaporated. The residue was purified by column chromatography on silica elution with 10% diethyl ether/ isohexanes to give the title compound (9.2 g, 75%) as an orange oil.

Description 71

2.4-Difluoro-6-prop- 1-ynylbenzaldehvde

To an ice-bath cooled mixture of 2,4-difluoro-6-hydroxybenzaldehyde (Description 70, 9.20 g; 58.2 mmol) and triethylamine (8.92 ml; 64.02 mmol) in anhydrous dichloromethane (100 ml) was added dropwise over 10 minutes trifluoromethanesulfonic anhydride (11.75 ml; 69.84 mmol) and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water (300 ml), and the aqueous phase extracted with DCM (100 ml). The combined organic layers were washed with saturated NaCl (100 ml), dried over Na2SO4, filtered through a 1 inch plug of sihca and evaporated. The residue (14.4 g; 49.6 mmol) and triethylamine (10.37 ml; 74.4 mmol) in anhydrous N,N-dimethylformamide (80 ml) contained within a large (200 ml capacity) sealed tube was cooled to -78°C and propyne gas bubbled through until the volume had increased by approx 10 ml. To this mixture was added Pd(PPli3)2Cl2 (1.74 g; 2.48 mmol) and Cul (449 mg; 4.96 mmol), the hd was put in place and the tube allowed to reach room temperature. The reaction was stirred for 2 hours after which TLC showed reaction was complete. The mixture was poured onto water (500 ml) and extracted with EtOAc (3 x 150 ml); the combined EtOAc layers were washed with water (3 x 400 ml), saturated NaCl (150 ml), dried over Na₂SO₄, filtered through a 1 inch plug of sihca and evaporated to give the title compound (8.7g, 97%).

Description 72 6.8-Difluoro-3-methvhsoquinohne

A mixture of 2,4-difluoro-6-prop-l-ynylbenzaldehyde (Description 71, 8.7 g; 48.8 mmol) and 2.0M ammonia in methanol (244 ml; 488 mmol) were heated together at 80°C in a Parr apparatus (approx 35psi achieved) for δ hours. The cooled mixture was evaporated and the residue purified by column chromatography on silica -elution with 100% dichloromethane to give the title compound (δ.2 g, 59%) as a brown sohd.

Description 73 6,8-Difluoro-3-methvhsoquinolin-5-amine To an ice-bath cooled solution of 6,8-difluoro-3-methyhsoquinoline (Description 72, 1.2 g; δ.35 mmol) in cone, sulfuric acid (7.6 ml) was added dropwise a mixture of fuming nitric acid (1 ml) and cone, sulfuric acid (1 ml) and the resulting mixture stirred at 0°C for 30 minutes. Poured onto ice/water (100 ml) and basified by the portionwise addition of NaHCOβ, then extracted with EtOAc (3 x 100 ml). The combined EtOAc layers were flushed with nitrogen and a spatula end of δ% palladium on carbon added and the reaction was stirred under a balloon of hydrogen for 3 hours. The catalyst was removed by filtration and the filtrate evaporated. The residue was purified by column chromatography on sihca elution with 1% MeOH in DCM + 0.6% NH4OH to give the title compound (930 mg, 89%).

Description 74

3-Methyl-7-(trifluoromethyl)isoquinohn-5-amine

Prepared using 2-hydroxy-5-trifluoromethylbenzaldehyde [see WO-A-9962902] in place of 2,4-difluoro-6-hydroxybenzaldehyde according to the procedures of Descriptions 71, 72, and 73 respectively.

Description 75

2-Fluoro-6-prop-l-vnylbenzaldehvde A mixture of 2-bromo-6-fluorobenzaldehyde [see Tetrahedron Letters (1992),

33(49), 7499-7502] (4.0 g; 19.7 mmol) and triethylamine (4.12 ml; 29.5 mmol) in anhydrous N,N-dimethylformamide (7δ ml) contained within a large (200 ml capacity) sealed tube was cooled to -78°C and propyne gas bubbled through until the volume had increased by approx 10 ml. To this mixture was added Pd(PPh₃)₂Cl2 (0.69 g; 0.99 mmol) and Cul (180 mg; 1.97 mmol), the hd was put in place and the tube allowed to reach room temperature and stir for 4 hours after which TLC showed the reaction was complete. The mixture was poured onto water (500 ml) and extracted with EtOAc (3 x 150 ml). The combined EtOAc layers were washed with water (3 x 400 ml), saturated NaCl (150 ml), dried over Na₂SO4, filtered through a 1 inch plug of sihca and evaporated to give the title compound (3.2 g, 100%).

Description 76

5 8-Fluoro-3-methvhsoquinohn-δ-amine

Prepared using 2-fluoro-6-prop-l-ynylbenzaldehyde (Description 7δ) in place of 2,4-difluoro-6-prop-l-ynylbenzaldehyde according to the procedures of Descriptions 72 and 73 respectively.

10 Description 77

(2-Bromo-4-fluorophenyl)methanol

To a solution of 2-bromo-4-fluorobenzoic acid (20g; 91mmol) in anhydrous THF (300 ml) at -10°C was added dropwise borane tetrahydrofuran complex (l.OM soln in THF) (136.5ml; 136.5mmol). After complete addition the reaction was allowed lδ to stir at room temperature for 4 hours. The reaction was quenched by the dropwise addition of water (20 ml). To the mixture was added saturated K2CO3 (200 ml) and water (300 ml). The organic layer was separated and the aqueous extracted with Et₂O (2 x 300 ml). The combined organics were washed with water (2 x 500 ml), saturated NaCl (200 ml), dried over Na₂SO4, filtered and

20 evaporated to give the title compound (18g, 96%) as a white sohd.

Description 78

2-Bromo-4-fluorobenzaldehvde

To a -78°C cooled solution of oxalyl chloride (8.43 ml; 96.58 mmol) in anhydrous

25 dichloromethane (300 ml) was added dropwise dimethyl sulfoxide (13.71 ml;

193.16 mmol). The mixture was stirred at -78°C for 5 minutes then a solution of (2-bromo-4-fluorophenyl)methanol (Description 77, 18 g; 87.8 mmol) in anhydrous dichloromethane (160 ml) was added slowly. The resulting mixture was stirred at -78°C for 15 minutes then triethylamine (36.71 ml; 263.4 mmol) was added and

30 the mixture allowed to warm to room temperature over 1 hour. The mixture was washed with water (2 x 500 ml), saturated NaCl (200 ml), dried over Na₂SO₄, filtered through a 2 inch plug of sihca gel and evaporated to give the title compound (16 g, 89%) as a white sohd. Description 79

6-Fluoro-3-methvhsoquinolin-δ-amine

Prepared using 2-bromo-4-fluorobenzaldehyde (Description 78) in place of 2-bromo-6-fluorobenzaldehyde according to the procedures of Descriptions 75, 72, and 73 respectively.

Description 80

2-Hvdroxy-δ-methoxy-3-nitrobenzaldehvde To a solution of 5-methoxysahcylaldehyde (22.62 g ; 148 mmol) in acetic acid (120 ml) was added dropwise over 1 hour a mixture of fuming nitric acid (7.1 ml) in acetic acid (25 ml). After complete addition the mixture was stirred at room temperature for 5 hours. The precipitate was removed by filtration, washed with ethanol and dried to give the title compound (20.3 g, 69%) as a bright yellow sohd.

Description 81

2-Formyl-4-methoxy-6-nitrophenyl trifluoromethanesulfonate

To an ice-bath cooled solution of 2-hydroxy-δ-methoxy-3-nitrobenzaldehyde (Description 80, 11.00 g; δδ.8 mmol) and triethylamine (10.11 ml; 72.54 mmol) in anhydrous dichloromethane (150 ml) was added slowly trifluoromethane sulfonic anhydride (11.73 ml ; 69.75 mmol) and the resulting mixture stirred at room temperature for 1.5 hours. The mixture was washed with water (250 ml), dried over Na₂SO4, filtered through a 1.5 inch plug of sihca and evaporated to give the title compound (17 g, 92%) as a yellow oil.

Description 82

7-Methoxyisoquinohn-5-amine

Prepared using 2-formyl-4-methoxy-6-nitrophenyl trifluoromethanesulfonate (Description 81) in place of 2-bromo-6-fluorobenzaldehyde according to the procedures of Descriptions 40, 41, and 43 respectively. Description 83

1.3-Dimethvhsoquinohn-5-amine

Prepared using 1,3-dimethyhsoquinohne (Chem Lett. 1983, 5, 791) in place of 3- methyhsoquinohne according to the procedures of Descriptions 44 and 43 5 respectively.

Description 84

4-Chloro-2-formyl-6-nitrophenyl trifluoromethanesulfonate

10 Prepared using 5-chlorosahcylaldehyde in place of 5-methoxysalicylaldehyde according to the procedures of Descriptions 80 and 81 respectively.

Description 85

7-Chloro-3-methyl-5-nitroisoquinohne lδ Prepared using 4-chloro-2-formyl-6-nitrophenyl trifluoromethanesulfonate (Description 84) in place of 2-bromo-6-fluorobenzaldehyde according to the procedures of Descriptions 76 and 72 respectively.

Description 86

20 7-Chloro-3-methyhsoquinolin-5-amine

To a nitrogen flushed solution of 7-chloro-3-methyl-δ-nitroisoquinohne (Description 85; 300 mg, 1.35 mmol) in methanol (30 ml) was added a spatula end of Palladium 5% on calcium carbonate poisoned with lead (Lindlar catalyst), and the resulting mixture stirred under a baUoon of hydrogen overnight. The catalyst

26 was removed by filtration and the filtrate evaporated. The residue was dissolved in methanol (20 ml) and sihca gel (2 g) added and evaporated to dryness. Loaded onto a sihca gel column and eluted with 1% MeOH in DCM + 0.5% NH4OH to give the title compound (190 mg , 73%) as an orange sohd.

30 Description 87

7-Chloroisoquinohn-5-amine

Prepared using 4-chloro-2-formyl-6-nitrophenyl trifluoromethanesulfonate (Description 84) in place of 2-bromo-6-fluorobenzaldehyde according to the procedures of Descriptions 40, 41 and 86 respectively. Description 88

8-Fluoro-3-methoxyisoquinohne-δ-carboxyhc acid

Prepared using 5-bromo-2-fluorobenzylamine in place of 2-bromobenzylamine according to the procedures of Descriptions 52, 53, 64, 56, and 56 respectively.

Description 89

6-Fluoroisoquinohn-5-amine

Prepared using 2-bromo-4-fluorobenzaldehyde (Description 78) in place of 2- bromo-6-fluorobenzaldehyde according to the procedures of Descriptions 40, 41, 44 and 43 respectively.

Description 90

7-Fluoroisoquinohn-5-amine Prepared using 2-bromo-5-fluorobenzoic acid in place of 2-bromo-4-fluorobenzoic acid according to the procedures of Descriptions 77, 78, 40, 41, 44 and 43 respectively.

Description 91 4-Methvhsoquinohn-5-amine

Prepared using 4-methyhsoquinoline (Tet. Lett. 1987, 28(44), 5291) in place of 3- methyhsoquinoline according to the procedures of Descriptions 44 and 43 respectively.

Description 92

8-(Trifluoromethyl)isoquinoline

A mixture of 2-trifluoromethylbenzaldehyde (15 g; 86 mmol) and aminoacetaldehyde dimethylacetal (9.37 ml; 86mmol) in toluene (75 ml) was heated at reflux under Dean/Stark conditions for 2 hours. The cooled reaction mixture was evaporated to dryness and the residue added dropwise to cone, sulfuric acid (200 ml) at 140°C ; after complete addition the heating was continued for 30 mins then the warm mixture was poured over ice. The mixture was filtered and the filtrate basified by the addition of 4N NaOH with cooling. The basic solution was extracted with Et₂O (x 3), the combined Et₂O layers were dried over Na2SO₄ , filtered and evaporated. The residue was dissolved in DCM and filtered through a short plug of sihca and evaporated to give 1.2g (Yield 7%).

Description 93 δ 8-(Trifluoromethyl)isoqυinohn-δ-amine

Prepared using 8-(trifluoromethyl)isoquinoline (Description 92) in place of 3- methylisoquinoline according to the procedures of Descriptions 44 and 43 respectively.

0 Description 94

2-Methoxy-4-(trifluoromethyl)benzonitrile

To a solution of 2-nitro-4-(trifluoromethyl)benzonitrile (22.48 g, 104 mmol) in anhydrous methanol (110 ml) was added dropwise 25% sodium methoxide in methanol (24.72 ml, 114.4 mmol), and the resulting mixture stirred at room 5 temperature for 1 hour. Water (110 ml) was added and the resulting sohds coUected by filtration. The sohds were dissolved in DCM (150 ml), washed with sat NaCl (75 ml), dried over Na2SO4, filtered and evaporated to give the title compound (19 g, 91%) as a white sohd.

0 Description 95

2-Methoxy-4-(trifluoromethyl)benzoic acid

To a solution of 2-methoxy-4-(trifluoromethyl)benzonitrile (Description 94; 19 g, 94.4 mmol) in ethanol (150 ml) was added a solution of potassium hydroxide (26.43 g ; 472 mmol) in water (100 ml) and the resulting mixture heated at reflux 5 overnight. The mixture was cooled and the ethanol removed by evaporation, the remaining aqueous phase was extracted with diethyl ether then acidified with 5N HCl. The acidic aqueous phase was then extracted with EtOAc (3 x 200 ml) and the combined organic layers washed with water, sat NaCl, dried over Na SO₄, filtered and evaporated to give the title compound (19.91 g, 95%). 0 Description 96

2-Methoxy-4-(trifluoromethyl)benzaldehvde

Prepared using 2-methoxy-4-(trifluoromethyl)benzoic acid (Description 96) in place of 2-bromo-4-fluorobenzoic acid according to the procedures of Descriptions 77 and 78 respectively.

Description 97

2-hvdroχy-4-(trifluoromethyl)benzaldehvde

A mixture of 2-methoxy-4-trifluoromethyl benzaldehyde (Description 96; 18 g, 88 mmol) and hthium chloride (11.19 g ; 264 mmol) in anhydrous N,N- dimethylformamide (100 ml) was heated at reflux for 3 hours. The mixture was cooled and poured into water (200 ml), then acidified by the addition of IN HCl. The mixture was extracted with ether (3 x 200 ml) then the combined ether layers washed with water (2 x 600 ml), sat NaCl (100 ml), dried over Na2SO4, filtered and evaporated to give the title compound (16.25 g, 97%).

Description 98

6-(Trifluoromethyl)isoquinolin-5-amine

Prepared using 2-hydroxy-4-(trifluoromethyl)benzaldehyde (Description 97) in place of 2-hydroxy-δ-methoxy-3-nitrobenzaldehyde according to the procedures of Descriptions 81, 40, 41, 44, and 43 respectively.

Description 99

7-(Trifluoromethyl)isoquinohn-5-amine Prepared using 2-hydroxy-5-(trifluoromethyl)benzaldehyde [see WO-A-9962902] in place of 2-hydroxy-δ-methoxy-3-nitrobenzaldehyde according to the procedures of Descriptions 81, 40, 41, 44, and 43 respectively.

Description 100

5-Fluoro-l-methylindene

A solution of δ-fl.uoro-1-indanone (25 g, 0.17 mol) in dry THF (100 ml) was added dropwise to a solution of methyl magnesium bromide (70 ml of 3N in diethyl ether, 0.21 mol) in dry THF (50 ml) at 0°C. The mixture was stirred at RT overnight. The reaction mixture was quenched with aq. HCl to pH 1 and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give the title compound as an oil (22.3 g, 91%).

Description 101

6-Fluoro-l-methvhsoquinoline

A solution of δ-fluoro-1-methylindene (Description 100, 22.3 g, O.lδ mol) in methanol (350 ml) was cooled to -78°C and ozonised for 9.5 h. The reaction mixture was purged with nitrogen and removed from the coohng bath. Sodium bicarbonate (20 g) and dimethyl sulfide (30 ml) were added and the reaction mixture stirred at RT for 6 hr. Ammonium hydroxide (200 ml) was then added and the reaction mixture stirred at RT for 48 hr. The resulting mixture was poured into water (1 htre) and extracted with dichloromethane (3 x 400 ml). The organic extracts were combined, washed with water and brine, dried over MgSO₄ and evaporated. The residue was purified by flash column chromatography using an eluant system of 1% MeOH/ 99% DCM to give the title compound (1.4 g, 5.8%).

Description 102

6-Fluoro-l-methyl-5-nitroisoquinoline

Prepared by nitration of 6-fluoro-l-methyhsoquinoline (Description 101) according to the procedure of Description 44 to give the title compound (630 mg, 30%).

Description 103

6-Fluoro-l-methylisoquinolin-5-amine Prepared by reduction of 6-fluoro-l-methyl-δ-nitroisoquinoline (Description 102) according to the procedure of Description 43 to give the title compound (435 mg, 96%). Description 104

5-Nitroisoquinohne- 1-carboxyhc acid

Isoquinohne-1-carboxyhc acid (3.98 g, 23.0 mmol) was dissolved in cone, sulfuric acid (16 ml) at 0 °C. A mixture of cone, sulfuric acid (5 ml) and fuming nitric acid (5 ml) was added over 10 min. and the reaction stirred for a further lh at 0 °C, then poured into ice-water (400 ml). The sohd was collected by filtration, then washed with water (100 ml), ethanol (100 ml) and ether (100 ml), then dried under vacuum to give the title compound (4.1 g, 82%).

10

Description 105

Methyl 5-nitroisoquinoline- 1-carboxylate

Potassium carbonate (23 g, 167 mmol) was added to a solution of δ-nitro- lδ isoquinohne- 1-carboxyhc acid (Description 104, 2.7 g, 12.4 mmol) in N,N- dimethylformamide (60 ml) at room temperature. Iodomethane (1.0 ml, 16.1 mmol) was then added and the reaction stirred at room temperature for 20 h.

Water (300ml) was added and the mixture was extracted with ethyl acetate (2 x

200 ml). The combined organic phases were washed with water (2 x 100 ml), 20 brine (100 ml) then dried (Na2SO4) and evaporated. Purification of the residue by column chromatography eluting with ethyl acetate - isohexane (7:13 increasing to

1:1) gave the title compound (δδ8 mg, 19%).

Description 106

2δ

Methyl 5-aminoisoquinohne- 1-carboxylate

Prepared by reduction of methyl δ-nitroisoquinohne-1-carboxylate (Description

105) according to the procedure of Description 45.

30 Description 107

Methyl-5-aminoisoquinohne-3-carboxylate

Prepared using isoquinoline-3-carboxylic acid in place of isoquinohne- 1-carboxyhc acid according to the procedures of Descriptions 104, 105 and 106 respectively. 35 Description 108

3-Chloro-5-nitroisoquinohne

3-Chloroisoquinohne (Description 49; 3.4 g, 20.7 mmol) was nitrated according to the method of Description 44. After addition of the base, the sohd was filtered off to give crude 3-chloro-5-nitroisoquinohne (9 g). A sample (6.8 g) was partitioned between ethyl acetate and 10% aqueous K-2CO3 solution (200 ml). The organic layer was extracted with more ethyl acetate (100 ml) and the combined organic phases dried (Na2SO ) and evaporated to give the title compound (2.10 g, 64%).

Description 109

3-(Oimethylamino)isoquinohn-5-amine

3-Chloro-5-nitroisoquinohne (Description 108, 160 mg, 0.767 mmol) was dissolved in 33% ethanohc dimethylamine (6 ml) and the mixture then heated in a sealed tube at 100 °C for 2.5 h. After coohng to room temperature the solvent and excess dimethylamine was evaporated and the residue reduced according to the procedure of Description 45 to give the title compound (85 mg, 59%).

Description 110

2-(4-Hydroxybut-l-ynyl)benzaldehvde

To a solution of 2-bromobenzaldehyde (10 g, 54 mmol) in anhydrous N,N- dimethylformamide (150 ml) was added 3-butyn-l-ol (6.13 ml, 81 mmol) and triethylamine (11.3 ml, 81 mmol), followed by copper (I) iodide (490 mg, 5.4 mmol) and Pd(PPh3)₂Cl2 (1.9 g, 2.7mmol), and the mixture degassed three times and stirred at room temperature overnight. The mixture was poured into water (600 ml) and extracted with EtOAc (3 x 150 ml); the combined EtOAc layers were washed with water (2 x 250 ml), sat NaCl (100 ml), then dried over Na2SO4 , filtered and evaporated. The residue was purified by column chromatography on silica eluting with 50% Et2θ in isohexanes to give the title compound (8.5 g, 90%) as an orange oil. Description 111

3-(2-Hvdroxyethyl)isoquinoline

A solution of 2-(4-hydroxybut-l-ynyl)benzaldehyde (Description 110; 8.50 g, 48.8 mmol) in 2M methanohc ammonia (122 ml, 244 mmol) contained in a Parr flask was heated at 80°C for 2 hours (approx 35 psi achieved). The cooled mixture was evaporated and the residue purified by column chromatography on sihca elution with a gradient rising from 1% MeOH in DCM + 0.5% NH₄OH to 5% MeOH in DCM + 0.5% NH4OH to give the title compound (6.2 g, 73%) as a beige sohd.

Description 112

3-(2-Azidoethyl)isoquinohne

To a ice-bath cooled solution of 3-(2-hydroxyethyl)isoquinoline (Description 111; 4.85 g, 28 mmol) and triethylamine (5.07 ml, 36.4 mmol) in anhydrous dichloromethane (100 ml) was added slowly methanesulfonyl chloride (2.49 ml, 32.2 mmol), and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water (200 ml), sat NaCl (100 ml), dried over Na₂SO4 , filtered and evaporated. The residue was dissolved in anhydrous N,N- dimethylformamide (100 ml) and sodium azide (2.00 g, 30.8 mmol) added and the resulting mixture stirred at room temperature for 4 days. The mixture was poured into water (400 ml), and extracted with EtOAc (3 x 100 ml). The combined EtOAc layers were washed with water (3 x 200 ml) , saturated aqueous NaCl (100 ml), dried over Na₂SO₄, filtered and evaporated to give the title compound (5.6 g, 100%).

Description 113

3-(2-Aminoethyl)isoquinoline To a solution of 3-(2-azidoethyl)isoquinohne (Description 112; 5.6 g, 28.3 mmol) in anhydrous tetrahydrofuran (50 ml) was added triphenylphosphine (14.85 g, 56.6 mmol) and water (0.509 ml, 28.3 mmol), and the resulting mixture stirred at room temperature overnight. The mixture was loaded directly onto a Bond-elut SCX cartridge and eluted with methanol until TLC indicated complete elution of triphenylphosphine. The product was then eluted with 2.0M ammonia in methanol. The basic fractions were collected and evaporated to give the title compound (2.7 g, 55%).

Description 114

Ethyl 2-isoquinohn-3-ylethylcarbamate

To an ice-bath cooled solution of 3-(2-aminoethyl)isoquinohne (Description 113;

2.70 g, lδ.7 mmol) and triethylamine (2.84 ml, 20.41 mmol) in anhydrous dichloromethane (75 ml) was added slowly ethyl chloroformate (1.65 ml, 17.27 mmol) and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water, sat NaCl, dried over Na₂SO₄ , filtered and evaporated. The residue was purified by column chromatography on sihca elution with a gradient rising from DCM to 2% MeOH in DCM + 0.5% NH₄OH to give the title compound (2.27 g, 59%).

Description 115

Ethyl 2-(δ-aminoisoquinohn-3-yl)ethylcarbamate Prepared using ethyl 2-isoquinolin-3-ylethylcarbamate (Description 114) in place of 3-methyhsoquinohne according to the procedures of Descriptions 44 and 43 respectively.

Description 116

tert-Butyl 2-(5-aminoisoquinohn-3-yl)ethylcarbamate

To a solution of potassium hydroxide (450 mg ; 8.02 mmol) in ethanol was added ethyl 2-(5-aminoisoquinohn-3-yl)ethylcarbamate (Description llδ; 1.04 g, 2.6 mmol), and the resulting mixture heated at reflux until HPLC indicated the reaction was complete (approx 5 days). The mixture was cooled and loaded directly onto a Bond-elut SCX cartridge. The cartridge was washed with methanol, and the product then eluted with 2M ammonia in methanol. The basic fractions were evaporated and the residue dissolved in dichloromethane (lδ ml). Di-tert butyl dicarbonate (830 mg, 3.8 mmol) was added and the resulting mixture stirred at room temperature for 1 hour, then evaporated to dryness to give the title compound (l.lg, 100%).

Description 117 δ

Isoquinohn-7-yl trifluoromethanesulfonate

7-Hydroxyisoquinohne (1.4 g, 9.6 mmol) and triethylamine (1.5 ml, 10.6 mmol) were added to ether (50 ml) under a nitrogen atmosphere at 0 °C. Trifluoromethylsulfonic anhydride (1.8 ml, 10.6 mmol) was added dropwise and 10 the mixture then warmed to room temperature for 3h. The layers were separated and the lower layer extracted with ether (2 x 100 ml). The combined organics were then dried (Na₂SO4) and evaporated to give the title compound as a brown oh (1.04 g).

lδ Description 118

2-(Trifluoromethyl)pyrimidine-δ-carboxyhc acid

To a solution of methyl 2-trifluoromethyl pyrimidine-5-carboxylate [see

WO-A-0066667] (5 g, 22.7 mmol) in methanol (100 ml) was added a solution of

20 hthium hydroxide (1.09 g, 4δ.4 mmol) and the resulting mixture stirred at room temperature overnight. The methanol was removed by evaporation and the residue further diluted with water (50 ml). Extracted with EtOAc (x 3) and the aqueous phase was then acidified by the addition of c.HCl. The precipitate was extracted into EtOAc (x3) and the combined organic layers washed with sat NaCl,

25 dried over Na₂SO4 , filtered and evaporated to give the title compound (2.0 g,

Description 119

30 δ-(Hydroxymethyl)-2-(trifluoromethv pyrimidine

To an ice-bath cooled solution of 2-(trifluoromethyl)pyrimichne-δ-carboxylic acid (Description 118; 2 g, 10.4 mmol) in anhydrous tetrahydrofuran (100 ml) was added dropwise borane tetrahydrofuran complex [l.OM solution in THF] (lδ.6 ml, 15.6 mmol), after complete addition the mixture was stirred at room temperature for 90 mins. The reaction was quenched by the careful addition of water (2 ml), foUowed by saturated aqueous K2CO3. The organic layer was separated, and the aqueous phase extracted with Et₂O. The combined organics were then washed with water, saturated NaCl, dried over Na₂SO₄ , filtered and evaporated to give the title compound (680 mg, 31%).

Description 120

5-Azidomethyl-2-(trifluoromethyl)pyrimidine To a solution of δ-(hydroxymethyl)-2-(trifluoromethyl)pyrimidine (Description 119; 680 mg, 3.26 mmol) and triethylamine (0.65 ml, 3.91 mmol) in anhydrous dichloromethane (15 ml) cooled in an ice-bath was added dropwise methanesulfonyl chloride (0.28 ml, 3.59 mmol), and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water and sat NaCl , dried over Na₂SO4 , filtered and evaporated. The residue was dissolved in anhydrous N,N-dimethylformamide (15 ml), sodium azide (233 mg, 3.59 mmol) was added and the resulting mixture stirred at room temperature overnight. The mixture was poured into water (100 ml) and extracted with EtOAc (3 x 15 ml). The combined EtOAc layers were washed with water (2 x 50 ml), saturated NaCl (25 ml), dried over Na₂SO4 , filtered and evaporated to give the title compound (660 mg, 100%).

Description 121

5-(Aminomethyl)-2-(trifluoromethyl')pyrimidine

To a solution of 5-(azidomethyl)-2-(trifluoromethyl)pyrimidine (Description 120; 660mg, 3.26mmol) in anhydrous THF (10 ml) was added triphenylphosphine (1.71g, 6.52mmol) and water (0.059ml, 3.26mmol) and the resulting mixture stirred at room temperature overnight. The mixture was evaporated and the residue purified by column chromatography on sihca elution with 5% MeOH in DCM + 0.5% NH4OH to give the title compound (320 mg, 5δ%) as a pale yellow sohd. Description 122

4-(Morphohn-4-ylmethyl)benzonitrile

To a solution of 4-cyanobenzylbromide (1.0 g, 5.1 mmol) in MeCN (10 ml) was 5 added morpholine (0.44 g, 0.44 ml, 5.1 mmol) and the reaction was stirred at room temperature for 1 h. The precipitate was filtered off and partioned between CH2CI2 and NaOH (2M). The organic layer was separated, dried over MgSO₄ and dried to give the desired nitrile (0.70 g, 68 %).

10 Description 123

4-uVIorphohn-4-ylmethyl)benzylamine

To a suspension of 4-(morphohn-4-ylmethyl)benzonitrile (Description 122, 0.5 g,

2.5 mmol) in THF (7 mL) at 0°C was added dropwise a solution of LiAhBU (1.0 M lδ in THF, 2.δ ml, 2.5 mmol). The reaction was stirred at 0°C for lh. Additional LiAlH₄ (1.0 M in THF, 1.0 ml, 1.0 mmol) was added and the reaction stirred for an additional 30 min. The reaction was quenched by the addition of water (0.13 mL) followed by 15 % NaOH solution (0.13 ml) and stirred vigorously for 1 h. The reaction was filtered through cehte, evaporated and azeotroped twice with

20 toluene. The amine was used crude.

Description 124

2-(2-Morphohn-4-ylethoxy)-4-(trifluoromethyl)benzonitrile 25 To a solution of 2-nitro-4-trifluoromethyl benzonitrile (0.5 g, 2.3 mmol) and 2- morphohn-4-yl-ethanol (0.37 g, 0.34 ml, 2.8 mmol) in DMF (4 ml) was added dropwise a solution of KOH (0.23 g, 4.1 mmol) in water (1.5 ml). After 10 min the reaction was poured into ice water and the white crystalline product collected by filtration, washed with water and dried (0.5 g, 72 %). 30 Description 125

2-(2-Morphohn-4-ylethoxy)-4-(trifluoromethyl)benzylamine To a solution of 2-(2-morphohn-4-ylethoxy)-4-(trifluoromethyl)benzonitrile (Description 124, 0.5 g, 1.67 mmol) in ethanol (30 ml) was added aqueous ammonia (33 % aq soln, 5 ml) and a slurry of 10 % Pd/C catalyst in water. The reaction was hydrogenated at 43 psi. After 45 min the reaction was complete. The catalyst was filtered off, the reaction condensed and the product azeotroped with toluene to give the desired amine (0.49 g, 96 %).

Description 126

Isoquinohne-5-carbonyl azide

Isoquinohne-5-carboxyhc acid monohydrate (5.00 g, 26.2 mmol) was suspended in dichloromethane (200 ml) and N,N-dimethylformamide (5 drops) added. Oxalyl chloride (4.57 ml, 52 mmol) was then added and the reaction stirred for 7h. The solvent and excess oxalyl chloride was then evaporated and the residue taken up in dichloromethane (200 ml). A solution of sodium azide (2.1 g, 32.3 mmol) and tetra-n-butylammonium bromide (850 mg) in water (50 ml) was then added in one portion and the mixture stirred for 20 min. The layers were separated and the aqueous phase extracted with more dichloromethane (100 ml). The combined organic phases were evaporated and the residue purified by flash column chromatography (eluant ethyl acetate - dichloromethane (1:4)) to give the title compound as a yellow sohd (2.27 g, 44 %).

Example 1

N-Benzyl-iV-isoquinohn-5-ylurea

Prepared from 5-aminoisoquinohne and benzyl isocyanate according to the procedure of Description 61. m/z (ES⁺) 278 (M + H)⁺.

Examples 2 to 16 were prepared according to the procedure of Description 60. Example 2

A^r-(l.l'-Biphenyl-4-ylmethyl)-N¹-isoquinohn-5-ylurea

Prepared from isoquinoline-5-carboxyhc acid [see WO 95/09843] and

4-phenylbenzylamine. m/z (ES⁺) 354 (M + H)⁺.

Example 3

N-(l.l'-Biphenyl-3-ylmethyl)-A^-isoquinohn-5-ylurea

Prepared from isoquinohne-5-carboxyhc acid and 3-phenylbenzylamine. m/z (ES⁺) 354 (M + H)⁺.

Example 4

N-Isoquinohn-5-yl-iV-(3-phenylpropyl)urea

Prepared from isoquinoline-5-carboxylic acid and 3-phenylpropylamine. m/z (ES⁺) 306 (M + H)⁺.

Example 5

N-Isoq uinohn- 5 -yl-iV -(1.2.3.4-tetrahvdronaphthalen-2- ylmethvDurea

Prepared from isoquinohne-δ-carboxyhc acid and l,2,3,4-tetrahydronaphthalen-2- ylmethylamine (Description 20). m/z (ES⁺) 332 (M + H)⁺.

Example 6

N-[2-(4-Chlorophenyl)ethyll-iV-isoquinolin-5-ylurea

Prepared from isoquinohne-5-carboxyhc acid and 2-(4-chlorophenyl)ethylamine. m/z (ES⁺) 326 (M + H)⁺.

Example 7

N-[3.δ-bis(Trifluoromethyl)benzyll-N-isoquinohn-5-ylurea Prepared from isoquinohne-δ-carboxyhc acid and 3,5-bis(trifluoromethyl)benzylamine. m/z (ES⁺) 414 (M + H)⁺. Example 8

N-[3-(3.4-dimethylphenyl)propyll-N-isoquinohn-5-ylurea

Prepared from isoquinohne-δ-carboxyhc acid and 3-(3,4-dimethylphenyl)- propylamine. m/z (ES⁺) 334 (M + H)⁺.

Example 9

N-(4-ferf-Butylbenzyl)-.-V-isoquinohn-8-ylurea

Prepared from isoquinohne-8-carboxyhc acid and 4-terf-butylbenzylamine. m/z (ES⁺) 334 (M + H)⁺.

10

Example 10

N-(4-ter -Butylbenzyl)-N-isoquinolin-δ-ylurea

Prepared from isoquinoline-5-carboxyhc acid and 4-tert-butylbenzylamine. m/z (ES⁺) 334 (M + H)⁺. lδ

Example 11

N-(4-fert-Butylbenzyl)-N-quinolin-δ-ylurea

Prepared from quinoline-5-carboxyhc acid [see WO 96/09843] and 4-tert- butylbenzylamine. m/z (ES⁺) 334 (M + H)⁺.

20

Example 12

N-(3-ter^-Butylbenzyl -iV-isoquinohn-5-ylurea

Prepared from isoquinohne-δ-carboxyhc acid and 3-tert-butylbenzylamine

(Description 9). m/z (ES⁺) 334 (M + H)⁺.

2δ

Example 13

N-[2-(4-tert-Butylphenyl)ethyl1-N-isoquinohn-δ-ylurea Prepared from isoquinoline-5-carboxylic acid and 2-(4-teτX butylphenyl)ethylamine. m/z (ES⁺) 348 (M + H)⁺.

30 Example 14

N-Isoquinohn-5-yl-N-[4-(trifluoromethyl)benzyllurea

Prepared from isoquinoline-5-carboxylic acid and 4-trifluoromethylbenzylamine. m/z (ES⁺) 346 (M + H)⁺.

Example 15

N-Isoquinohn-5-yl-iV-[3-(trifluoromethyl)benzyl1urea

Prepared from isoquinohne-5-carboxyhc acid and 3-trifluoromethylbenzylamine. m/z (ES⁺) 346 (M + H)⁺.

10

Example 16

N-Isoquinohn-5-yl-N'-{2-[4-(trifluoromethyl phenyllethyl}urea Prepared from isoquinohne-δ-carboxyhc acid and 2-[4-(trifluoromethyl)phenyl]ethylamine (Description 6). m/z (ES⁺) 360 (M + H)⁺. lδ

Example 17

N-(2-Oxidoisoquinohn-δ-yl)-N-l4-(trifluoromethyl)benzyl]urea

To a suspension of N-isoquinohn-5-yl-N'-[4-(trifluoromethyl)benzyl]urea

(Example 14; 100 mg , 0.29 mmol) in chloroform (25 ml) was added Oxone

20 (541 mg, 0.87 mmol), foUowed by wet alumina Grade III (lg), and the resulting suspension heated at reflux for 60 minutes. Whilst the mixture was still hot it was filtered to remove alumina and Oxone, the sohds were washed with more chloroform, then methanol, and the filtrate evaporated to dryness. The residue was purified by preparative TLC eluting with 10% MeOH in dichloromethane +

25 0.5% NH4OH, and the product triturated with a mixture of dichloromethane/iso- hexanes, filtered and dried to give the title compound (11 mg, 10%) as a white sohd. m/z (ES⁺) 362 (M + H)⁺.

Examples 18 to 51 were prepared according to the procedure of Description 60.

30

Example 18

N-Isoquinohn-5-yl-iV¹-{2-[3-(trifluoromethyl)phenyllethyl>urea Prepared from isoquinohne-δ-carboxyhc acid and 2-[3-(trifluoromethyl)phenyl]ethylamine. m/z (ES⁺) 360 (M + H)⁺. Example 19

N-Isoquinohn-δ-yl-N-{3-[4-(trifluoromethv phenynpropyllurea Prepared from isoquinohne-5-carboxyhc acid and δ 3-[4-(trifluoromethyl)phenyl]propylamine (Description 22). m/z (ES⁺) 374 (M + H)⁺.

Example 20

N-Isoquinohn-δ-yl-N-^-ftrifluoromethyDbenzyllurea 0 Prepared from isoquinoline-8-carboxylic acid and 4-(trifluoromethyl)benzylamine.

Example 21

N-[3-Fluoro-4-(trifluoromethyl)benzyl]-N-isoquinohn-δ-ylurea 5 Prepared from isoquinohne-δ-carboxyhc acid and 3-fluoro-4- (trifluoromethyl)benzylamine. m/z (ES⁺) 364 (M + H)⁺.

Example 22

N- r2-Fluoro-4-(trifl.uoromethyl)benzyl] - JV-isoquinohn-δ-ylurea 0 Prepared from isoquinoline-δ-carboxyhc acid and 2-fluoro-4- (trifluoromethyl)benzylamine. m/z (ES⁺) 364 (M + H)⁺.

Example 23

N-Isoqxιinohn-δ-yl-N-{3-r3-(trifluoromethyl)phenvnpropyl>urea δ Prepared from isoquinoline-5-carboxyhc acid and

3-[3-(trifluoromethyl)phenyl]propylamine (Description 23). m/z (ES⁺) 374 (M + H)⁺.

Example 24 0 N-Isoquinohn-δ-yl-iV-r4-(trifluoromethoxy)benzyllurea Prepared from isoquinoline-5-carboxyhc acid and 4-(trifluoromethoxy)benzylamine. m/z (ES⁺) 362 (M + H)⁺. Example 25

A^r-{[6-(4-Fluorophenyl)pyridin-3-yl]methv -iV¹-isoquinohn-5-ylurea Prepared from isoquinohne-δ-carboxyhc acid and [6-(4-fluorophenyl)pyridin-3- yl]methylamine (Description 26). m/z (ES⁺) 373 (M + H)⁺.

Example 26 ■Λ^r-Isoquinohn-8-yl-iV-{3-r4-(trifluoromethyl)phenyllpropyl)urea Prepared from isoquinohne-8-carboxyhc acid and 3-[4-(trifluoromethyl)phenyl]propylamine (Description 22). m/z (ES⁺) 374 (M + H)⁺.

Example 27

N-Quinolin-δ-yl-N-{3-[4-(trifluoromethyl)phenyl]propyl)urea Prepared from quinohne-5-carboxyhc acid and 3-[4-(trifluoromethyl)phenyl]propylamine (Description 22). m/z (ES⁺) 374 (M + H)⁺.

Example 28

N-Isoquinohn-8-yl-N-(3-r3-(trifluoromethyl)phenvnpropyl)urea Prepared from isoquinohne-8-carboxyhc acid and

Example 29 N-Quinohn-5-yl-iV-l3-[3-(trifluoromethyl)phenyl1propyl)urea Prepared from quinohne-δ-carboxyhc acid and 3-[3-(trifluoromethyl)phenyl]propylamine (Description 23). m/z (ES⁺) 374 (M + H)⁺.

Example 30

N-Isoquinohn-8-yl-N-r4-(trifluoromethoxy)benzyllurea Prepared from isoquinohne-8-carboxyhc acid and 4-(trifluoromethoxy)benzylamine. m/z (ES⁺) 362 (M + H)⁺. Example 31

N-Qιnnohn-δ-yl-Λ 4-(trifluoromethoxy)benzyIlurea

Prepared from quinohne-5-carboxyhc acid and 4-(trifluoromethoxy)benzylamine. δ m/z (ES⁺) 362 (M + H)⁺.

Example 32

N-(2.3-Dihvdro- lH-inden-2-ylmethyl)-iV-isoquinohn-5-ylurea Prepared from isoquinoline-δ-carboxyhc acid and 2,3-dihydro-lH-inden-2- 10 ylmethylamine. m/z (ES⁺) 318 (M + Η)⁺.

Example 33

N-Isoquinohn-δ-yl-N-(4-phenylcvclohexyl)urea

Prepared from isoquinohne-δ-carboxyhc acid and 4-phenylcyclohexylamine. lδ m/z (ES⁺) 346 (M + H)⁺.

Example 34

N-Isoquinohn-δ-yl-N-(6.7.8.9-tetrahvdro-5H-benzo[ ]r71annulen-6-ylmethyl)urea Prepared from isoquinohne-δ-carboxyhc acid and 6,7,8,9-tetrahydro-δH- 20 benzo[α][7]annulen-6-ylmethylamine hydrochloride (Description 26). m/s (ES⁺) 346 (M + Η)⁺.

Example 35

N-Isoquinohn-5-yl-JV^,-(6.7.8.9-tetrahydro-δH-benzo[αir71annulen-7-ylmethyl)urea 25 Prepared from isoquinohne-5-carboxyhc acid and 6,7,8,9-tetrahydro-δH- benzo[ ] [7] annulen- 7-ylmethylamine hydrochloride (Description 28). m/z (ES⁺) 346 (M + Η)+.

Example 36

30 N-isoquinolin-δ-yl-N-{[5-(trifluoromethvDpyridin-2-yllmethyllurea Prepared from isoquinohne-δ-carboxyhc acid and 2-aminomethyl-5- (trifluoromethyl)pyridine (Description 2). m/z (ES⁺) 347 (M + H)⁺. Example 37

N-[(4-ter^-Butylpyridin-2-yl)methyll-iv¹-isoquinohn-5-ylurea

Prepared from isoquinohne-5-carboxyhc acid and 2-aminomethyl-4-ter£- butylpyridine (Description 5). m/z (ES⁺) 335 (M + H)⁺.

Example 38

N- [(6-ter^Butylpyri( n-3-yl)methvIl -JV-isoquinolin-5-ylurea

Prepared from isoquinohne-5-carboxyhc acid and 3-aminomethyl-6-terf- butylpyridine (Description 11). m/z (ES⁺) 335 (M + H)⁺.

Example 39

JV- [(2-ter^-Butylpyridin-4-yl^')methyl] -JV-isoquinolin-5-ylurea

Prepared from isoquinohne-5-carboxyhc acid and 4-aminomethyl-2-tert- butylpyridine (Description 13). m/z (ES⁺) 335 (M + H)⁺.

Example 40

JV- [(6-fert-Butylpyridin-2-yl)methyn -N-isoquinolin-5-ylurea

Prepared from isoquinoline-5-carboxyhc acid and 2-aminomethyl-6-ter£- butylpyridine (Description 16). m/z (ES⁺) 335 (M + H)⁺.

Example 41

N-Isoquinohn-5-yl-JV-{[6-(trifluoromethyl)pyridin-3-yllmethyllurea Prepared from isoquinoline-5-carboxyhc acid and 3-aminomethyl-6- (trifluoromethyl)pyridine. m/z (ES⁺) 347 (M + H)⁺.

Example 42

N-Isoquinohn-5-yl-JV-{3-r6-(trifluoromethyl)pyridin-3-yllpropyl urea

Prepared from isoquinohne-5-carboxyhc acid and 3-[6-(trifluoromethyl)pyridin-3- yl]propylamine (Description 18). m/z (ES⁺) 375 (M + H)⁺. Example 43

JV-Isoquinohn-5-yl-JV-[3-(lH-pyrazol-l-yl benzyllurea

Prepared from isoquinohne-5-carboxyhc acid and 3-(lH-pyrazol-l-yl)benzylamine hydrochloride (Description 29). m/z (ES⁺) 344 (M + Η)⁺.

Example 44

JV-Isoquinohn-5-yl-JV-[4-(lH-pyrazol-l-yl)benzvnurea

Prepared from isoqιιinoline-5-carboxylic acid and 4-(lH-pyrazol-l-yl)benzylamine hydrochloride (Description 30). m/z (ES⁺) 344 (M + Η)⁺.

Example 45

JV-Isoquinohn-5-yl-JV-r(2-phenyl-1.3-thiazol-5-yl)methyllurea

Prepared from isoquinohne-5-carboxyhc acid and (2-phenyl-l,3-thiazol-δ- yl)methylamine. m/z (ES⁺) 361 (M + H)⁺.

Example 46

N-Isoquinolin-5-yl-JV-[(2-thien-2-yl-1.3-thiazol-4-yl)methyllurea

Prepared from isoquinohne-δ-carboxyhc acid and (2-thien-2-yl-l,3-thiazol-4- yl)methylamine. m/z (ES⁺) 367 (M + H)⁺.

Example 47

JV-Isoquinohn-δ-yl-JV- [(4-phenyl- 1.3-thiazol-2-yl)methyl] urea

Prepared from isoquinoline-δ-carboxylic acid and (4-phenyl-l,3-thiazol-2- yl)methylamine. m/z (ES⁺) 361 (M + H)⁺.

Example 48

N-Isoquinohn-δ-yl-JV- [(2-phenyl- 1.3-thiazol-4-yl)methyl] urea

Prepared from isoquinohne-δ-carboxyhc acid and (2-phenyl-l,3-thiazol-4- yl)methylamine. m/z (ES⁺) 361 (M + H)⁺. Example 49

N-Isoquinohn-5-yl-JV-[2-(4-phenyl-1.3-thiazol-2-yl)ethyllurea

Prepared from isoquinoline-5-carboxylic acid and 2-(4-phenyl-l,3-thiazol-2- yl)ethylamine. /z (ES⁺) 375 (M + H)⁺.

Example 50

N-Isoquinohn-5-yl-JV-[(5-phenvhsoxazol-3-yl)methvnurea

Prepared from isoquinohne-5-carboxyhc acid and (5-phenylisoxazol-3- yl)methylamine. m/z (ES⁺) 345 (M + H)⁺.

Example 51

N-Isoquinohn-5-yl-JV-[(3-phenvhsoxazol-5-yl)methyl1urea

Prepared from isoquinoline-5-earboxylic acid and (3-phenyhsoxazol-5- yl)methylamine. m/z (ES⁺) 346 (M + H)⁺.

Example 52

N-(8-Fluoroisoquinohn-δ-yl)-JV-r4-(trifluoromethyl)benzyl]urea Prepared from 8-fluoroisoquinohn-5-amine (Description 43) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES⁺) 364 (M + H)⁺.

Example 53

N-Isoquinohn-δ-yl-N-methyl-JV-^-faifluoromethvDbenzyllurea Sodium hydride (60 % dispersion in oil, 7 mg, 0.17 mmol) was added to a suspension N-isoquinolin-δ-yl-JV-[4-(trifluoromethyl)benzyl]urea (Example 14; 48 mg, 0.14 mmol) in THF (3 mL) at room temperature and the reaction was stirred until effervescence ceased (20 minutes). Methyl iodide (11 μL, 0.17 mmol) was added and the reaction stirred at room temperature for 3 hours. TLC analysis (10 % MeOH in CH2CI2) indicated only one major product. The reaction was evaporated in vacuo and the product isolated by preparative TLC (4 % MeOH in CH2CI2) to give the title compound, m/z (ES⁺) 360 (M + H)⁺.

Examples 54 to 60 were prepared according to the procedure of Description 60. Example 54

JV-Isoquinolin-δ-yl-N-methyl-N-[4-(trifluoromethyl)benzyl]urea Prepared from isoquinohne-5-carboxyhc acid and N-methyl-N-[4- (trifluoromethyl)benzyl] amine (Description 31). m/z (ES⁺) 190 (M + H)⁺.

Example 55 JV-Isoquinohn-5-yl-JV-{l-[4-(trifluoromethyl)phenyllethyl)urea Prepared from isoquinohne-δ-carboxyhc acid and l-[4-(trifluoromethyl)phenyl]ethylamine (Description 32). m/z (ES⁺) 360 (M + H)⁺.

Example 56

N-(1.3-Diphenylpropyl)-JV-isoquinohn-5-ylurea

Prepared from isoquinoline-5-carboxylie acid and 1,3-diphenylpropylamine (Description 33). m/z (ES⁺) 382 (M + H)⁺.

Example 57

N-Isoquinohn-5-yl-JV-[(3-phenyl-1.2.4-oxadiazol-5-yl)methvnurea Prepared from isoquinohne-5-carboxyhc acid and (3-phenyl-l,2,4-oxadiazol-5- yl)methylamine hydrochloride (Description 34). m/z (ES⁺) 346 (M + H)⁺.

Example 58

N- [(2-Benzyl- 1.3-thiazol-4-yl)methyll -JV-isoquinohn-5-ylurea Prepared from isoquinoline-5-carboxylic acid and 2-benzyl-l,3-thiazol-4- yl)methylamine (Description 35). m/z (ES⁺) 375 (M + H)⁺.

Example 59

N-Isoquinolin-5-yl-JV-{[l-(2-methylphenyl)-lH-Pyrazol-4-yl]methvhurea Prepared from isoquinoline-5-carboxyhc acid and [l-(2-methylphenyl)-lH- pyrazol-4-yl]methylamine (Description 36). m/z (ES⁺) 358 (M + Η)⁺. Example 60

JV-(3-Methoxyisoquinohn-8-yl)-JV- 4-(trifluoromethyl)benzvnurea Prepared from 3-methoxyisoquinoline-8-carboxylic acid (Description 56) and 4- (trifluoromethyl)benzylamine. m/z (ES⁺) 376 (M + H)⁺.

Example 61 JV-Cinnohn-5-yl-JV-r4-(trifluoromethyl)benzyllurea Prepared from cinnohn-5-amine (Sci Pharm. 1982, 50, 246) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES⁺) 347 (M + H)⁺.

Examples 62 to 64 were prepared according to the procedure of Description 60.

Example 62 N-(4-fer^Butylbenzyl)-N'-cinnohn-δ-ylurea

Prepared from cinnohn-5-amine (Sci Pharm. 1982, 50, 246) and (A-tert- butylbenzyl) acetic acid, m/z (ES⁺) 335 (M + H)⁺.

Example 63 N-(3-Cyclohexylpropyl)-JV-isoquinohn-5-ylurea

Prepared from isoquinohne-δ-carboxyhc acid and 3-cyclohexylpropylamine hydrochloride (Description 37). m/z (ES⁺) 312 (M + H)⁺.

Example 64 JV-Isoquinohn-5-yl-JV-(6.7.8.9-tetrahydro-δH-benzo[αl T71 annulen- 7-yl)urea Prepared from isoquinohn-5-amine and 6,7,8,9-tetrahydro-δH- benzo[α][7]annulene-7-carboxylie acid (Description 38). m/z (ES⁺) 332 (M + Η)⁺.

Example 65 N-Isoquinohn-5-yl-JV-r4-(trifluoromethyl)benzyllthiourea

To a solution of l,l'-thiocarbonyldi-2(lH)-pyridone (330 mg, 1.4 mmol) in dichloromethane (13 ml) under nitrogen was added, dropwise, a solution of 4-(trifluoromethyl)benzylamine (200 μl, 1.4 mmol) in dichloromethane (10 ml). The solution was stirred at room temperature for 16 hours. 5-Aminoisoquinohne (245 mg, 0.0017 mol) was added to the reaction mixture, which was then heated at reflux for 2 days and evaporated. Preparative TLC (eluant 5% methanol/ 95% dichloromethane) gave a product band also containing 5-aminoisoquinoline. The mixed product (230 mg) was dissolved in acetonitrile (40 ml) and tetrafluorophthahc anhydride (700 mg, 3.2 mmol) was added. The reaction was stirred at room temperature for 16 hours. Ethyl acetate (60 ml) was added to the reaction mix which was then washed with saturated aqueous sodium bicarbonate (3 x 20 ml). The organic extract was evaporated and the residue purified by preparative TLC (eluant system 5% methanol/ 95% dichloromethane) to give the title compound (77 mg, 23%). m/z (ES⁺) 362 (M + 1)⁺.

Example 66

N-Isoquinohn-6-yl- JV- [4-(trifluoromethyl)benzyl] urea Prepared from 6-aminoisoquinohne (Description 51) and

[4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES⁺) 346 (M + H)⁺.

Example 67 N-Isoquinohn-6-yl-JV-r4-(trifluoromethoxy)benzyl]urea Prepared from 6-aminoisoquinohne (Description 51) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES⁺) 362 (M + H)⁺.

Example 68

N-(3-Methyhsoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzyl]urea Prepared from 3-methyhsoquinohn-5-amine (Description 45) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES⁺) 360 (M + H)⁺. Example 69

JV-(l-Chloroisoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzvnurea Prepared from l-chloroisoquinohn-5-amine (Description 48) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES⁺) 380, 382 (M + H)⁺.

Example 70

N-[l-(Dimethylamino)isoquinohn-5-yll-JV-[4-(trifluoromethyl)benzyl]urea N-(l-Chloroisoquinohn-5-yl)-N-(4-trifluoromethylbenzyl)urea (Example 69; 60 mg) was suspended in ethanol (5 ml). Ethanohc dimethylamine (33%, 2 ml) was added and the mixture heated to 100 °C in a sealed tube for 16 hours after which time TLC indicated complete reaction. The reaction mixture was evaporated and the residue purified by preparative thin layer chromatography (5% methanol-dichloromethane eluant) to give the title compound (20 mg). m/z (ES⁺) 389 (M + H)⁺.

Example 71

JV-(3-Methvhsoquinohn-δ-yl)-JV-[4-(trifluoromethoxy)benzyl]urea Prepared from 3-methyhsoquinolin-5-amine (Description 46) and [4- (trifluoromethoxy)benzyl] isocyanate (Description 59) according to the procedure of Description 61. m/z (ES⁺) 376 (M + H)⁺.

Example 72

^-(S-Methyhsoquinohn-δ-vD-N'-^-faifluoromethvDbenzyllurea A sample of 3-methyl-5-nitroisoquinohne (Description 44) enriched in the nitration byproduct 3-methyl-8-nitroisoquinohne was reduced according to

Description 4δ and the mixture of amines reacted with

[4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. Isomer separation of the products gave the title compound. m/z (ES÷) 360 (M + H)⁺. Example 73

JV-(3-Chloroisoquinohn-δ-yl)-JV-[4-(trifluoromethyl)benzvnurea Prepared from 3-chloroisoquinohn-5-amine (Description 60) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES⁺) 380, 382 (M + H)⁺.

Example 74 JV-(3-Methylcinnohn-δ-yl -JV-[4-(trifluoromethyl)benzyl1urea Prepared from 3-methylcinnolin-5-amine and [4-(trifluoromethyl)benzyl]isocyanate (Description 68) according to the procedure of Description 61. m/z (ES⁺) 361 (M + H)⁺.

Example 75

JV-Cinnohn-5-yl-JV-[4-(trifluoromethoxy)benzyl1urea Prepared from cinnohn-5-amine [Sci Pharm. 1982, 50, 246] and

[4- (trifluoromethoxy)benzyl] isocyanate (Description 59) according to the procedure of Description 61. m/z (ES⁺) 363 (M + H)⁺.

Example 76 N-(l-hvdroxyisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzvnurea

N-(l-chloroisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzyl]urea (Example 69; 47 mg, 0.12 mmol) was added to a mixture of 3N HCl (aq. 5 ml) and THF (1 ml). The mixture was heated at 90 °C for 20 hours, then 6N HCl (aq. 2 ml) was added and the reaction heated at 90 °C for a further 20 hours. After coohng to room temperature, ethyl acetate (20 ml) was added and the layers separated (some sohd was suspended in the organic layer). The organic phase was washed with saturated aqueous NaHCOβ (20 ml), then evaporated. The residue was triturated in refluxing isopropyl alcohol (5 ml), then cooled to room temperature. The white sohd was collected by filtration and washed with isopropyl alcohol (2 1 ml) to give the title compound (22 mg). m/z (ES⁺) 362 (M + H)⁺. Example 77

N-f4-(trifluoromethyl)benzyl1-JV-[3-(trifluoromethyl)isoquinohn-5-yllurea Prepared from 3-(trifluoromethyl)isoquinohn-5-amine (Description 64) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES⁺) 414 (M + H)⁺.

Example 78

N-(l-chloro-3-ethyhsoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzyllurea Prepared from l-chloro-3-ethyhsoqxιinolin-5-amine (Description 66) and [4- (trifluoromethyl)benzyl] isocyanate (Description 58) according to the procedure of Description 61. m/z (ES⁺) 408 , 410 (M + H)⁺.

The following quinohn-6-yl derivatives were also prepared by similar methodology:

Example 79 N-phenyl-N'- [quinohn-6-vH urea Prepared from 6-aminoquinohne and phenyl isocyanate. m/z (ES⁺) 264 (M + H)⁺.

Example 80

N-(2-naphthyl)-N'-[quinohn-6-yllurea

Prepared from 6-aminoquinohne and 2-naphthyl isocyanate. m/z (ES⁺) 314 (M + H)⁺.

Example 81

N-(4-nitrophenyl)-N^f-[quinohn-6-yl1urea

Prepared from 6-aminoquinoline and 4-nitrophenyl isocyanate. /z (ES⁺) 309 (M + H)⁺.

Example 82

N- f3.5-bis(trifluoromethyl)phenyll -JV- rquinohn-6-yll urea

Prepared from 6-aminoquinohne and 3,5-bis(trifluoromethyl)phenyl isocyanate. Example 83

JV-(4-phenoxyphenyl)-N'-[quinohn-6-yl1urea

Prepared from 6-aminoquinohne and 4-phenoxyphenyl isocyanate. 5 7tt/£ (ES⁺) 356 (M + H)⁺.

Example 84

N-(4-acetylphenyl)-N-fquinohn-6-yl]urea

Prepared from 6-aminoquinohne and 4-acetylphenyl isocyanate. 10 m/z (ES⁺) 306 (M + H)⁺.

Example 85

N-benzyl-N^f-[quinohn-6-yllurea

Prepared from 6-aminoquinohne and benzyl isocyanate. m/z (ES⁺) 278 (M + H)⁺. lδ

Example 86

N-[quinohn-6-yll-N'-[4-(trifluoromethoxy)phenyllurea

Prepared from 6-aminoquinohne and 4-(trifluoromethoxy)phenyl isocyanate. m/z (ES⁺) 348 (M + H)⁺.

20

Example 87

N-(4-cyanophenyl)-N'-[quinohn-6-yl]urea

Prepared from 6-aminoquinohne and 4-cyanophenyl isocyanate. m/z (ES⁺) 289 (M + H)⁺.

26

Example 88

JV-(l.l'-biphenyl-4-yl)-N^,-lquinohn-6-yllurea

Prepared from 6-aminoquinohne and 4-biphenyl isocyanate. m/z (ES⁺) 340 (M + H)⁺.

30

Example 89

N- f4- (dimethylamino)phenyl] -JV - [qυinohn- 6- yll urea

Prepared from 6-aminoquinohne and 4-(dimethylamino)phenyl isocyanate. m/s (ES⁺) 307 (M + H)⁺.

Example 90

N-(1.3-benzodioxol-δ-yl)-N'-[quinohn-6-yl]urea Prepared from 6-aminoquinohne and 3,4-(methylenedioxy)phenyl isocyanate. m/z (ES⁺) 308 (M + H)⁺.

Example 91

N-cyclohexyl-N'- [qxιinolin-6-yll urea Prepared from 6-aminoquinohne and cyclohexyl isocyanate. m/z (ES⁺) 270 (M + H)⁺.

Example 92

JV- [(+/- - 1-phenylethyl] -JV'- [quinohn-6-yl] urea Prepared from 6-aminoquinohne and (+/-)- 1-phenylethyl isocyanate. m/z (ES⁺) 292 (M + H)⁺.

The above exemplified compounds of the present invention have been tested in the following assay and generally possess an IC50 < 1 μM and, in the majority of cases, < 200 nM.

Biological Methodology

Determination of in vitro activity

CHO cells, stably expressing recombinant human VRl receptors and plated into black-sided 384-well plates, were washed twice with assay buffer (Hepes-buffered sahne) and then incubated with luM Fluo-3-AM for 60 minutes in darkness. Cells were washed twice more to remove excess dye, before being placed, along with plates containing capsaicin and test compounds in a Molecular Devices FLIPR. The FLIPR simultaneously performed automated pharmacological additions and recorded fluorescence emmission from Fluo-3. In all experiments, basal fluorescence was recorded, before addition of test compounds and subsequent addition of a previously determined concentration of capsaicin that evoked 80% of the maximum respsonse. Inhibition of capsaicin evoked increases in intracellular [Ca²⁺] were expressed relative to wells on the same plate to which capcaicin was added in the absence of test compounds. Increases in intracellular [Ca²⁺] occuring after addition of test compound alone, prior to addition of capsaicin, allow determination of intrinsic agonist or partial agonist activity, if present. 5

Determination of in vivo efficacy in a capsaicin paw flinch model (Method adapted from Taniguchi et al, 1997, Br J Pharmacol. 122(5):809-12) To determine in vivo functional occupancy of VRl receptors, compounds are administered orally to male Sprague Dawley rats typically 1 hour prior to

10 receiving an intraplantar injection of capsaicin (2μg dissolved in ethanol) and the number of flinches of the injected paw is recorded for δ minutes immediately thereafter. Statistical analysis is performed using one-way ANOVA followed by Dunnett's test; p values <0.0δ compared to capsaicin/vehicle-treated rats are considered significant. lδ

Determination of in vivo efficacy in a model of inflammatory pain (Method adapted from Hargreaves et al, 1988 Pain, 32(l):77-88). Antinociceptive activity is determined using a rat carrageenan-induced thermal hyperalgesia assay. Inflammatory hyperalgesia is induced by intraplantar

20 injection of carrageenan (lambda-carrageenan 0.1 ml of 1% solution made up in sahne) into one hind paw. Compounds are given oraUy typically 2 hours after carrageenan and paw withdrawal latancies determined 1 hour later. Paw withdrawal latencies to apphcation of noxious thermal stimuh to plantar surface of the hind paw are measured using the Hargreaves apparatus. Thermal

26 hyperalgesia is defined as the difference in paw withdrawal latencies for sahne/vehicle- and carrageenan/vehicle-treated rats. Paw wthdrawal latencies for drug treated rats are expressed as a percentage of this response. Statistical analysis is performed using one-way ANOVA foUowed by Dunnett's test; p values <0.05 compared to carrageenan/vehicle-treated rats are considered significant.

30 Example 93

JV-(l-Methylisoquinohn-δ-yl)-JV-[4-(trifluoromethyl)benzyl1urea Prepared from l-methyhsoquinohn-5-amine (Description 68) and [4-(trifluoromethyl)benzyl]isocyanate (Description 68) according to the procedure of Description 61. m/z (ES⁺) 360 (M + H)⁺.

Example 94

N-(l-Methyhsoquinohn-δ-yl)-JV-[4-(trifluoromethoxy)benzyllurea Prepared from 1-methyhsoquinolin-δ-amine (Description 68) and [4- (trifluoromethoxy)benzyl] isocyanate (Description 59) according to the procedure of Description 61. m/z (ES⁺) 376 (M + H)⁺.

Example 95

N-(6.8-Difluoro-3-methvhsoquinohn-5-yl)-N'-r4-(trifluoromethyl)benzyllurea Prepared from 6,8-difluoro-3-methyhsoquinohn-5-amine (Description 73) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES⁺) 396 (M + H)⁺.

Example 96 N-[3-Methyl-7-(trifluoromethyl)isoquinohn-5-vn-JV-[4- (trifluoromethvDbenzyll urea

Prepared from 3-methyl-7-(trifluoromethyl)isoquinohn-δ-amine (Description 74) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES⁺) 428 (M + H)⁺.

Example 97 N-(8-Fluoro-3-methvhsoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzvnurea Prepared from 8-fluoro-3-methyhsoquinohn-δ-amine (Description 76) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES⁺) 378 (M + H)⁺. Example 98

N-(6-Fluoro-3-methyhsoquinohn-5-yl)-JV-[4-(trifl.uoromethyl)benzyl]urea Prepared from 6-fluoro-3-methyhsoquinohn-δ-amine (Description 79) and [4- δ (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES⁺) 378 (M + H)÷.

Example 99

^(e-Fluoro-S-methvhsoquinohn-δ-vD-JV-^-ftrifluoromethoxy^benzyllurea 10 Prepared from 6-fluoro-3-methyhsoquinohn-δ-amine (Description 79) and [4-

(trifluoromethoxy)benzyl]isocyanate (Description 59) according to Description 61. m/z (ES⁺) 394 (M + H)⁺.

Example 100 lδ N- (3-Methylcinnohn- δ - yl) - JV- [4- (trifluoromethoxy)benzyIj urea Prepared from 3-methylcinnolin-δ-amine and

[4- (trifluoromethoxy)benzyl] isocyanate (Description 59) according to the procedure of Description 61. m/z (ES⁺) 377 (M + H)⁺.

20 Example 101

N-(7-Methoxyisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzvnurea

Prepared from 7-methoxyisoquinohn-δ-amine (Description 82) and [4-

(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES⁺) 376 (M + H)⁺. 25

Example 102

JV-(1.3-Dimethyhsoquinohn-5-yl)-JV-[4-(trifluoromethyl benzyllurea

Prepared from l,3-dimethyhsoquinohn-5-amine (Description 83) and [4-

(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61.

30 m/z (ES⁺) 374 (M + H)⁺. Example 103

JV-(7-Chloro-3-methyhsoquinohn-5-yl)-JV-[4-(trifl.uoromethv benzvnurea Prepared from 7-chloro-3-methyhsoqτιinohn-δ-amine (Description 86) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES⁺) 394 (M + H)⁺.

Example 104

N-(7-Chloroisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzvnurea Prepared from 7-chloroisoquinohn-5-amine (Description 87) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES⁺) 380 (M + H)⁺.

Example 105

N-(8-Fluoro-3-methoxyisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzyl]urea Prepared from 8-fluoro-3-methoxyisoquinoline-δ-carboxylie acid (Description 88) and 4-(trifluoromethyl)benzylamine according to Description 60. m/z (ES⁺) 394 (M + H)⁺.

Example 106 N-(6-Fluoroisoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzyllurea

Prepared from 6-fluoroisoquinohn-δ-amine (Description 89) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. rn/ø (ES⁺) 364 (M + H)⁺.

Example 107

JV-(6-Fluoroisoquinohn-δ-yl)-JV-[4-(trifluoromethoxy)benzyl]urea Prepared from 6-fluoroisoquinolin-5-amine (Description 89) and [4- (trifluoromethoxy)benzyl]isocyanate (Description 69) according to Description 61. m/z (ES⁺) 394 ⁽M + B.)f

Example 108

N-(7-Fluoroisoquinohn-δ-yl)-JV-r4-(trifluoromethyl)benzvnurea

Prepared from 7-fluoroisoquinolin-δ-aιnine (Description 90) and [4-

(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES⁺) 364 (M + H)⁺. Example 109

N-(4-Methyhsoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzyl]urea Prepared from 4-methyhsoquinohn-5-amine (Description 91) and [4- (trifluoromethyl)benzyl]isocyanate (Description 68) according to Description 61. m/z (ES⁺) 360 (M + H)⁺.

Example 110

JV-[8-(trifluoromethyl)isoquinohn-δ-vn-JV-[4-(trifl.uoromethyl)benzyllurea

To a solution of 8-(trifluoromethyl)isoquinohn-δ-amine (Description 93; lδO mg, 0.708 mmol) in CDC1₃ (10 ml) was added [4- (trifluoromethyl)benzyl] isocyanate (Description 58) [0.506M soln in DCM; 1.403 ml, 0.71 mmol) and the resulting mixture heated at reflux overnight. NMR analysis showed a deficit of the [4- (trifluoromethyl)benzyl] isocyanate in comparison to remaining 8- (trifluoromethyl)isoquinolin-5-amine so a further portion of [4- (trifluoromethyl)benzyl]isocyanate [0.606M solution in DCM] (1.403ml ;

0.71mmol) was added and refluxing continued for 2 days. The cooled reaction mixture was evaporated to dryness and purified by column chromatography on silica elution with 1% MeOH in DCM + 0.5% NH₄OH. NMR showed the product was the bis acylated urea. This material was dissolved in methanol (5 ml) and K2CO3 (600 mg, 3.6 mmol) added and the mixture stirred at room temperature for 2.5 hours. The mixture was filtered and the residue purified by preparative TLC eluting with 10% MeOH in DCM + 0.5% NH₄OH to give the title compound (100 mg, 34%) as a white sohd. m/z (ES⁺) 414 (M + H)⁺.

Example 111

JV- [6-(trifluoromethyl)isoquinohn-δ-yll -JV- r4-(trifluoromethyl)benzyllurea To a solution of 6-(trifluoromethyl)isoquinohn-5-amine (Description 98; 100 mg, 0.47 mmol) in anhydrous toluene (5 ml) was added [4-

(trifluoromethyl)benzyl]isocyanate (Description 68) [0.506M soln in DCM] (1.88 ml ; 0.94 mmol) and the mixture heated at reflux overnight. Further [4-

(trifluoromethyl)benzyl]isocyanate [0.606M soln in DCM] (1.88 ml ; 0.94 mmol) was added and heating continued for 4 days. The toluene was removed, the residue dissolved in methanol (10 ml) and a spatula end of potassium carbonate added. The mixture was then heated at reflux for 15 mins. The mixture was cooled and filtered and the nitrate evaporated. The residue was purified by mass directed HPLC to give the title compound (8 mg, 4%) as a white sohd. m/z (ES⁺) 414 (M + H)⁺.

Example 112

N-[7-(trifiuoromethyl)isoquinohn-δ-yll-JV-r4-(trifluoromethyl)benzyl1urea Prepared from 7-(trifluoromethyl)isoquinohn-5-amine (Description 99) and [4- (trifluoromethyl)benzyl]isocyanate (Description 68) according to Description 61. m/z (ES⁺) 414 (M + H)⁺.

10

Example 113

N-[7-(trifluoromethyl)isoquinohn-5-yl1-JV-r4-(trifluoromethoxy)benzyl]urea Prepared from 7-(trifluoromethyl)isoquinolin-δ-amine (Description 99) and [4- (trifluoromethoxy)benzyl]isocyanate (Description 59) according to Description 61. lδ m/z (ES⁺) 414 (M + H)⁺.

Example 114

N-(6-Fluoro-l-methvhsoquinohn-δ-v -N'-[4-(trifluoromethyl)benzyl1urea Prepared from 6-fluoro-l-methyhsoquinohn-5-amine (Description 103) and [4- 20 (trifluoromethyl)benzyl]isocyanate (description 68) according to the procedure of description 61. m/z (ES⁺) 378 (M + H)⁺.

Example 115

N-(l-Cyanoisoqxι ol-in-5-yl -N^,-f4-(trifluoroιnethyl)benzyl]urea 25 To a solution of N-(l-cHoroisoquinolin-5-yl)-N-[4-(trifluoromethyl)benzyl]urea

(Example 69) (250 mg, 0.7mmol) in DMF (5 ml) was added zinc cyanide (43 mg,

0.37 mmol) and tetrakis(triphenylphosphine)paUadium (76 mg, 0.07mmol). The reaction was heated at 80°C, under an atmosphere of nitrogen, for 72 hr, with the addition of extra tetrakis(triphenylphosphine)palladium (76 mg, 0.07 mmol) after

30 16 hr. Reaction mixture was quenched with water and extracted with ethyl acetate (3 5 ml), dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using an eluant system of 3% methanol/97% DCM increasing to 5% MeOH/ 95% DCM. RecrystaUisation in ethanol of a small portion of product gave a pure sample of the title compound (50 mg, 65.6%). m/z

35 (ES⁺) 371, 373 (M + H)⁺. Example 116

^^-(Mefl oxycarbony isoquinol-m-S-yll-N^{^}-^faifluoroinethyl^bei-izy^urea Prepared from methyl δ-aminoisoquinohne-1-carboxylate (Description 106) and δ [4-(trifluoromethyl)benzyl]isocyanate (description 68) according to the procedure of description 61. m/z (ES⁺) 404 (M + H)⁺.

Example 117

N-Q-Carboxyisoquinolin-S-yh-N'-f^faifluoromethyl^benzyllurea 10 N-[l-(Methoxycarbonyl)isoquinohn-5-yl]-N-[4-(trifluoromethyl)benzyl]urea (Example 116, δδ mg, 0.136 mmol) was dissolved in a mixture of THF (3 ml), methanol (1 ml) and water (1 ml), then hthium hydroxide monohydrate (6 mg, 0.14 mmol) was added. The reaction was stirred at room temperature until aU the ester had been consumed, then the solvents were evaporated and δ% aqueous lδ NaH2PO4 solution (pH 4, δ ml) was added to the residue. After stirring for lδ min. the pale yeUow sohd was coUected by filtration, washed with water (2 ml) and dried under vacuum to give the title compound (39 mg, 73 %). m/z (ES⁺) 390 (M + H)⁺.

20 Example 118

N-(l-Aminoisoquinohn-δ-yl)-N'- 4-(trifluoromethyl)benzynurea A mixture of N-(l-carboxyisoquinolin-5-yl)-N'-[4-(trifluoronαethyl)berιzyl]urea (Example 117, 309 mg, 0.794 mmol), diphenylphosphoryl azide (210 μl, 0.975 mmol) and Methyla ine (210 μl, 1.50 mmol) in 1,4-dioxane (25 ml) was heated at 100 °C,

25 under a nitrogen atmosphere for 1.5 h. Water (0.25 ml) was then added and the reaction mixture heated for a further 1 hour. The reaction mixture was then cooled to room temperature, filtered and the filtrate evaporated. The residue was purified using a Bond-Elut SCX ion-exchange cartridge, first eluting non-basic materials with methanol, then eluting the product with 2M methanohc ammonia. The basic fractions

30 were evaporated and further purified by flash column chromatography (eluant 5 % MeOH - 95% dichloromethane increasing to 10% MeOH - 90% dichloromethane). The product was then passed through a second SCX purification to give the title compound (77 mg, 27%). m/z (ES⁺) 361 (M + H)⁺. Example 119

JV- [1- (HvdroxymethvDisoquinolin-δ-yll - JV- r4-(trifluoromethyl)benzvn urea N-[l-(Methoxycarbonyl)isoquinohn-5-yl]-N-[4-(trifluoromethyl)benzyl]urea (Example 116, 70 mg, 0.174 mmol) was suspended in a mixture of THF (5 ml) and toluene (5 ml). Lithium borohydride (50 mg, 2.27 mmol) was added and the reaction mixture heated at 60 °C for 1 hour. The reaction was cooled to room temperature and allowed to stand for 1 week. The crystalline product was coUected by filtration, washed with toluene (2 ml), then triturated with 1:1 THF- dichloromethane (2 ml), triturated again with THF (2 ml) and dried under vacuum to give the title compound (8 mg, 12 %). m/z (ES⁺) 376 (M + H)⁺.

Example 120

^^-(MethoxycarbonyDisoquinolin-δ-yll-N'-f^faifluorornethyDbenzy^urea Prepared from methyl 5-aminoisoquinohne-3-carboxylate (Description 107) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES⁺) 404 (M + H)⁺.

Example 121

N-(3-Carboxyisoquinolin-5-yl)-N'-[4-(trifluoromethyl)benzyllurea Prepared from N-[3-(methoxycarbonyl)isoquinolin-5-yl]-N'-[4-

(trifluoromethyl)benzyl]urea (Example 120) according to the procedure of Example 117. m/z (ES⁺) 390 (M + H)⁺.

Example 122 N-[3-(Dimethylamino isoquinolin-5-yll-JV-[4-(trifluoromethyl)benzyl1urea

Prepared from 3-(dimethylamino)isoquinolin-δ-amine (Description 109) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of description 61. m/z (ES⁺) 389 (M + H)⁺.

Example 123

N-r3-(2-Aminoethyl)isoquinohn-5-yll-JV-r4-(trifluoromethyl)benzvnurea To a solution of terf-butyl 2-(5-aminoisoquinohn-3-yl)ethylcarbamate (Description 116; 200 mg, 0.7 mmol) in deuterated chloroform (δ ml) was added [4- (trifluoromethyl)benzyl]isocyanate (0.506M solution in DCM) (Description 58; 1.38 ml, 0.7 mmol), and the resulting mixture heated at reflux overnight. The reaction mixture was cooled and the precipitate removed by filtration, washed with DCM and dried. The sohd was dissolved in methanol (10 ml) and hydrogen chloride gas passed through the mixture for δ mins, after which time the mixture was left standing for 1 hour. The mixture was evaporated and purified using an SCX cartridge - appropriate fractions were evaporated to give the title compound (26 mg, 9%) as a white sohd. m/z (ES⁺) 389 (M + H)⁺.

Example 124 ^(δ-Methoxyisoquinohn-δ-yD-JV-^-ftrifluoromethvDbenzy^urea

Prepared from 8-methoxyisoquinohn-δ-amine which was prepared from 8- methoxy-δ-nitroisoquinohne (J. Het. Chem. 37(5), 1293) according to Description 43 and immediately used in reaction with [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES⁺) 376 (M + H)⁺.

Example 125 N-Isoquinohn-7-yl-JV-[4-(trifluoromethyl)benzyl]urea

A mixture of isoquinohn-7-yl trifluoromethanesulfonate (Description 117, 1.04 g, 3.7δ mmol), cesium carbonate (1.6 g, 4.88 mmol), benzophenone imine (747 mg, 4.13 mmol), BINAP (100 mg, 0.16 mmol) and paUadium acetate (18 mg, 0.08 mmol) in tetrahydrofuran (lδ ml) was degassed (N2 x 3) then heated at reflux for 18 h. More BINAP (100 mg, 0.16 mmol) and paUadium acetate (18 mg, 0.08 mmol) were added and the reaction heated for a further 24 h. The reaction was then cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with more ethyl acetate (50 ml) and the combined organic layers were evaporated. The residue was taken up in tetrahydrofuran (40 ml) and 2N hydrochloric acid (aq. 10 ml) was added. After 2h, the THF was evaporated, 3N hydrochloric acid (aq. 100 ml) was added and the mi-xture washed with ethyl acetate (2 x 75 ml). The aqueous layer was then basified by addition of 47% aqueous sodium hydroxide solution and extracted with dichloromethane (3 x 50 ml). The combined organic layers were dried (Na₂SO4) and evaporated to give crude isoquinohn-7-amine (198 mg) which was reacted directly with [4- (trifluoromethyl)benzyl] isocyanate (Description 58) according to Description 61 to give the title compound (100 mg, 8%). m/z (ES⁺) 346 (M + H)⁺.

Example 126

5 N-JV-Diisoquinohn-δ-ylurea

Prepared from isoquinoline-5-carboxyhc acid and isoquinohn-δ-amine according to Description 60. m/z (ES⁺) 315 (M + H)⁺.

Example 127 0 N-Isoquinohn-5-yl-JV-[4-(trifluoromethyl)phenvnurea

Prepared from isoquinohn-5-amine and 4-(trifluoromethyl)phenyl isocyanate according to Description 61. m/z (ES⁺) 332 (M + H)⁺.

Example 128 5 N-Isoquinohn-δ-yl-JV-{ 2-(trifluoromethyl)pyrimidin-5-yllmethyl|urea Prepared from isoquinohne-5-carboxyhc acid and 5-(aminomethyl)-2- (trifluoromethyl)pyrimidine (Description 121) according to the procedure of Description 60. m/z (ES⁺) 348 (M + H)⁺.

0 Example 129

Ethyl 3-{r(isoquinohn-5-ylamino carbonyllamino}-2-[4-(trifl.uoromethyl)benzyll propanoate

Ethyl 2-cyano-3-[4-(trifluoromethyl)phenyl]prop-2-enoate (136 mg,0.δ mmol), paUadium hydroxide (20 wt% Pd (dry basis on carbon), 20 mg) in ethanol (20 ml) δ containing 2N hydrochloric acid (1 ml) was placed on a Parr apparatus at 3δ psi hydrogen pressure and shaken for 1.5 hours. The reaction mixture was filtered and evaporated to give the corresponding¹ amine which was taken up in THF (5 ml). In a separate flask isoquinohn-δ-amine (72mg, O.δmmol) in THF (δ ml) at 0 °C was treated with triphosgene (48 mg, 0.166 mmol) foUowed by triethylamine 0 (140 μL). After 30 minutes, the amine solution was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then filtered and evaporated. Purification by column chromatography using 2.δ%methanol in dichloromethane gave the desired product (49mg). m/z (ES⁺) 446 (M + H)⁺. Example 130

3-{[(isoquinohn-5-ylamino)carbonvnaminol-2-[4-⁽trifl.uoromethyl)benzvnpropanoic acid Ethyl 3-{[(isoquinohn-δ-ylamino)carbonyl] amino}-2- [4-(trifluoromethyl)benzyl] propanoate (Example 129, 23 mg, 0.05 mmol) in aqueous THF (1:1, 2 ml) was treated with hthium hydroxide (5 mg, 0.1 mmol) and stirred at room temperature for 20 h. The mixture was evaporated then partitioned between 7 % aqueous citric acid and dichloromethane (2:1, 6ml). A precipitate formed which was coUected by filtration and dried azeotropicaUy by adding toluene and evaporating to give the desired compound (8.4 mg). m/z (ES⁺) 418 (M + H)⁺.

Example 131

N-Isoquinohn-δ-yl-JV-[4-(morphohn-4-ylmethyl)benzyllurea A solution of isoquinohne-δ-carbonyl azide (Description 126, 60 mg, 0.2δ mmol) in toluene (5 mL) was heated at 76 °C for 1 h. The reaction was cooled to 50 °C and 4-(morphohn-4-ylmethyl)benzylamine (Description 123, 0.31 mmol) was added as a solution in CH2CI2 (1 ml). The precipitated product was coUected by filtration and washed with hexane, then further purified using mass-directed HPLC to give the title compound (2.5 mg, 3%). m/z (ES⁺) 376 (M + H)⁺.

Example 132

N-Isoquinohn-5-yl-JV-[2-(2-morpholin-4-ylethoxy)-4-(trifluoromethyl)benzyllurea A solution of isoquinohne-δ-carbonyl azide (Description 126, 43 mg, 0.22 mmol) in toluene (4 mL) was heated at 80 °C for 50 min. The reaction was cooled to 50 °C and 2-(2-morphohn-4-ylethoxy)-4-(trifluoromethyl)benzylamine (Description 125, 66 mg, 0.22 mmol) was added as a solution in toluene (1 ml). The precipitated product was coUected by filtration and washed with dichloromethane to give the title compound (83 mg, 80%). m/z (ES⁺) 475 (M + H)⁺.

Claims

A compound of formula (I):

(I) wherein

A, B, D and E are each C or N with the proviso that one or more are N; R¹ and R² are each independently hydrogen, halogen, hydroxy, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, haloCi-ealkyl, hydroxyCι-6alkyl, Ci-βalkoxy, haloCi-ealkoxy, hydroxyCi-ealkoxy, C3-7cycloalkyl, C3-5cycloalkylCι-4alkyl, NR⁷R⁸, carboxy, esterified carboxy, Ci-βalkyl substituted with a group selected from NR⁷R⁸, carboxy and esterified carboxy, or Ci-βalkoxy substituted with a group selected from NR⁷R⁸, carboxy and esterified carboxy; R³ and R⁴ are each independently hydrogen, Ci-βalkyl, C2-6alkenyl or C₂-6alkynyl; R⁵ and R⁶ are, at each occurrence, independently hydrogen, Ci-βaUcyl, C2-6alkenyl, C2-6alkynyl, Ci-βalkoxy, Ci-βacyloxy, carboxy, esterified carboxy, CONR⁷R⁸, SO2R⁷, SO2NR⁷R⁸, aryl, heteroaryl, heterocyclyl, or Ci-ealkyl substituted with a group selected from hydroxy, Ci-βalkoxy, Ci-βacyloxy, carboxy, esterified carboxy, NR⁷R⁸, CONR⁷R⁸, SR⁷, SO2R⁷, SO₂NR⁷R⁸, aryl, heteroaryl and heterocyclyl; or R⁵ and R⁶ and the carbon atom to which they are attached together form a carbocychc ring of 3 to 6 carbon atoms;

R⁷ and R⁸ are, at each occurrence, independently hydrogen, Ci-βalkyl, C2-6alkenyl, C₂-6alkynyl, C3-7cycloalkyl or fluoroCi-ealkyl; or R⁷ and R⁸ and the nitrogen atom to which they are attached together form a heteroahphatic ring of 4 to 7 ring atoms, optionaUy substituted by one or two groups selected from hydroxy or Cι-4alkoxy, which ring may optionaUy contain as one of the said ring atoms an oxygen or a sulfur atom, a group S(O) or S(O)₂, or a second nitrogen atom which wiU be part of a NH or NR^a moiety where R^a is Cι-4alkyl optionaUy substituted by hydroxy or Cι-4alkoxy; X is an oxygen or sulfur atom or the group =NCN;

Y is an aryl, heteroaryl, carbocyclyl or fused-carbocyclyl group; and n is either zero or an integer from 1 to 3; or a pharmaceuticaUy acceptable salt, N-oxide or a prodrug thereof.
2. A compound according to claim 1 in which X is O.
3. A compound according to claim 1 or 2 in which R³ and R⁴ are hydrogen.
4. A compound according to claim 1, 2 or 3 in which B is nitrogen and A, D and E are carbon.
δ. A compound according to any preceding claim in which Y is an aryl group selected from unsubstituted phenyl or naphthyl and phenyl or naphthyl substituted by one or two substituents selected from halogen, Cι-4alkyl, Cι-4alkoxy, haloCι-4alkyl, haloCι-4alkoxy, phenyl, cyano, nitro, pyrazolyl, di(Cι-6alkyl)amino, phenoxy, -OCH2O- and Ci-βalkylcarbonyl; or a heteroaryl group selected from pyridyl, thiazolyl, isoxazolyl, oxadiazolyl and pyrazolyl wherein each heteroaryl group is optionaUy substituted with one or two substituents selected from Cι-₄alkyl, Cι-4alkoxy, haloCι-4alkyl, haloCι-4alkoxy, unsubstituted heteroaryl or phenyl which may be substituted by Ci-ealkyl or halogen; or a carbocyclyl group which is a Cs^cycloalkyl radical that is unsubstituted or substituted by a phenyl ring; or a fused-carbocyclyl group which is a C5-7cycloalkyl radical that is fused to a phenyl ring.
6. A compound according to any preceding claim wherein R⁵ and R⁶ each independently represent a hydrogen atom or a Cι-4alkyl or phenyl group.
7. A pharmaceutical composition comprising a compound according to any preceding claim or a pharmaceuticaUy acceptable salt or N-oxide thereof.
8. A compound according to any one of claims 1 to 6 or a pharmaceuticaUy acceptable salt or N-oxide thereof for use in a method of treatment of the human or animal body by therapy.
9. Use of a compound according to any one of claims 1 to 6 or a pharmaceuticaUy acceptable salt or N-oxide thereof for use in the manufacture of a medicament for treating diseases and conditions in which pain and/or inflammation predominates.
10. A method of treating a subject suffering from a disease or condition in which pain and/or inflammation predominates which comprises administering to that subject a therapeuticaUy effective amount of a compound according to claim 1 or a pharmaceuticaUy acceptable salt or N-oxide thereof.