WO2009005459A1 - Phenyl-1,2, 3,4-tetrahydroisoquinolinone derivatives and their use in the treatment of a pain disorder - Google Patents

Abstract

The present invention relates to new compounds and pharmaceutically-acceptable salts thereof, and to new intermediates used in the preparation thereof, pharmaceutical compositions containing said compounds and to the use of said compounds in therapy.

Description

Phenyl-1 , 2 , 3 , 4-tetrahydroisoquinolinone derivatives and their use in the treatment of a pain disorder .

NEW COMPOUNDS 930

Field of the invention

The present invention relates to new compounds, to a pharmaceutical composition containing said compounds and to the use of said compounds in therapy. The present invention also relates to processes for the preparation of said compounds.

Background

The current treatment regimes for pain conditions utilise compounds which exploit a very limited range of pharmacological mechanisms. One class of compounds, the opioids, stimulates the endogenous endorphine system; an example from this class is morphine. Compounds of the opioid class have several drawbacks that limit their use, e.g. emetic and constipatory effects and negative influence on respiratory capability. The second major class of analgesics, the non-steroidal antiinflammatory analgesics of the COX-I or COX-2 types, also have liabilities such as insufficient efficacy in severe pain conditions and at long term use the COX-I inhibitors cause ulcers of the mucosa. Mechansims of analgesic effects of other currently used medicines are insufficiently characterized and/or have limited therapeutic potential.

Local anesthetics, that are known to block most types of sodium channels in nerves, are useful for relieving pain in small areas of the human body and for blocking nerve conduction from the periphery to the central nervous system. They can also be used in the last-mentioned way to block sensory signalling by instilling solutions of local anesthetics at the spinal cord. Due to their high toxicity, in particular heart toxicity, they can not, however, be used for systemic administration as generally useful analgesics. There remains thus a need for more selective modulators of sodium channels involved in pain signal conduction.

Nine sodium channel subtypes have been cloned and functionally expressed to date. (Wood JN, Baker M.. Current Opinion in Pharmacology 2001, 1, 17-21). They are differentially expressed throughout muscle and nerve tissues and show distinct biophysical properties. All voltage-gated sodium channels (NaV:s) are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent gating. By application of genetic analysis it has been shown that a mutation in the gene coding for sodium channel NaVl .7, making this protein non- functional, can make a human become almost insensitive to pain (Cox JJ et al. Nature 2006, 444, 894-898).

It is well known that the voltage-gated sodium channels in nerves play a critical role in neuropathic pain (Baker MD and Wood JN. Trends in Pharmacological Sciences 2001, 22, 27-31). Injuries of the peripheral nervous system often result in neuropathic pain persisting long after the initial injury resolves. Examples of neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias. It has been shown in human patients as well as in animal models of neuropathic pain, that damage to primary afferent sensory neurons can lead to neuroma formation and spontaneous activity, as well as evoked activity in response to normally innocuous stimuli. Navl .7 is expressed in human neuromas, which are swollen and hypersensitive nerves and nerve endings that are often present in chronic pain states {Acta Neurochirurgica 2002, 144, 803-810).

In rat models of peripheral nerve injury, ectopic activity in the injured nerve corresponds to the behavioral signs of pain. In these models, intravenous application of the sodium channel blocker and local anesthetic lidocaine can suppress the ectopic activity and reverse the tactile allodynia at concentrations that do not affect general behavior and motor function (Mao J and Chen LL, Pain, 2000, 87, 7-17).

In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias. Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS).

4-Phenyl-l,2,3,4-tetrahydro-isoquinolin-4-ols are known from the literature and have been reported to inhibit uptake of norepinephrine in nerve synapses thus making them potentially useful as antidepressants (Kihara et al. Chemical & Pharmaceutical Bulletin 1995, 43, 1543-6, and literature cited). Specific examples of 4-(2-methoxyphenyl)-l,2,3,4- tetrahydro-isoquinolin-4-ols have not been described in the literature.

DISCLOSURE OF THE INVENTION

According to the invention there is provided compounds of formula I,

wherein: Y is selected from -NH₂,; -OH; -NHSO₂CH₃; Ci_-3alkoxy; and H;

R¹ is selected from H; C^aUcyl; Ci-ofluoroalkyl; Ci-₆alkoxyalkyl; C₂-₆alkenyl; and C_2-6alkynyl;

R² is selected from H;

Ci_-6 fluorooalkyl; Ci-₆alkoxyalkyl; C_3-6alkenyl; C_3-6alkynyl; C_3-7Cycloalkyl; Ci_₆alkanoyl; Ci-₆alkanesulfonyl; C₆-i₂arylalkyl; a 5- or 6-membered heteroaryl containing at least one nitrogen atom; phenyl; and C i-6 hydroxyalkyl;

R³ is selected from H;

Ci-₆alkoxyalkyl; C_2-6alkenyl; and C_2-6alkynyl;

R⁴ and R⁵ is each and independently selected from H; halo; -NO₂; -CN; carbamoyl; sulphamoyl; Ci_₆alkyl; Ci-_όhaloalkyl; Ci_₆alkoxy; Ci-_όhaloalkoxy; C_2-6alkenyl; C_2-6alkynyl; Ci_6alkanoyl; Ci_6alkanoyloxy; Λ/-(Ci-6alkyl)amino; 7V,7V-(Ci-6alkyl)_ncarbamoyl wherein n is 0-2; Ci-6alkylS(O)a wherein a is 0 to 2; Ci_6alkoxycarbonyl; TV-(C i.6alkyl)sulphamoyl; Λ/,Λ/-(Ci-6alkyl)₂Sulphamoyl; and d-ealkylsulphonylamino;

R⁶ and R⁷ is each and independently selected from H; halo; -NO₂; -CN; carbamoyl; sulphamoyl; Ci_₆alkyl; Ci-_δhaloalkyl; Ci_₆alkoxy; Ci-_δhaloalkoxy; C₂-₆alkenyl; C₂-₆alkynyl; Ci_6alkanoyl; Ci_6alkanoyloxy; Λ/-(Ci-6alkyl)amino; Λ/,Λ/-(Ci.6alkyl) _ncarbamoyl wherein n is 0-2; Ci-6alkylS(O)a wherein a is 0 to 2; Ci_6alkoxycarbonyl; TV-(C i.6alkyl)sulphamoyl; Λ/,Λ/-(Ci.6alkyl)₂Sulphamoyl; Ci-6alkylsulphonylamino; 5- or 6-membered heterocyclyl; and a 5- or 6-membered heteroaryl containing at least one nitrogen atom;

R⁸ is selected from halo; C_1-6alkyl;

C₂-₆alkenyl; C₂-₆alkynyl;

C3_6carbocyclyl;

Ci-δhaloalkyl-O-;

C_3-4 cycloalkyl-O-; C_3-6Ca^OCyCIyI-O-; Ci_-6alkyl-S-; Ci_-6haloalkyl-S-; and

Cs-όCarbocyclyl-S-;

R⁹ is selected from C₂-₆alkyl; Ci-efluoroalkyl; Ci_-4alkoxyalkyl-Ci_-4 alkyl; C_3-6Cyanoalkyl; C₂-₆alkenyl; C₂-₆alkynyl; C_3-7carbocyclyl; C_3-scarbocyclylalkyl; C_3-scarbocyclylalkynyl; C₂-₆ fluoroalkylsulfonyl; C₂-₆alkylsulfanyl; C_2-6 alkoxy; Ci.₆fluoroalkoxy; C_3-6alkylsulfonyl; C_3-6alkylsulfmyl; phenyl;

as well as a pharmaceutically acceptable salt or optical isomer thereof, or a salt of said optical isomer.

One embodiment of the invention is a compound of formula I, wherein

Y is selected from H; -NH₂; -OH; and -NHSO₂CH₃;

R¹ is selected from H; and C_1-6alkyl;

R² is selected from H; C_1-6alkyl; Ci-ofluoroalkyl; C3_7Cycloalkyl; Ci_6alkanoyl; Ci_-6 hydroxyalkyl; Ci_-6alkanesulfonyl; C_6-i₂arylalkyl; phenyl; and pyridinyl;

R³ is H or Ci-βalkyl;

R⁴ and R⁵ is each and independently selected from H and Ci_6alkoxy;

R⁶ and R⁷ is each and independently selected from H; halo; Ci_6alkoxy; Ci-δfluoroalkoxy;

-OCF₃; and pyrimidine; R⁸ is selected from halo; C_1-6alkyl; and C_1-6alkoxy; and

R⁹ is selected from C_2-6alkyl; C_2-6haloalkyl; C_3-6cyanoalkyl; C2-6alkoxy; and

C2-6haloalkoxy.

One embodiment of the invention is related to compounds of formula I wherein Y is selected from -NH₂, -OH, -NHSO₂CH₃, and Ci_-3alkoxy. In still an aspect Y is selected from -NH₂, -OH, hydrogen and Ci_-3alkoxy.

A further embodiment of the invention is related to compounds of formula I wherein R¹ is selected from H and C_1-6alkyl such as methyl, ethyl, propyl, or butyl.

Yet an embodiment of the invention is related to compounds of formula I wherein R² is selected from H;, C_1-6alkyl, C_1-6fluoroalkyl, C_3-7cycloalkyl, C_1-6alkanoyl,

C_1-6alkanesulfonyl, C_6-12arylalkyl, and a 5- or 6-membered heteroaryl containing at least one nitrogen atom.

Yet an embodiment of the invention is related to compounds of formula I wherein R² is selected from benzyl; phenyl; pyridinyl; hydrogen; methyl; ethyl; cyclopropyl; i-propyl; i- butyl; -CH₂-CH₂-OH; -CH₂-CH₂-O-CH₃; -CH₂-CH₂-CH₂-F; and -SO₂-CH₃. One embodiment of the invention is related to compounds of formula I wherein R³ is selected from H and C_1-4alkyl.

In yet an embodiment of the invention R³ is methyl.

One embodiment of the invention is related to compounds of formula I wherein R⁴ and R⁵ is each and independently selected from H and Ci_6alkoxy.

In yet an embodiment of the invention R⁴ and/or R⁵ is each and independently methoxy.

In one embodiment of the invention R⁵ is H.

One embodiment of the invention is related to compounds of formula I wherein R⁶ and R⁷ iseach and independently selected from H, halo,

Ci-όhaloalkoxy, and a 5- or 6- membered heterocyclyl group containing from 1 to 4 heteroatom(s) selected from N, S, and O such as imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl.

In yet an embodiment of the invention R⁶ and R⁷ is each and independently selected from methoxy, -OCF3 and chloro.

One embodiment of the invention is related to compounds of formula I wherein R⁸ is selected from halo,

and

In yet an embodiment of the invention R⁸ is selected from methoxy, ethoxy, methyl and chloro.

One embodiment of the invention is related to compounds of formula I wherein R⁹ is selected from C_2-6alkyl, C_2-6haloalkyl, C_3-6cyanoalkyl, C_2-6alkoxy, and C_2-6haloalkoxy. In a further aspect of the invention R⁹ is selected from C₂-₆alkyl, C₂-₆monofluoroalkyl, C₂-₆difluoroalkyl, C₂-₆trifluoroalkyl, C₂-₆tetrafluoroalkyl, C_3-6Cyanoalkyl, C₂-₆alkoxy, and C2-6fluoroalkoxy.

In still an aspect of the invention R⁹ is selected from butyl; i-butyl; Cx-y aryl such as phenyl; -0-CH-(CH₂F)₂;. -C-(CH₃)₂-CN;

-(CHz)₃-F; CF3; -OCF₃; -0-CH₂-CH₂-CF₃; -CH₂-CH₂-C-(CH₃)(F₂); -CH₂-C-(CH₃)₂-F; (CH₃)₂-CH-O-; -C-(CH₃)₂-O-CH₃; -0-CH-CF₃.

In one embodiment of the invention R⁹ is bonded to the phenyl ring at para-position in relation to R⁸.

One embodiment of the invention is a compound selected from any one of:

• 2-Benzyl-4-(5-tert-butyl-2-methoxyphenyl)-5,7-dimethoxy- 1,2,3,4- tetrahydroisoquinolin-4-ol;

• 4-{5-[2-fluoro-l-(fluoromethyl)ethoxy]-2-methoxyphenyl}-2-methyl-l,2,3,4- tetrahydroisoquinolin-4-ol;

• 2-Benzyl-4-(5-tert-butyl-2-methoxyphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-cyclopropyl-l,2,3,4-tetrahydroisoquinolin-4-ol; • 2-Benzyl-4-(5-isopropoxy-2-methoxyphenyl)-l ,2,3,4-tetrahydroisoquinolin-4-ol;

• 2-Benzyl-4-(5-tert-butyl-2-methoxyphenyl)-3-methyl-l,2,3,4-tetrahydroisoquinolin-4- ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-8-chloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4- ol; • 4-(5-tert-Butyl-2-methoxy-phenyl)-2-benzyl-7-trifluoromethoxy-l ,2,3,4-tetrahydro- isoquinolin-4-ol;

• 2-Benzyl-4-(5-tert-butyl-2-ethoxyphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 2-Benzyl-4-(2-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-l,2,3,4- tetrahydroisoquinolin-4-ol; • 2-Benzyl-4-(5-butyl-2-methylphenyl)-l ,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-[5-(3-Fluoropropyl)-2-methoxyphenyl]-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol; • 4-(5-tert-Butyl-2-methoxyphenyl)-l,2-dimethyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2,3-dimethyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-ethyl-5,7-dimethoxy-l,2,3,4- tetrahydroisoquinolin-4-ol; • 4-(5-tert-Butyl-2-methoxyphenyl)-2-isopropyl-5,7-dimethoxy-l,2,3,4- tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-5,7-dimethoxy-2-(2-methoxyethyl)-l,2,3,4- tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-5,7-dimethoxy-2-(pyridin-4-yl)-l,2,3,4- tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-(pyridin-4-yl)-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-ethyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 2-[3-(2-Ethyl-4-hydroxy - 1 ,2,3,4-tetrahydroisoquinolin-4-yl)-4-methoxyphenyl]-2- methylpropanenitrile; • 4-(5-tert-Butyl-2-methoxyphenyl)-2-(3-fluoropropyl)-l,2,3,4-tetrahydroisoquinolin-4- ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-5,7-dimethoxy-2-methyl-l,2,3,4- tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-7-trifluoromethoxy-l,2,3,4-tetrahydro- isoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 2-Ethyl-4-(2-methyl-5-trifluoromethylphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(2-Methoxy-5-(trifluoromethoxy)phenyl)-2 -methyl- 1, 2, 3,4-tetrahydroisoquinolin-4- ol;

• 2-(3-(4-Hydroxy-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)-4-methoxyphenyl)-2- methylpropanenitrile;

• 2-(3-(4-Hydroxy-l,2,3,4-tetrahydroisoquinolin-4-yl)-4-methoxyphenyl)-2- methylpropanenitrile; • 4-(5-Butyl-2-methoxyphenyl)-2-methyl-l ,2,3,4-tetrahydroisoquinolin-4-ol; • 4-[5-(3,3-Difluorobutyl)-2-methoxyphenyl]-2-methyl-l,2,3,4-tetrahydroisoquinolin-4- ol;

• 4-(5-tert-Butyl-2-chlorophenyl)-2 -methyl- 1, 2, 3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-Isopropoxy-2-methoxyphenyl)-2 -methyl- l,2,3,4-tetrahydroisoquinolin-4-ol; • 4-(5-tert-Butyl-2-methoxyphenyl)-3-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-ethoxyphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(2-Methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-2-methyl-l,2,3,4- tetrahydroisoquinolin-4-ol;

• 4-(5-Butyl-2-methylphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol; • 4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinoline;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-amine;

• N-(4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-l,2,3,4-tetrahydroisoqumolin-4- yl)methanesulfonamide;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-(methylsulfonyl)-l,2,3,4-tetrahydroisoqumolin-4- ol;

• 4-(2-Methoxy-5-((3,3,3,-trifluoro-propoxy)-phenyl)-7-trifluoromethoxy-l,2,3,4- tetrahydro-isoquinolin-4-ol;

• 4-[2-Methoxy-5-(l-methoxy-l-methyl-ethyl)-phenyl]-7-trifluoromethoxy-l,2,3,4- trtrahydroisoquinolin-4-ol; • 4-[5-(3-Fluoro-3-methyl-butyl)-2-methoxy-phenyl]-2-methyl-l,2,3,4-tetrahydro- isoquinolin-4-ol;

• 4-[5-(3-fluoro-3-methyl-butyl)-2-methoxy-phenyl]-l,2,3,4-tetra-hydro-isoquinolin-4- ol;

• 2-Benzyl-4-(4-methoxy-biphenyl-3-yl)-l,2,3,4-tetrahydro-isoquinolin-4-ol; • 4-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-ethyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 2-Benzyl-8-bromo-4-(5-tert-butyl-2-methoxy-phenyl)-l,2,3,4-tetrahydro-isoquinolin-4- ol;

• 2-Benzyl-4-(5-tert-butyl-2-methoxy-phenyl)-8-pyrimidin-5-yl-l,2,3,4-tetrahydro- isoquinolin-4-ol; • 4-[5-(2-Fluoro-2-methyl-propyl)-2-methoxy-phenyl]-7-methoxy-l,2,3,4-tetrahydro- isoquinolin; and • 2-Methyl-4-[5-(2-Fluoro-2-methyl-propyl)-2-methoxy-phenyl]-7-methoxy-l,2,3,4- tetrahydro-isoquinolin.

Listed below are definitions of various terms used in the specification and claims to describe the present invention.

The term "C_m-n" or "C_m-n group" used alone or as a prefix, refers to any group having m to n carbon atoms.

The term "alkyl" used alone or as a suffix or prefix, refers to straight or branched chain hydrocarbyl radicals comprising from 1 to 12 carbon atoms.

The term "cycloalkyl," used alone or as suffix or prefix, refers to a saturated monovalent ring-containing hydrocarbon radical comprising from 3 to 12 carbon atoms.

In the haloalkyl groups (including fluoroalkylgroups), arylalkyl groups, alkoxyalkyl groups, cyanoalkyl groups, alkylsulfanyl groups, alkylsulfonyl groups, and alkylsulfinyl groups "alkyl" refers to a divalent alkylene group.

The term "monofluoroalkyl" comprises alkyl groups having one fluoro atom substituted on any one of the alkyl group carbon atoms. The term "difluoroalkyl" comprises alkyl groups having two fluoro atoms substituted on any one or two of the alkyl group carbon atoms. The term "trifluoroalkyl" comprises alkyl groups having three fluoro atoms substituted on any one, two, or three of the alkyl group carbon atoms. The term "tetrafluoroalkyl" comprises alkyl groups having four fluoro atoms substituted on any one, two, three, or four of the alkyl group carbon atoms. These definitions are applicable both for straight chain alkyl groups and for branched chain alkyl groups having one fluoro atom substituted on any one of the alkyl group carbon atoms.

The term "alkoxy" used alone or as a suffix or prefix, refers to radicals of the general formula -O-R, wherein R is an alkyl. The term "alkenyl" used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at from 2 to 12 carbon atoms.

The term "alkynyl" used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond and comprising from 2 to 12 carbon atoms.

As used herein, "carbocyclylalkyl" refers to alkyl substituted by carbocyclyl.

As used herein, "carbocyclylalkynyl" refers to alkynyl substituted by carbocyclyl.

The term "amine" or "amino" refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbyl radical.

The term "aromatic" refers to hydrocarbyl radicals having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising from 6 to 14 carbon atoms.

The term "aryl" used alone or as suffix or prefix, refers to a hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising from 5 to 14 carbon atoms, wherein the radical is located (bonded) onto a carbon of the aromatic ring.

The term "cycloalkyl," used alone or as suffix or prefix, refers to a monovalent ring- containing hydrocarbon radical comprising from 3 to 12 carbon atoms.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine radicals.

A "carbocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring of from 3-12 atoms. As used herein, the term "heterocarbocyclyl" or "heterocyclyl" refers to saturated or unsaturated carbocyclyl groups wherein one or more of the ring-forming atoms of the heterocarbocyclyl group is a heteroatom such as O, S, N, or P. Heterocyclyl groups can be aromatic (e.g., "heteroaryl") or non-aromatic (e.g., "heterocycloalkyl"). Heterocyclyl groups can correspond to fully hydrogenated and partially hydrogenated heteroaryl groups. Heterocarbocyclyl groups can contain, in addition to at least one heteroatom, from 1 to 20 carbon atoms and can be attached to another atom or molecule through a carbon atom or through a heteroatom.

The term "hydrocarbyl" refers to any structure comprising only carbon and hydrogen atoms having up to 14 carbon atoms.

The term "mammal" includes any of various warm-blooded vertebrate animals of the class Mammalia, including but not limited to humans, generally characterized by a covering of hair on the skin.

The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.

For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined', 'defined hereinbefore' or 'defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

Methods of Preparation One aspect of the present invention provides a process for preparing a compound of formula I or salt thereof.

Throughout the following description of such processes it isto be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in "Green's Protective Groups in Organic Synthesis" P.G.M. Wuts, T. W. Green, Wiley, New York, 2007. References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, "Advanced Organic Chemistry", March, 4^th ed. McGraw Hill (1992) or, "Organic Synthesis", Smith, McGraw Hill, (1994). For representative examples of heterocyclic chemistry see for example "Heterocyclic Chemistry", J. A. Joule, K. Mills, G. F. Smith, 3^rd ed. Chapman and Hall (1995), p. 189- 224 and "Heterocyclic Chemistry", T. L. Gilchrist, 2^nd ed. Longman Scientific and Technical (1992), p. 248-282.

The term "room temperature" and "ambient temperature" shall mean, unless otherwise specified, a temperature between 16 and 25 ⁰C.

Abbreviations:

DMF 7V,7V-dimethylformamide

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

HOBt 1-hydroxybenzotriazole hydrate

THF tetrahydrofuran

TFA trifluoroacetic acid

Et ethyl

Ac acetyl DIBAL diisobutylaluminum hydride

M molar

HBTU 0-Benzotriazol- 1 -yl-AWA^AP-tetramethyluronium hexafluorophosphate

Boc tert-butoxycarbonyl

MCPBA meta-chloroperoxybenzoic acid

PG protective group

One embodiment of the invention relates to processes for the preparation of the compound of Formula I according to Methods A and B, comprising; Method A

Or PG Solvent

II Ia whereby the target compound of Formula Ia is obtained from the ketone of formula II wherein each substituent R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is each and independently as defined for compounds of Formula I; or can be converted to such a group after the compound of Formula Ia is obtained. The coupling of the electrophilic ketone with the other nucleophilic benzene fragment containing a metal M to give the alcohol Ia can be performed under conditions known to one skilled in the art. Examples of the metal M useful in accordance with the invention are Mg²⁺ and Li⁺ but may also be Na⁺ or Zn²⁺ which are prepared by conventional methods.

The ketones of formula II are either known or can be prepared by a variety of methods known from the literature, for example Grethe et al. Journal of Organic Chemistry 1968, 33, pp 491-494 and pp 494-503. Method B whereby the target compound of formula I is obtained from another compound of formula Ib via Ia by introducing the R² substituent using standard methods described in the literature, for example:

A variation of this method is to use an N-benzyl compound Ic under hydrogeno lytic conditions in methanol, preferably in the presence of formaldehyde, or ethanol whereby the intermediate amine Ib is formed. This amine then undergoes reductive alkylation in the reaction mixture.

Each substituent R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is each and independently as defined for compounds of Formula I above. Method C whereby the target compound of formula I is obtained from another compound of formula Ia by replacing the OH group with another group.

Method D whereby a N-(2-iodobenzyl)-alpha-amino-acetophenone is cyclized to the product Ia by means of zerovalen nickel in DMF (see for example Heterocycles 1989, 14,

957).

Each substituent R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is each and independently as defined for compounds of Formula I above.

Intermediates

A further embodiment of the invention relates to a compound selected from 7-Trifluoromethoxy-2,3-dihydro-4(lH)-isoquinolinone; 8-Chloro-2,3-dihydro-4(lH)-isoquinolinone; and 2-Benzyl-l-methyl-2,3-dihydro-4(lH)-isoquinolinone;

EXAMPLES General methods All starting materials are commercially available or described in the literature. The ¹H NMR spectra were recorded on a Varian 400. The mass spectra were recorded using a Water Micromass ZQ equipped with electrospry. The LC system used was 75% acetonitrile and 25% of a 0.1% formic acid solution in water. Preparation of intermediates IM-I to IM-5 IM-I.

2-Benzyl-7-trifluoromethoxy-23-dihvdro-lH-isoquinolin-4-one. Na2CO3 ( 7.5 g, 70.8 mmol) was added to a solution of 2-bromomethyl-4- trifluromethoxy-benzoic acid methyl ester ( 4.45 g, 14.2 mmol) and benzylamino-acetic acid tert-butyl ester ( 4.7 g, 21.3 mmol) in DMF (5OmL). The mixture was heated overnight at 50 ⁰C. After quenching with water and extraction with diethylether the crude compound was purified by SG chromatography using 0.5% of ethyl acetate in hexane gave 3.62 g (59.9 %) of 2-[(benzyl-tert-butoxycarbonylmethyl-amino)-methyl]-4- trifluromethoxy-benzoic acid methyl ester as a yellowish oil. IH NMR (400 MHz, CDCl₃), δ (ppm) 7.85 (d, 1 H) 7.70 (br. s., 1 H), 7.26 - 7.40 (m, 4 H), 7.18 - 7.26 (m, 1 H), 7.12 (d, 1 H), 4.22 (s, 2 H), 3.88 (s, 3 H), 3.81 (s, 2 H), 3.20 (s, 2 H) 1.49 (s, 9 H). F19-NMR (377 MHz, CDC13): d = -58.20.

This compound (1.8g, 4.23 mmol) was treated with potassium-tøt-butoxide (2.37g, 21.2 mmol) in benzene (50 mL) at room temperature. The resulting mixture was refluxed for 3 h at 80-90 ⁰C. The reaction mixture was concentrated under reduced pressure to give a yellow solid which was treated with 10 ml of cone HCl in benzene (5 mL). The mixture was refluxed for 1 h at 80-90 ⁰C. After cooling to room temperature followed by basic work-up the crude product was purified by SGC using 10 % ethyl acetate in hexane Yield of the title product: 398 mg (35.1 %).

IM-2.

2-Benzyl-8-bromo-2.3-dihydro-lH-isoquinolin-4-one.

This compound was prepared as described for IM-I starting with NBS bromination of methyl 3-bromo-2-methyl-benzoate follwed by amination as described above to give 2- [(benzyl-tert-butoxycarbonyl-methyl-amino)-methyl]-3-bromo-benzoic acid methyl ester. ¹R NMR (400 MHz, CDCl₃) δ ppm 7.63 (d, J=7.42 Hz, 1 H) 7.55 (d, J=7.42 Hz, 1 H) 7.09 - 7.30 (m, 6 H) 4.47 (s, 2 H) 3.85 (s, 3 H) 3.77 (s, 2 H) 3.10 (s, 2 H) 1.48 (s, 10 H). This compound was cyclized as described followed by decarboxylation. IM-3

2-Benzyl-3-methyl-,2,3-dihydroisoquinoline-4(lH)-one

2-Benzyl-3-methyl-4-oxo-l,2,3,4-tetrahydroisoquinoline-3-carboxylate (3 g, 9.28 mmol), 2N NaOH ( 80 mL), and EtOH (50 mL) were refluxed for 3h; acidified with 6N HCl, reflux 3h; basified with 6N NaOH; extracted with CH₂Cl₂ to give the title product 180 mg (8 %). ¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.05 (d, IH), 7.50 (m, IH), 7.40-7.20 (m, 6H), 7.1 (d, IH), 4.1 (d, IH), 3.85 (d, IH), 3.75 (m, 2H), 3.60 (q, IH), 1.4 (s, 3H).

IM-4. 2-Cvclopropyl-2.3-dihvdroisoquinolin-4(lH)-one

2-Cyclopropyl-4-oxo-l,2,3,4-tetrahydroisoquinoline-3-carboxylate was treated as described for IM-3 to give the title product (47%). ¹H-NMR (400 MHz, CDCl₃): δ= 8.02 (IH, m), 7.55 (IH, m), 7.35 (IH, m), 7.25 (IH, m), 3.92 (2H, s), 3.52 (2H, s), 1.91 (IH, m), 0.55 (4H, m).

IM-5.

2-Benzyl-7-methoxy-2,3-dihvdro-lH-isoquinolin-4-one.

Benzyl-(3-methoxy-benzyl)-amino] -acetic acid ethyl ester (1 g, 3.19 mmol) was slowly added to 7 mL of H2SO4 at 0-5 ⁰C. The mixture was stirred under N₂ at 100 ⁰C for about 6 h and then was cooled to room temperature and quenched with ice cooled NaOH solution (6N, 40 mL). The solution was extracted with DCM (2x70 mL). The extract was washed with brine. Concentration gave the desired product. Yield: 0.38 g (45 %). IH NMR (CDC13): δ (ppm): 8.00 (d, IH), 7.40-7.20 (m, 5H), 6.85 (d, IH), 6.65 (s, IH), 3.85 (s, 3H), 3.85-3.70 (m, 4H), 3.45 (s, 2H). MS (ES): m/z 268.07 (M+H)

Example 1

2-Benzyl-4-(5-tert-butyl-2-methoxyphenvπ-5.7-dimethoxy-1.2.3.4-tetrahvdroisoquinolin- 4-ol

This example teaches the application of Method A which comprises addition of an organometallic phenyl reagent to an 2-alkyl-2,3-dihydroisoquinolin-4(lH)-one. 2-Bromo-4-tert-butyl-l-methoxybenzene (0.982 g, 4.04 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise to magnesium turnings (3.0 eq ) at room temperature under nitrogen. The temperature was slowly raised to 4O⁰C and stirring continued for 10 minutes. The mixture was stirred at room temperature for 1 h and then cooled to O⁰C. A solution of 2-benzyl-5,7-dimethoxy-2,3-dihydroisoquinolin-4(lH)-one ( 1.0 g, 3.36 mmol) in anhydrous tetrahydrofuran was added slowly dropwise and after 1 h the reaction mixture was slowly quenched with water. After diluting the reaction mixture with diethylether the organic phase was separated from aqueous, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Crude product was purified by silica gel column chromatography eluting with 50% ethyl acetate and hexane gave 0.7 g (45 %) of the desired product. ¹R NMR (400 MHz, CDCl₃): δ (ppm) 7.60 (bs, IH), 7.22-7.28 (m, 5H), 7.19 (d, IH), 6.63 (d, IH), 6.20 (d, 2H), 3.80 (s, 6H), 3.79 (s, 3H), 3.34 (d, 4H), 3.05 (dd, 2H), 1.21 (s, 9H). MS (ES⁺): 282.11

The following Examples 2-14 were prepared according to Method A or a mixture of Methods A and B starting from a suitably substituted 2,3-dihydroisoquinolin-4(lH)-one. Example 2

4-(5-[2-fluoro-l-(fluoromethvπethoxyl-2-methoxyphenyli-2-methyl-1.2.3.4- tetrahvdroisoquinolin-4-ol.

The compound was prepared using a variation of Method A. BuLi (0.95 mL; 2M solution in THF ) was added to a solution of 2-bromo-4-(l,3-difiuoropropan-2-yloxy)-l- methoxybenzene (520 mg, 1.85 mmol) in 2 mL THF at -78 ⁰C for 5 min; then CeCB (220mg, 0.89 mmol ) in 1 mL of THF was added. The reaction mixture was kept at - 78 ⁰C for 20 min. 2-Methyl-2,3-dihydroisoquinolin-4(lH)-one (190 mg, 1.18 mmol) in 1 mL THF was added dropwise. After 40 min at -78 ⁰C, water was added and then diethyl ether. The separated organic solvents were washed with saturated sodium chloride and dried over MgSO₄ . The crude product after removal of solvents was chromatographed on silical gel with DCM/ MeOH (9.5:0.5) to give the title compound, 11 mg (2.6 %). ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.55 (bs, IH), 7.16 (t, IH), 7.09-7.01 (m, 2H), 6.94-6.88 (m, 2H), 6.75 (d, IH), 4.76-4.72 (m, 2H), 4.64-4.61 (m, 3H), 3.64 (d, IH), 3.42 (d, IH), 3.32 (s, 3H), 3.07 (d, IH), 2.77 (d, IH), 2.42 (s, 3H). ¹⁹F NMR (400 MHz, CDCl₃): δ (ppm) -33.4. MS(ES⁺): 364.12.

Example 3

2-Benzyl-4-(5-tert-butyl-2-methoxyphenvπ-1.2.3.4-tetrahvdroisoquinolin-4-ol.

From 2-benzyl-2,3-dihydroisoquinolin-4(lH)-one and l-bromo-5-tert-butyl-2- methoxybenzene. ¹H-NMR (400 MHz, CDCl₃): δ = 7.64 (IH, m), 7.30-7.00 (1OH, m), 6.76 (IH, m), 3.85-3.55 (4H, m), 3.38 (3H, s), 3.25 (IH, m), 2.95 (IH, m), 1.25 (9H, s).

Example 4

4-(5-tert-Butyl-2-methoxyphenyl)-2-cvclopropyl-l,2,3,4-tetrahvdroisoquinolin-4-ol.

From 2-cyclopropyl-2,3-dihydroisoquinolin-4(lH)-one and l-bromo-5-tert-butyl-2- methoxybenzene. ¹H-NMR (400 MHz, CDCl₃): δ= 7.86 (IH, m), 7.28 (IH, m), 7.15-7.00 (3H, m), 6.92-6.70 (2H, m), 4.05 (IH, d), 3.76 (IH, d), 3.72 (3H, s, br), 3.38 (3H, s), 3.36 (IH, d), 3.05 (IH, dd), 1.90 (IH, m), 1.36 (9H, s), 0.55-0.45 (4H, m).

Example 5

2-Benzyl-4-(5-isopropoxy-2-methoxyphenyl)-l,2,3,4-tetrahvdroisoquinolin-4-ol.

From 2-benzyl-2,3-dihydroisoquinolin-4(lH)-one and l-bromo-5-isopropoxy-2- methoxybenzene. ¹R NMR (400 MHz, CDCl₃): δ (ppm) 7.25 (m, 5H), 7.18-7.01 (m, 5H), 6.79 (dd, IH), 6.72 (d, IH), 4.45 (m, IH), 4.30 (bs, IH), 3.85 (d, IH), 3.75 (d, IH), 3.68- 3.60 (m, 2H), 3.35 (s, 3H), 3.25 (d, IH), 2.78 (d, IH), 1.28 (d, 6H). Example 6

2-Benzyl-4-(5-tert-butyl-2-methoxyphenvπ-3-methyl-1.2.3.4-tetrahvdroisoquinolin-4-ol.

From 2-benzyl-3-methyl-2,3-dihydroisoquinolin-4(lH)-one and l-bromo-5-tert-butyl-2- methoxybenzene. ¹R NMR (400 MHz, CDCl₃): δ (ppm) 7.38 (bs, IH), 7.24 (d, IH), 7.20 (d, IH), 7.18 (m, 2H), 7.15-7.08 (m, 3H), 7.03 (m, IH), 6.92 (m, 2H), 6.76 (d, IH), 4.55 (bs, IH), 3.75 (d, 2H), 3.65 (d, IH), 3.57 (s, 3H), 3.53 (d, IH), 3.49 (m, 2H), 1.18 (s, 9H), 1.06 (d, 3H). MS(ES⁺); 416.23

Example 7

4-(5-tert-Butyl-2-methoxyphenyl)-8-chloro-2 -methyl- 1, 2, 3,4-tetrahvdroisoquinolin-4-ol.

From 2-benzyl-8-chloro-2,3-dihydroisoquinolin-4(lH)-one and l-bromo-5-tert-butyl-2- methoxybenzene. ¹H-NMR (400 MHz, CDCl₃): δ= 7.94 (IH, m), 7.30 (IH, m), 7.18 (IH, m), 7.00 (IH, m), 6.84 (IH, m), 6.74 (IH, m), 4.35 (IH, s, br, OH), 4.05 (IH, m), 3.35 (3H, s, OMe), 3.32 (IH, m), 3.12 (IH, m), 2.80 (IH, m), 2.52 (3H, s, Me), 1.35 (9H, s).

Example 8

4-(5-tert-Butyl-2-methoxy-phenvπ-2-benzyl-7-trifluoromethoxy-1.2.3.4-tetrahvdro- isoquinolin-4-ol.

From IM-I and l-bromo-5-tert-butyl-2-methoxybenzene. ¹H-NMR (400 MHz, CDCl₃): δ = 7.70 (IH, s, br), 7.30-7.20 (6H, m), 7.05(1H, d) 6.96-6.87 (2H, m), 6.75 (IH, d), 4.15 (IH, s, br), 3.84 (IH, d), 3.76(1H, d), 3.66(1H, d), 3.58 (IH, d), 3.40 (3H, s), 3.24 (IH, d), 2.87 (IH, d), 1.32 (9H, s). F¹⁹-NMR (377 MHz, CDCl₃): δ = -58.20.

Example 9 2-Benzyl-4-(5-tert-butyl-2-ethoxyphenyl)-l,2,3,4-tetrahvdroisoquinolin-4-ol.

From 2-benzyl-2,3-dihydroisoquinolin-4(lH)-one and l-bromo-5-tert-butyl-2- ethoxybenzene. ¹R NMR (400 MHz, CDCl₃): δ (ppm) 7.75 (bs, IH), 7.35-7.22 (m, 6H), 7.12 (ddd, IH), 7.08-6.92 (m, 3H), 6.70 (d, IH), 3.95 (bs, IH), 3.86 (m, 2H), 3.76 (d, IH), 3.66 (d, IH), 3.53 (d, IH), 3.35 (m, IH), 3.27 (d, IH), 2.88 (d, IH), 1.32 (s, 9H), 0.78 (t, 3H). Example 10

2-Benzyl-4-(2-methoxy-5-(2.2.2-trifluoroethoxy)phenvπ-1.2.3.4-tetrahvdroisoquinolin-4- ol.

From 2-benzyl-2,3-dihydroisoquinolin-4(lH)-one and l-bromo-5-(2,2,2-trifluoro-ethoxy)- 2-methoxybenzene. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.32-7.22 (m, 6H), 7.15 (ddd, IH), 7.12-7.02 (m, 2H), 6.98 (d, IH), 6.87 (dd, IH), 6.75(d, IH), 4.32 (m, 2H), 4.05 (bs, IH), 3.87 (d, IH), 3.75-3.58 (m, 3H), 3.53 (s, 3H), 3.21 (d, IH), 2.80 (d, IH).

Example 11

2-Benzyl-4-(5-butyl-2-methylphenyl)-l,2,3,4-tetrahvdroisoquinolin-4-ol.

From 2-benzyl-2,3-dihydroisoquinolin-4(lH)-one and l-bromo-5-butyl-2-methylbenzene. ¹U NMR (400 MHz, CDCl₃): δ (ppm) 7.85 (s, IH), 7.42-6.92 (m, 1 IH), 3.98-3.60 (m, 4H), 3.50 (d, IH), 2.90 (m, 2H), 2.65 (t, 2H), 1.65 (m, 5H), 1.35 (m, 2H), 0.98 (t, 3H). Example 12

4-r5-(3-Fluoropropyπ-2-methoxyphenyl1-2-methyl-1.2.3.4-tetrahvdroisoquinolin-4-ol.

From 2-methyl-2,3-dihydroisoquinolin-4(lH)-one and l-bromo-5-(3-fluoropropyl)-2- methoxybenzene.Yield 65mg (53%). ¹H-NMR (400 MHz, CDCl₃): δ = 7.68 (IH, m), 7.15- 7.05 (4H, m), 6.95 (IH, m), 6.75 (IH, m), 4.55 (IH, t), 4.42 (IH, t), 4.35 (IH, s, br), 3.68 (IH, m), 3.42 (IH, m), 3.35 (3H, s, OMe), 3.08 (IH, m), 2.80-2.70 (3H, m), 2.42 (3H, s, N- Me), 2.05 (2H, m). F¹⁹-NMR (377 MHz, CDCl₃): δ = -220.0.

Example 13

4-(5-tert-Butyl-2-methoxyphenyl)-l,2-dimethyl-l,2,3,4-tetrahvdroisoquinolin-4-ol.

From l,2-dimethyl-2,3-dihydroisoquinolin-4(lH)-one and l-bromo-5-tert-butyl-2- methoxybenzene according to the method described in Example 1. Yield 5 %. IH NMR (400 MHz, CDC13): d (ppm) 7.77 (bs, IH), 7.30 (m, IH), 7.17 (t, IH), 7.08-7.04 (m, 2H), 6.94 (d, IH), 6.77(d, IH), 3.98 (q, 2H), 3.62 (d, IH), 3.43 (s, 3H), 2.55 (d, IH), 2.48 (s, 3H), 1.32 (s, 9H).

The starting ketone was prepared as follows. To a solution of l,2-Dimethyl-4-oxo-l,2,3,4- tetrahydro-isoquinoline-3-carboxylic acid tert-butyl ester (2.Og, 7.26 mol) in benzene (30 mL) was added PTSA (2g). The resulting mixture was refluxed 3hr at 80 ⁰C. Solvent removal gave the crude product which was purified by column chromatography (40 % EtOAc in hexane) to provide desired product 220 mg (17 %). IH-NMR (400 MHz, CDCB): d 8.02 (dd, IH), 7.55 (ddd, IH), 7.35 (ddd, IH), 7.25 (dd, IH), 4.02 (q, IH), 3.68 (d, IH), 3.40 (d, IH), 2.51 (s, 3H), 1.42 (d, 3H).

Example 14

4-(5-tert-Butyl-2-methoxyphenyl)-2,3-dimethyl-l,2,3,4-tetrahvdroisoquinolin-4-ol.

Procedure as described in Example 23 using 2-benzyl-4-(5-tert-butyl-2-methoxyphenyl)-3- methyl- 1, 2,3, 4-tetrahydroisoquinolin-4-ol (140 mg, 0.34 mmol). Yield 27 mg (23.5 %). ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.84 (bs, IH), 7.27 (dd, IH), 7.12 (ddd, IH), 7.06-7.00 (m, 2H), 6.82 (d, IH), 6.72 (d, IH), 3.88 (d, IH), 3.64 (d, IH), 3.32 (s, 3H), 3.20 (q, IH), 2.44 (s, 3H), 1.35 (s, 9H), 0.95 (d, 3H). MS(ES⁺): 340.11.

The starting material 2-benzyl-4-(5-tert-butyl-2-methoxyphenyl)-3-methyl-l,2,3,4- tetrahydroisoquinolin-4-ol was prepared in 25 % yield from 2-benzyl-3-methyl-2,3- dihydroisoquinolin-4(lH)-one and l-bromo-5-tert-butyl-2-methoxybenzene as described in Example 1. Spectral data for. ¹R NMR (400 MHz, CDCl₃): δ (ppm) 7.38 (bs, IH), 7.24 (d, IH), 7.20 (d, IH), 7.18 (m, 2H), 7.15-7.08 (m, 3H), 7.03 (m, IH), 6.92 (m, 2H), 6.76 (d, IH), 4.55 (bs, IH), 3.75 (d, 2H), 3.65 (d, IH), 3.57 (s, 3H), 3.53 (d, IH), 3.49 (m, 2H), 1.18 (s, 9H), 1.06 (d, 3H). MS(ES⁺): 416.23 Example 15

4-(5-tert-Butyl-2-methoxyphenyl)-2-ethyl-5.7-dimethoxy-1.2.3.4-tetrahvdroisoquinolin-4- ol.

This example teaches the application of Method B when this involves direct alkylation of a secondary amine which is a further substituted l,2,3,4-tetrahydroisoquinolin-4-ol. 4-(5-tert-Butyl-2-methoxyphenyl)-5,7-dimethoxy-l,2,3,4-tetrahydroisoquinolin-4-ol (0.140 g, 0.376 mmol) in tetrahydrofuran (10 mL) was treated with CsCCβ (0.244 g, 0,752 mmol) and ethyl iodide (0.118 g, 0,752 mmol). The reaction mixture was stirred at room temperature for 4 h and then concentrated under reduced pressure. The product was purified by SG chromatography, eluting with ethyl acetate to ethyl acetate plus methanol (9.5:05) gave 41 mg (27 %) of the desired product. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.81 (bs, IH), 7.19 (d, IH), 6.72 (d, IH), 6.26 (d, IH), 6.20 (d, IH), 3.92 (d, IH), 3.79 (s, 3H), 3.70 (bs, IH), 3.41 (d, IH), 3.38 (s, 3H), 3.30 (s, 3H), 3.00 (dd, IH), 2.80 (dd, IH), 2.50-2.62 (m, 2H), 1.90 (s, 9H), 1.19 (t, 3H). MS (ES⁺): 400.21

The following Examples 16-22 were prepared according to Method B as described in Example 15.

Example 16

4-(5-tert-Butyl-2-methoxyphenvπ-2-isopropyl-5.7-dimethoxy-1.2.3.4- tetrahydroisoquinolin-4-ol.

From 4-(5-tert-Butyl-2-methoxyphenyl)-5,7-dimethoxy-l,2,3,4-tetrahydroisoquinolin-4-ol and isopropyliodide. Yield 53 mg (47 %). ¹U NMR (400 MHz, CDCl₃): δ (ppm) 7.81 (bs, IH), 7.19 (d, IH), 6.72 (d, IH), 6.29 (d, IH), 6.19 (d, IH), 3.80 (bs, IH), 3.79 (s, 3H), 3.62 (dd, IH), 3.40 (s, 3H), 3.38 (s, 3H), 3.30 (s, 3H), 2.95 (d, 3H), 1.39 (s, 9H), 1.19 (d, 3H), 1,09 9d, 3H). MS (ES⁺): 414.19

Example 17

4-(5-tert-Butyl-2-methoxyphenyl)-5.7-dimethoxy-2-(2-methoxyethvπ-1.2.3.4- tetrahvdroisoquinolin-4-ol.

From 4-(5-tert-Butyl-2-methoxyphenyl)-5,7-dimethoxy-l,2,3,4-tetrahydroisoquinolin-4-ol and 2-methoxyethyliodide. Yield 45 mg (39 %). ¹R NMR (400 MHz, CDCl₃): δ (ppm) 7.79 (bs, IH), 7.19 (dd, IH), 6.70 (dd, IH), 6.28 (d, IH), 6.20 (d, IH), 3.82 (dd, IH), 3.79 (s, 3H), 3.60 (m, 4H), 3.39 (s, 3H), 3.38 (s, 3H), 3.30 (s, 3H), 3.00 (d, IH), 2.70-2.90 (m, 2H), 2.50-2.62 (m, 2H), 1.30 (s, 9H). MS (ES⁺): 430.18

Example 18

4-(5-tert-Butyl-2-methoxyphenyl)-5,7-dimethoxy-2-(pyridin-4-yl)-l,2,3,4- tetrahvdroisoquinolin-4-ol.

A mixture of 4-(5-tert-butyl-2-methoxyphenyl)-5,7-dimethoxy-l,2,3,4- tetrahydroisoquinolin-4-ol (0.100 g, 0.269 mmol), 4-chloropyridine (0.061 g, 0.538 mmol), and dimethylaminopyridin (2.5 eq) in DMF (10 mL) was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure followed by extractive work-up. The crude product was purified by SG chromatography, eluting with ethyl acetate to ethyl acetate and methanol (19:1). Yield 28 mg (26 %). ¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.19 (bs 2H), 7.39 (s, IH), 7.19 (d, IH), 7.14 (t, IH), 7.09 (d, IH), 7.02 (dd, IH), 3.90 (d, IH), 3.55 (d, IH), 3.05 (d, IH), 2.90 (m, IH), 2.75 (d, IH), 2.45 (s, 3H), 1.25 (d, 6H). MS (ES⁺): 449.20

Example 19

4-(5-tert-Butyl-2-methoxyphenyl)-2-(pyridin-4-yl)-l,2,3,4-tetrahvdroisoquinolin-4-ol.

4-(5-tert-Butyl-2-methoxyphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol (lOOmg, 0.32mmol), Cs₂CO₃ (524mg, 1.60 mmol), and 4-fluoropyridineHCl (86mg, 0.0.64 mmol) in DMF (0.5mL) were stirred for 48h at RT. Work-up as in Example 18 gave 50 mg (40%). ¹H- NMR (400 MHz, CDCl₃): δ = 8.05 (2H, m), 7.42-7.20 (5H, m), 6.85 (2H, m), 6.50 (2H, m), 4.52 (2H, m), 4.38 (IH, m), 3.80 (3H, s), 3.62 (IH, m), 1.25 (9H, s).

Example 20

4-(5-tert-Butyl-2-methoxyphenyl)-2-ethyl-l,2,3,4-tetrahvdroisoquinolin-4-ol.

From 4-(5-tert-butyl-2-methoxyphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol and ethyliodide. Yield 36 mg (66%). ¹H-NMR (400 MHz, CDCl₃): δ = 7.95 (IH, m), 7.25-7.00 (4H, m), 6.95 (IH, m), 6.85 (IH, m), 3.95 (IH, m), 3.55 (IH, m), 3.33 (3H, s), 3.10 (IH, m), 2.95 (IH, m), 2.62 (2H, m),1.25 (9H, s), 1.09 (3H, t).

Example 21

2-r3-(2-Ethyl-4-hvdroxy - 1 ,2,3,4-tetrahvdroisoquinolin-4-yl)-4-methoxyphenyll-2- methylpropanenitrile.

From 2-(3-(4-hydroxy -1 ,2,3,4-tetrahydroisoquinolin-4-yl)-4-methoxyphenyl)-2- methylpropanenitrile and ethyliodide. Yield 36mg (74%). ¹H-NMR (400 MHz, CDCl₃): δ= 8.01 (IH, m), 7.45 (IH, m), 7.20-7.00 (3H, m), 6.83-6.78 (2H, m), 3.96 (IH, d, J= 12.0 Hz), 3.55 (IH, d, J= 12.0 Hz), 3.35 (3H, s), 3.08 (IH, d, J= 11.5 Hz), 2.95 (IH, d, J = 11.5 Hz), 2.65 (2H, s), 1.75 (3H, s), 1.70 (3H, s), 1.10 (3H, t, J= 6.7 Hz).

Example 22

4-(5-tert-Butyl-2-methoxyphenyl)-2-(3-fluoropropyπ-1.2.3.4-tetrahvdroisoquinolin-4-ol.

Yield 34.8 mg (42 %). From 4-(5-tert-butyl-2-methoxyphenyl)-l,2,3,4- tetrahydroisoquinolin-4-ol and 3-fluoropropyliodide. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.78 (bs, IH), 7.29 (dd, IH), 7.15 (ddd, IH), 7.07 (m, 2H), 6.96 (d, IH), 6.77 (d, IH), 4.53 (t, IH), 4.40 (t, IH), 3.98 (bs, IH), 3.90 (d, IH), 3.57 (d, IH), 3.40 (s, 3H), 3.18 (d, IH), 2.85 (d, IH), 2.68 (m, 2H), 19.2 (m, 2H), 1.34 (s, 9H). ¹⁹F NMR (400 MHz, CDCl₃): δ (ppm) -220.5. MS (ES⁺): 372.16. Example 23

4-(5-tert-Butyl-2-methoxyphenvπ-5.7-dimethoxy-2-methyl-1.2.3.4-tetrahvdroisoquinolin- 4-ol.

This example teaches the application of a variation of Method B which comprises hydrogeno lytic debenzylation of a further substituted 2 -benzyl- 1,2,3, 4- tetrahydroisoquinolin-4-ol giving rise to the secondary amine or, when performed in methanol or ethanol, the 2-methyl or 2-ethyl l,2,3,4-tetrahydroisoquinolin-4-ol by concurrent reductive alkylation.

The product from Example 1 (0.100 g, 0.269 mmol) in methanol (10 mL) was treated with 20 mg of 10% Pd/C and formaldehyde (1.2 eq). The reaction mixture was stirred under hydrogen at 1 atm pressure. Completion of reaction was confirmed by TLC the catalyst was filtered off through celite. Concentratation of the filtrate under reduced pressure gave 15 mg (14 %). ¹U NMR (400 MHz, CDCl₃): δ (ppm) 7.79 (bs, IH), 7.19 (dd, IH), 6.72 (dd, IH), 6.24 (d, IH), 6.20 (d, IH), 3.80 (s, 3H), 3.79 (bs, IH), 3.41 (bs, IH), 3.39 (s, 3H), 3.30(s, 3H), 2.41 (s, 3H), 1.90 (s, 9H). MS (ES⁺): 386.07.

The following Examples 24-38 were prepared as described in Example 23. Example 24

4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-7-trifluoromethoxy-1.2.3.4-tetrahvdro- isoquinolin-4-ol.

The compound from Example 8 gave 38 mg (41 %) of the desired product 4-(5-tert-buty\- 2-methoxy-phenyl)-2-methyl-7-trifluoromethoxy- 1 ,2,3 ,4-tetrahydro-isoquinolin-4-ol. H¹ - NMR (400 MHz, CDCl₃): δ = 7.90 (IH, d), 7.30 (IH, dd), 6.98-6.88 (3H, m), 6.75 (IH, d), 4.19 (IH, s, br) 3.72 (IH, d), 3.42 (IH, d), 3.37 (3H, s), 3.08 (IH, dd), 2.80 (IH, dd), 2.44 (3H, s),1.30 (9H, s).

Example 25

4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-l,2,3,4-tetrahvdroisoquinolin-4-ol.

The compound from Example 3 gave 58 mg (71%) of the title compound. H¹ -NMR (400 MHz, CDCl₃): δ = 7.925 (IH, m), 7.30-7.00 (4H, m), 6.91 (IH, m), 6.70 (IH, m), 4.05 (IH, s, br) 3.78 (IH, m), 3.42 (IH, m), 3.38 (3H, s), 3.05 (IH, m), 2.90 (IH, m), 2.42 (3H, m),1.30 (9H, s). Example 26

4-(5-tert-Butyl-2-methoxyphenvπ-1.2.3.4-tetrahvdroisoquinolin-4-ol.

The compound from Example 3 by hydrogenation in ethyl acetate gave 68 mg (29.5 %) of

the title compound. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.46 (d, IH), 7.27 (m, IH), 7.17 (ddd, IH), 7.13-7.02 (m, 3H), 6.78 (d, IH), 4.25 (bs, 2H), 4.05 (s, 2H), 3.58 (d, IH), 3.53 (s, 3H), 3.18 (d, IH), 1.25 (s, 9H).

Example 27

2-Ethyl-4-(2-methyl-5-trifluoromethylphenyl)-l,2,3,4-tetrahvdroisoquinolin-4-ol.

The compound 2-benzyl-4-(2-methyl-5-trifluoromethylphenyl)- 1,2, 3,4- tetrahydroisoquinolin-4-ol by hydrogenation in ethanol gave 14 mg (21%) of the title compound. IH-NMR (400 MHz, CDC13): δ = 8.40 (IH, m), 7.45 (IH, m), 7.20-7.00 (4H, m), 6.86-6.82 (IH, m), 4.05 (IH, m), 4.00 (IH, s, br), 3.50 (IH, m), 2.85 (IH, m), 2.80 (IH, m), 2.55 (2H, m), 1.78 (3H, s), 1.15 (3H, t, J = 6.7 Hz).

Example 28

4-(2-Methoxy-5-(trifluoromethoxy)phenvπ-2-methyl-1.2.3.4-tetrahvdroisoquinolin-4-ol.

The compound 2-benzyl-4-(2-methoxy-5-(trifluoromethoxy)phenyl)- 1,2, 3,4- tetrahydroisoquinolin-4-ol. gave 21 mg (31%) of the title compound. ¹H-NMR (400 MHz, CDCl₃): δ = 7.80 (IH, m), 7.19-7.02 (4H, m), 6.88 (IH, m), 6.75 (IH, m), 4.20 (IH, s, br), 3.70 (IH, m), 3.40 (IH, m), 3.35 (3H, s), 3.04 (IH, m), 2.75 (IH, m), 2.42 (3H, s).

Example 29

2-(3-(4-Hvdroxy-2-methyl-1.2.3.4-tetrahvdroisoquinolin-4-vπ-4-methoxyphenvπ-2- methylpropanenitrile.

The compound 2-[3-(2-benzyl-4-hydroxy- 1,2, 3,4-tetrahydroisoquinolin-4-yl)-4- methoxyphenyl]-2-methylpropanenitrile gave 30 mg (18 %) of the title compound. ¹H- NMR (400 MHz, CDCl₃): δ= 7.95 (IH, m), 7.46 (IH, m), 7.20-7.00 (3H, m), 6.88-6.80 (2H, m), 3.75 (IH, m), 3.45 (IH, m), 3.38 (3H, s), 3.08 (IH, m), 2.78 (IH, m), 2.45 (3H, s), 1.75 (3H, s), 1.70 (3H, s) ppm Example 30

2-(3-(4-Hvdroxy-1.2.3.4-tetrahvdroisoquinolin-4-vπ-4-methoxyphenvπ-2- methylpropanenitrile.

The compound 2-(3-(2-benzyl-4-hydroxy-l, 2, 3,4-tetrahydroisoquinolin-4-yl)-4- methoxyphenyl)-2-methylpropanenitrile by hydrogenation in ethyl acetate gave 45mg (27%) of the title compound. ¹H-NMR (400 MHz, CDCl₃): δ= 7.62 (IH, m), 7.42 (IH, m), 7.19 (IH, m), 7.14-7.06 (2H, m), 6.98 (IH, m), 6.86 (IH, m), 4.08 (2H, m), 3.51 (3H, s), 3.50 (IH, m), 3.10 (IH, m), 2.78 (IH, m), 2.45 (3H, s), 1.70 (6H, s)

Example 31

4-(5-Butyl-2-methoxyphenyl)-2-methyl-l,2,3,4-tetrahvdroisoquinolin-4-ol.

The compound 2-benzyl-4-(5-butyl-2-methoxyphenyl)-l ,2,3,4-tetrahydroisoquinolin-4-ol gave 42 mg (48%) of the title compound. ¹H-NMR (400 MHz, CDCl₃): δ= 7.68 (IH, m), 7.18-6.98 (4H, m), 6.85-6.74 (2H, m), 4.30 (IH, s, br), 3.68 (IH, m), 3.42 (IH, m), 3.35 (3H, s), 3.08 (IH, m), 2.78 (IH, m), 2.60 (2H, m), 2.42 (3H, s), 1.60 (2H, m), 1.37 (2H, m), 0.95 (3H, t). Example 32

4-r5-(3.3-Difluorobutvπ-2-methoxyphenyl1-2-methyl-1.2.3.4-tetrahvdroisoquinolin-4-ol.

The compound 2-benzyl-4-[5-(3,3-difluorobutyl)-2-methoxyphenyl]-l, 2,3,4- tetrahydroisoquinolin-4-ol gave 25mg (30%) of the title compound. ¹H-NMR (400 MHz, CDCl₃): δ = 7.68 (IH, m), 7.17-7.04 (4H, m), 6.91 (IH, m), 6.77 (IH, m), 3.67 (IH, m), 3.45 (IH, m), 3.35 (3H, s, OMe), 3.10 (IH, m), 2.83-2.76 (3H, m), 2.44 (3H, s, Me), 2.20 (2H, m), 1.63 (3H, t). F¹⁹-NMR (377 MHz, CDCl₃): δ = -91.5.

Example 33

4-(5-tert-Butyl-2-chlorophenyl)-2 -methyl- 1, 2, 3,4-tetrahvdroisoquinolin-4-ol.

The compound 2-benzyl-4-(5-tert-Butyl-2-chlorophenyl)- 1,2, 3,4-tetrahydroisoquinolin-4- ol gave (52mg, 53%) of the title compound. ¹H-NMR (400 MHz, CDCl₃): δ= 8.26 (IH, m), 7.28-7.04 (5H, m), 6.86 (IH, m), 4.24 (IH, s, br, OH), 3.75 (IH, m), 3.47 (IH, m), 3.23 (IH, m), 2.80 (IH, m), 2.45 (3H, s, Me), 1.35 (9H, s).

Example 34

4-(5-Isopropoxy-2-methoxyphenvπ-2-methyl-1.2.3.4-tetrahvdroisoquinolin-4-ol.

The compound from Example 5 gave 41 mg (48.2 %) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.45 (bs, IH), 7.15 (t, IH), 7.02 (d, IH), 6.97 (d, IH), 6.79 (dd, IH), 6.73 (d, IH), 4.51 (m, IH), 4.42 (bs, IH), 3.59 (d, IH), 3.40 (d, IH), 3.30 (s, 3H), 3.17 (d, IH), 2.78 (d, IH), 2.40 (s, 3H), 1.35 (m, 6H). MS (ES⁺):328.11

Example 35 4-(5-tert-Butyl-2-methoxyphenyl)-3-methyl-l,2,3,4-tetrahvdroisoquinolin-4-ol.

The N-benzyl compound used as an intermediate in Example 14 gave 27 mg (23.5 %) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.84 (bs, IH), 7.27 (dd, IH), 7.12 (ddd, IH), 7.06-7.00 (m, 2H), 6.82 (d, IH), 6.72 (d, IH), 3.88 (d, IH), 3.64 (d, IH), 3.32 (s, 3H), 3.20 (q, IH), 2.44 (s, 3H), 1.35 (s, 9H), 0.95 (d, 3H). MS(ES⁺): 340.11.

Example 36

4-(5-tert-Butyl-2-ethoxyphenyl)-2-methyl-l,2,3,4-tetrahvdroisoquinolin-4-ol.

The compound from Example 9 gave 68 mg (51 %) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.98 (d, IH), 7.27 (m, IH), 7.12 (ddd, IH), 7.05-6.98 (m, 2H), 6.88 (d, IH), 6.68 (d, IH), 4.27 (bs, IH), 3.82 (q, IH), 3.65 (d, IH), 3.40-3.28 (m, 2H), 3.10 (d, IH), 2.80 (d, IH), 2.42 (s, 3H), 1.35 (s, 9H), 0.73 (t, 3H). MS(ES⁺): 340.23.

Example 37 4-(2-Methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-2-methyl-l,2,3,4-tetrahvdroisoquinolin-4- ol.

The compound from Example 10 gave 28 mg (39 %) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.53 (d, IH), 7.16 (ddd, IH), 7.10-7.00 (m, 2H), 6.93-6.85 (m, 2H), 6.76 (d, IH), 3.40 (d, IH), 3.32 (s, 3H), 3.06 (d, IH), 2.75 (d, IH), 2.42 (s, 3H). ¹⁹F NMR (400 MHz, CDCl₃): δ (ppm) -74.5. MS(ES⁺):368.02.

Example 38

4-(5-Butyl-2-methylphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol.

The compound from Example 11 gave 37.0 mg (44 %) of the title compound. ¹H NMR

(400 MHz, CDCl₃): δ (ppm) 7.95 (d, IH), 7.19 (ddd, IH), 7.12-7.02 (m, 3H), 6.98-6.94 (m, 2H), 4.15 (bs, IH), 3.75 (d, IH), 3.48 (d, IH), 2.82 (m, 2H), 2.65 (t, 2H), 2.45 (s, 3H), 1.65 (m, 5H), 1.39 (m, 2H), 0.95 (t, 3H). MS(ES⁺): 310.11 Example 39

4-(5-tert-Butyl-2-methoxyphenvπ-2-methyl-1.2.3.4-tetrahvdroisoquinoline.

To a solution of the aminoalchol from Example 25 (35 mg, 0.1 lmmol) and Et3SiH (187mg, 1.62 mmol) in DCM (0.5mL) was added TFA (83 μL, 1. lmmol) at O⁰C. The mixture was allowed to warm to RT overnight. The reaction was quenched (2 N Na₂CO₃) followed by extraction (DCM), washing (brine) and drying (MgSO4). The crude product gave good NMR. Purification by chromatography provided compound 5 (30 mg, 90%) with >95% HPLC purity. ¹H-NMR (400 MHz, CDCl₃): δ = 7.21 (IH, m), 7.13-7.00 (4H, m), 6.88-6.81 (2H, m), 4.75 (IH, m), 3.78 (IH, m), 3.75 (IH, s), 3.58 (IH, m), 3.05 (IH, m), 2.52 (IH, m), 2.42 (3H, s), 1.20 (9H, m).

Example 40

4-(5-tert-Butyl-2-methoxyphenvπ-2-methyl-1.2.3.4-tetrahydroisoquinolin-4-amine.

Step 1. Boron trifluoride etherate (131 mg, 0.92mmol) was added dropwise at RT to a stirred solution of 4-(5-tert-butyl-2-methoxyphenyl)-2-methyl-l,2,3,4- tetrahydroisoquinolin-4-ol from Example 25 (lOOmg, 0.3 lmmol) and TMSN₃ (106 mg, 0.92mmol) in benzene (2.5 mL). The mixture was stirred 24h at RT. The reaction was quenched with saturated NaHCO₃ and extracted with DCM. The combined organic phase was washed with brine, dried (MgSO4) and concentrated. Removal of DCM provided crude azide (1 lOmg, 0.31mmol) for next step without further purification.

Step 2. The azide from Step 1 was dissolved in ether (8mL) followed by addition of LAH (33mg, 0.87mmol). The mixture was refluxed overnight. The reaction was quenched with water and extracted with ether followed by standard workup. Purification by chromatography (Hex/EAl/1) provided >95%HPLC pure title product (lOOmg, 95%). ¹H- NMR (400 MHz, CDCl₃): δ= 7.93 (IH, m), 7.27 (IH, m), 7.10-6.98 (3H, m), 6.82-6.73 (2H, m), 3.83 (IH, m), 3.42 (IH, m), 3.30 (3H, s, OMe), 3.02 (IH, m), 2.70 (IH, m), 2.42 (3H, s, Me), 2.18 (2H, s, br), 1.35 (9H, s).

Example 41

N-(4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-l,2,3,4-tetrahvdroisoquinolin-4- vDmethanesulfonamide.

The product from Example 40 was used without further purification. To a solution of the crude product from Example 40 (35mg, 0.1 lmmol) and DMAP (26mg, 0.22mmol) in DCM (ImL) was added MsCl (15mg, 0.13mmol) at O⁰C. The mixture was stirred 8hr at RT followed by the standard workup. Purification by chromatography (Hex/EA 1/1) afforded the desired product (18mg, 41%). ¹H-NMR (400 MHz, CDCl₃): δ= 8.05 (IH, m), 7.30-7.05 (5H, m), 6.73 (IH, m), 5.68 (IH, s, br, NH), 3.95 (IH, m), 3.55 (IH, m), 3.35 (3H, s), 3.12 (IH, m), 2.85 (IH, m), 2.42 (3H, s), 2.28 (3H, s), 1.35 (9H, s). Example 42

4-(5-tert-Butyl-2-methoxyphenvπ-2-(methylsulfonvπ-1.2.3.4-tetrahvdroisoquinolin-4-ol.

To a solution of 4-(5-tert-butyl-2-methoxyphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol from Example 26 (50 mg, O.lόmmol) and 2,6-lutidine (52mg, 0.48mmol) in DCM (ImL) was added MsCl (18mg, O.lόmmol) at -78⁰C. The mixture was stirred 30 min at -78⁰C followed by the standard workup. Purification by chromatography (Hex/EA 2/1) afforded desired compound (41mg, 66%). ¹H-NMR (400 MHz, CDCl₃): δ= 7.35-7.05 (6H, m), 6.85 (IH, m), 4.65 (IH, m), 4.43 (IH, m), 4.05 (IH, m), 4.02 (IH, s, br, OH), 3.65 (IH, m), 3.62 (3H, s, OMe), 2.55 (3H, s, Me), 1.22 (9H, s).

Example 43

4-(2-Methoxy-5-((3 ,3 ,3 ,-trifluoro-propoxy)-phenvO-7-trifluoromethoxy- 1 ,2,3 ,4-tetrahvdro- isoquinolin-4-ol.

Following the procedure of Example 1 starting from IM-I and 2-bromo-l-methoxy-4- (3,3,3-trifiuoro-propoxy)benzene (825mg, 2.76 mmol), 2-benzyl-4-(2-methoxy-5-(2,2,2,- trifluoro-ethoxy)-phenyl)-7-trifluoromethoxy- 1 ,2,3 ,4-tetrahydro-isoquinolin-4-ol was obtained. This was hydrogenolysed to give the title compound. ¹H NMR (CDCl₃): δ ppm 7.18(d, 1 H), 6.85-7.02 (m, 3H), 6.80 (m, 2 H), 4.15 (m, 2 H), 4.05(s, 2H), 3.58 (s, 3 H), 3.52 (d, 1 H), 3.15(d, 1 H), 3.10 (d, IH), 2.62(m, 2H). F¹⁹-NMR (377 MHz, CDCl₃): δ = ■

58, -65.

Example 44

5 4-r2-Methoxy-5-(l-methoxy-l-methyl-ethyl)-phenyll-7-trifluoromethoxy-l,2,3,4- trtrahydroisoquinolin-4-ol.

Following the procedure of Example 1 starting from IM-I and l-bromo-2-methoxy-5-(l- i o methoxy- 1 -methyl-ethyl)benzene the compound 2-benzyl-4- [2-methoxy-5 -( 1 -methoxy- 1 - methyl-ethyl)phenyl]-7-trifluoromethoxy-l,2,3,4-tetrahydro-isoquinolin-4-ol was obtained. This was hydrgenolysed to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.37 (m, 2 H), 7.18 (d, 1 H), 6.92 (m, 2H), 6.80 (d, 1 H), 4.08 (s, 2 H), 3.65 (s, 3 H), 3.52 (d, 1 H), 3.18 (d, 1 H), 3.02 (s, 3 H), 1.45(s, 6H). ¹⁹F-NMR (377 MHz, CDCl₃): δ = -58.

15

Example 45

4-r5-(3-Fluoro-3-methyl-butyl)-2-methoxy-phenyll-2-methyl-l,2,3,4-tetrahvdro- isoquinolin-4-ol.

Following the procedure of Example 1 starting from 2-benzyl-2,3-dihydro-lH-isoquinolin- 20 4-one and 2-bromo-4-(3-fiuoro-3 -methyl-butyl)- 1-methoxy-benzene the N-benzyl product was obtained. Hydrogenolysis in the presence of formaldehyde gave the title product. ¹H NMR (CDCl₃) δ ppm 7.70 (br. s., 1 H) 6.99 - 7.20 (m, 5 H) 6.85 - 6.96 (m, 1 H) 6.75 (d, J=8.22 Hz, 1 H) 3.76 (d, J=14.48 Hz, 1 H) 3.46 (d, J=14.48 Hz, 1 H) 3.35 (s, 3 H) 3.11 (d, J=I 1.35 Hz, 1 H) 2.76 - 2.84 (m, 1 H) 2.67 - 2.76 (m, 2 H) 2.45 (s, 3 H) 1.88 - 2.03 (m, 2 H) 1.44 (s, 3 H) 1.39 (s, 3 H). ¹⁹F-NMR (377 MHz, CDCl₃): δ =-139.

Example 46 4-r5-(3-fluoro-3-methyl-butyl)-2-methoxy-phenyll-l,2,3,4-tetra-hvdro-isoquinolin-4-ol.

Prepared analogously to the compound in Example 45 but running hydrogenolysis in the absence of formaldehyde. ¹R NMR (CDCl₃) δ ppm 7.26 (s, 1 H) 7.18 (dd, J=7.43, 1.57 Hz, 2 H) 7.02 - 7.13 (m, 3 H) 6.79 (d, J=8.22 Hz, 1 H) 4.05 (br. s., 2 H) 3.65 (d, J=4.70 Hz, 1 H) 3.56 (d, J=3.52 Hz, 1 H) 3.50 - 3.55 (m, 3 H) 3.15 (d, J=13.30 Hz, 1 H) 2.60 - 2.71 (m, 2 H) 1.81 - 1.95 (m, 2 H) 1.41 (s, 3 H) 1.36 (s, 3 H). F¹⁹-NMR (377 MHz, CDCl₃): δ =- 139.

Example 47 2-Benzyl-4-(4-methoxy-biphenyl-3-yl)-l,2,3,4-tetrahydro-isoquinolin-4-ol

Following the procedure of Example 1 starting from 2-benzyl-2,3-dihydro-lH-isoquinolin- 4-one and 3-bromo-4-methoxy-biphenyl the N-benzyl product was obtained. Hydrogenolysis gave the title product. ¹H NMR (CDCl₃) δ ppm 7.62 (s, IH), 7.55(m. 3H), 7.38(m, 2H), 7.32 (m, IH), 7.15-7.20 (m, 3H), 7.08 (m, IH), 6.90 (d, IH), 4.08(s, 2H), 3.73(s, 3H), 3.55 (d, IH), 3.20(d, IH). Example 48

4-(5-tert-Butyl-2-methoxy-phenvπ-2-hvdroxy-ethyl-1.2.3.4-tetrahvdroisoquinolin-4-ol.

A mixture of 4-(5-tert-butyl-2-methoxy-phenyl)-l,2,3,4-tetrahydro-isoquinolin-4-ol (120 mg, 0.385 mmol) from Example 48, 2-(2-bromo-ethoxy)-tetrahydropyran (160 mg, 0.765 mmol), and DMAP (140 mg, 1.15 mmol) in DMF (8 mL) was stirred overnight at room temperature. The crude product was dissolved in MeOH and treated with 6N HCl (0.5 mL) at room temperature for about 1 h. SGC using 20 % ethyl acetate in hexane as eluant gave the desired product. Yield: 30 mg (22 %). ¹R NMR (400 MHz, CDCl₃): δ (ppm) 7.18-7.40 (m, 5H), 7.12 (d, IH), 6.82 (d, IH), 4.25 (bs, IH), 3.85(d, IH), 3.78 (d, IH), 3.63 (s, 3H), 3.55 (m, 2H), 3.33(d, IH), 2.85(d, IH), 2.62(m, 2H)1.25 (s, 9H).

Example 49

2-Benzyl-8-bromo-4-(5-tert-butyl-2-methoxy-phenvπ-1.2.3.4-tetrahvdro-isoquinolin-4-ol.

Following the procedure of Example 1 starting from 2-benzyl-8-bromo-2,3-dihydro-lH- isoquinolin-4-one and l-bromo-2-methoxy-5-tert-butylbenzene the title compound was obtained. It was used directly in the next Example 50. Example 50

2-Benzyl-4-(5-tert-butyl-2-methoxy-phenvπ-8-pyrimidin-5-yl-1.2.3.4-tetrahydro- isoquinolin-4-ol.

2M aq. sodium carbonate (0.68 mL) was added to a mixture of the compound from Example 50 (215 mg, 0.45 mmol), pyrimidin-5-boronic acid (85 mg, 0.686 mmol) and tetrabutyl ammonium bromide (15 mg, 0.047 mmol) in toluene (15 mL, degassed) while stirring under nitrogen at room temperature. Bis(triphenyl-phosphine)Pd(II)Cl₂ (31.6 mg (0.045 mmol) was added and the mixture was refiuxed overnight and filtered through a short bed of celite. The crude residue was purified by SGC using 10-20% ethyl acetate in hexane gave the title product in a yield of 78 mg (36 %). IH NMR (CDCl₃) δ ppm 9.22 (s, 1 H) 8.74 (s, 2 H) 7.60 (bs, 1 H) 7.08-7.35 (m, 9 H) 6.76 (d, 1 H) 4.06 (br. s., 1 H) 3.50 - 3.73 (m, 4 H) 3.43 (s, 3 H) 3.19 (d, J=I 1.32 Hz, 1 H) 2.82(d, 1 H) 1.31 (s, 9 H)

Example 51

4-[5-(2-Fluoro-2-methyl-propyl)-2-methoxy-phenyll-7-methoxy-1.2.3.4-tetrahvdro- isoquinolin.

Following the procedure of Example 1 starting from 2-benzyl-2,3-dihydro-lH-isoquinolin- 4-one and 2-bromo-4-(2-fluoro-2-methyl-propyl)-l-methoxy-benzene (0.742 g, 2.84 mmol) the compound 2-benzyl-4-[5-(2-fluoro-2-methyl-propyl)-2-methoxy-phenyl]-7- methoxy-l,2,3,4-tetrahydro-isoquinolin-4-ol was obtained. This was hydrogenolysed to give the title product. ¹R NMR (CDCl₃): δ (ppm): 7.15(d, IH), 7.05 (d, IH), 7.00 (s, IH), 6.80 (d, IH), 6.70 (d, IH), 6.55 (d, IH), 4.00 (s, 2H), 3.80 (s, 3H), 3.70 (s, 3H), 3.50 (s, IH), 3.15 (s, IH), 2.80 (dd, 2H), 1.30 (dd, 6H); ¹⁹F (CDCl₃): δ (ppm): -138

Example 52

2-Methyl-4-r5-(2-Fluoro-2-methyl-propyl)-2-methoxy-phenyll-7-methoxy-l,2,3,4- tetrahydro-isoquinolin.

The compound from Example 51 was hydrogenolysed in the presence of formaldehyde to give the title product. ¹R NMR (400MHZ, CDCl₃): δ (ppm): 7.60 (s, IH), 7.20 (d, IH), 6.90 (d, IH), 6.80 (d, IH), 6.60 (m, 2H), 4.70 (s, IH), 3.80 (m, 4H), 3.50 (m, 4H), 3.20 (d, IH), 2.90 (m, 3H), 2.50 (s, 3H), 1.40 (dd, 6H); ¹⁹F (CDCl₃): δ (ppm): -137.20; MS (ES): m/z 374.07 (M+H)⁺

Pharmaceutical compositions

According to one embodiment of the present invention there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

The pharmaceutical composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration e.g. as an ointment, patch or cream or for rectal administration e.g. as a suppository. In general the above compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers.

A suitable daily dose of a compound of the invention in the treatment of a mammal, in- eluding man, is approximately from 0.1 to 100 mg/kg bodyweight at peroral administration and from about 0.01 to 250 mg/kg bodyweight at parenteral administration.

The typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician.

Medical Use

Compounds according to the present invention are contemplated to be useful in therapy. Compounds of formula I as herein described and claimed, or a pharmaceutically acceptable salt thereof, as well as their corresponding active metabolites, exhibit a high degree of potency at the sodium channel NaV 1.7 and also selectivity for this channel compared with other essential sodium channels. Accordingly, compounds of the present invention are expected to be useful in the treatment of conditions associated with upregulation of NaVl .7 and other sodium channels present in C-fibers.

Compounds of the invention may be used to produce an inhibitory effect of sodium channels in mammals, including man.

One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, in the manufacture of a medicament for the treatment of NaVl .7 mediated disorders.

Compounds of formula I according to the invention are expected to be useful for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.

Still an aspect of the invention is the use of a compound of formula I, for the treatment of a vascular headache such as migraine.

Yet an aspect of the invention is the use of a compound of formula I, for the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is the use of a compound of formula I, for the treatment of epilepsy.

One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, for the treatment of pain conditions related to arthritis, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis or ischeamic pain.

One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, in therapy.

Still an embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, for the manufacture of a medicament for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout. Still an aspect of the invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of a vascular headache such as migraine.

Yet an aspect of the invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of of epilepsy.

Still an embodiment of the invention relates to a method for the treatment of any one of the following pain disorders such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout; whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.

Still an aspect of the invention is a method for the treatment of a vascular headache such as migraine, whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.

Yet an aspect of the invention is a method for the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder, whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment. Still an embodiment of the present invention is a method for the treatment of epilepsy, whereby a compound of formula I as hereinbefore defined is administered to a subject in need of such treatment.

Yet an embodiment of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.

Still an aspect of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of a vascular headache such as migraine.

Yet an aspect of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is a compound of formula I as hereinbefore defined, for use in the treatment of epilepsy.

COMBINATIONS Pain treatment as defined herein may be applied as a sole therapy or may involve, in addition to a compound according to the invention, administration of other analgesics or adjuvant therapy. Such therapy may for example include in combination with a compound of the present invention, one or more of the following categories of pain-relieving ingredients:

a) opioid analgesics, for example morphine, ketobemidone or fentanyl; b) analgesics of the NSAID or COX- 1/2 class, for example ibuprofene, naproxene, celecoxib or acetylsalicylic acid, and their analogues containing nitric oxide- donating groups; c) analgesic adjuvants such as amitriptyline, imipramine, duloxetine or mexiletine; d) NMDA antagonists for example ketamine or dextrometorfan; e) sodium channel blocking agents, for example lidocaine; f) anticonvulsants, for example carbamazepine, topiramate or lamotrigine; g) anticonvulsant/analgesic amino acids such as gabapentin or pregabalin; h) cannabinoids.

Each active compound of such a combination may be administered simultaneously, separately or sequentially.

BIOLOGICAL TESTS Biological Tests

Expression of voltage-gated sodium channel in cell lines:

Gene(s) encoding the full-length protein of the voltage-gated sodium channel of interest are cloned and expressed under a suitable promoter in a suitable cell line, as well known in the art. The so constructed stable cell lines are used in screening assays to identify suitable compounds active on voltage-gated sodium channels. Suitable screening assays are as follows.

Li+ influx assay The cell line expressing the voltage-gated sodium channel of interest is plated in conventional 96 or 384 well tissue plates at a suitable cell density (for example 40000 cells/well in 96 well plate, or 20000 cells/well in 384 well plate). The cells are then repeatedly washed with a suitable Na free buffer using a suitable commercially available washer (for example EL-405 washer) until all tissue culture medium is removed from the wells. A suitable Na- free buffer could have the composition (mM) Choline chloride 137, KCl 5.4, MgSO₄ 0.81, CaCl₂ 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. After completion of all wash steps, cells are incubated in the suitable Na free buffer for 15 min. Then, the Na free buffer is removed and cells are incubated with a buffer rich in LiCl for 60 min at 37⁰C. The LiCl buffer is also enriched in potassium ions, causing a depolarizing stimulus to the cells. Such a buffer may have the composition (mM): LiCl 100, KCl 50, MgSO₄ 0.81, CaCl₂ 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. To enhance signal-to-noise ratio, an effective concentration (for example 100 μM) of the voltage-gated sodium channel opener veratridine, or any other suitable voltage-gated sodium channel opener, may be added to the medium to enhance signal detection. Furthermore, and also to enhance signal-to-noise ratio, an effective concentration (for example 10 μg/ml) of suitable scorpion venom may also be added to the medium to delay channel inactivation. In order to find a modulator of the voltage-gated sodium channel of interest, the assay can be complemented with compounds from a compound library. Compounds of interest are added to the Li-rich solution, one in each well. At the end of the incubation period cells are repeatedly washed with Na free buffer until all extracellular LiCl is removed. Cell lysis is obtained through incubation of cells with triton (1%) for 15 min, or any other suitable method. The resulting cell lysate is then introduced into an atomic absorption spectrophotometer, thus quantifying the amount of Li-influx during the procedure described above.

The described assay can be run with any atomic absorption spectrophotometer using plates of 96-well format, 384-well format, or any other conventional plate format. The described assay can be applied to cell lines expressing any given one or more of the voltage-gated sodium channel alpha subunits, as well as any given combination of one of the voltage- gated alpha subunits with any one or more beta subunit.

If needed the cell line of choice can be further hyperpolarised by expression of a suitable potassium leak ion channel, for example TREK-I, either by transient co-transfection or through establishment of a stable co-transfected cell line. The successful expression of a leak K current can be verified using traditional intracellular electrophysiology, either in whole cell patch-clamp, perforated patch-clamp or conventional two-electrode voltage- clamp. A cell line of choice modified to successfully express a voltage-gated sodium channel of interest together with a suitable potassium leak ion channel transfected can then be used for screening using atomic absorptions spectrometry, as described above.

Whole-cell voltage clamp electrophysiology assay Electrophysiological recordings of sodium currents in cells stably expressing the voltage- gated sodium channel of interest confirms activity and provides a functional measure of the potency of compounds that specifically affect such channels.

Electrophysiological studies can be performed using automated patch-clamp electrophysiology platforms, like Ion Works HT, Ion Works Quattro, PatchXpress, or any other suitable platform. The cell line expressing the voltage-gated sodium channel of interest is plated in appropriate well tissue plates, as provided by the manufacturer of the automated patch-clamp platforms. Suitable extracellular and intracellular buffer for such experiments are applied according to the instructions given by the manufacturer of the automated patch-clamp platforms. Cells that express the voltage-gated sodium channel protein of interest are exposed to drugs through the pipetting system integrated in the platforms. A suitable voltage stimulus protocol is used to activate the voltage-gated sodium channel proteins of interest. A suitable stimulus protocol may consist of eight voltage pulses, each to -20 mV and 50 ms in length, and separated from each other by 330 ms intervals at a potential of -90 mV or -65 mV, but may also have other suitable parameters.

Electrophysiological studies can also be performed using the whole cell configuration of the standard patch clamp technique as described in the literature. In this assay, cells that express the human voltage-gated sodium channel protein of interest are exposed to the drugs by conventional microperfusion systems and a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channels. Example

Title compounds of the above Examples were tested in Whole-cell voltage clamp electrophysiology assay described above and were found to exhibit pIC50 values as shown in the table below.

In vivo experiments

A compound of the invention when given by systemic injection to mice or rats, may specifically reduce pain behavior in the formalin test. This test is an accepted model of clinical pain in man, involving elements of nociceptor activation, inflammation, peripheral sensitization and central sensitization (A Tjølsen et al. Pain 1992, 51, 5). It can therefore be inferred that a compound of the present invention is usefulas a therapeutic agent to relieve pain of various origins.

Compounds of formula I may showin analgesic activity in the intraarticular FCA (Freund's complete adjuvant) test in the rat, a model of inflammatory pain fladarola et al. Brain Research 1988, 455, 205-12J and in the Chung nerve lesion test in the rat, a model for neuropathic pain (Kim and Chung. Pain 1992, 50, 355). The analgesic effects in the animal models may be obtained after doses that do not produce tissue concentrations leading to conduction block in nerve fibers. Thus, the analgesic effects can not be explained by the local anesthetic properties of the compounds mentioned in the publication by Kornet and Thio. Analgesic efficacy after systemic administration is not a general property of drugs with local anesthetic effects (Scott et al. British Journal of Anaesthesia 1988, 61, 165-8).

Claims

Claims:

1. A compound of Formula I

wherein: Y is selected from -NH₂,; -OH; -NHSO₂CH₃; Ci_-3alkoxy; and H;

R¹ is selected from H; C^aUcyl; d-efluoroalkyl; Ci-₆alkoxyalkyl; C₂-₆alkenyl; and C₂-₆alkynyl;

R is selected from H; C_1-6alkyl; C_1-6 fluorooalkyl;

C_3-6alkenyl; C_3-6alkynyl; C_3-7Cycloalkyl; Ci_₆alkanoyl; Ci-₆alkanesulfonyl; C₆-i₂arylalkyl; a 5- or 6-membered heteroaryl containing at least one nitrogen atom; phenyl; and C i-6 hydroxyalkyl;

R is selected from H; C_1-4alkyl;

Ci-₆alkoxyalkyl; C₂-₆alkenyl; and C_2-6alkynyl;

R⁴ and R⁵ is each and independently selected from H; halo; -NO2; -CN; carbamoyl; sulphamoyl; C_1-6alkyl; C_1-6haloalkyl; Ci_6alkoxy; Ci-όhaloalkoxy; C_2-6alkenyl; C_2-6alkynyl; C_1-6alkanoyl; C_1-6alkanoyloxy; 7V-(C_1-6alkyl)amino; N,7V-(C_1-6alkyl)_ncarbamoyl wherein n is 0-2; Ci-6alkylS(O)a wherein a is 0 to 2; C_1-6alkoxycarbonyl; TV-(C _1-6alkyl)sulphamoyl; iV,iV-(C_1-6alkyl)₂sulphamoyl; and Ci_-6alkylsulphonylamino; R⁶ and R⁷ is each and independently selected from H; halo; -NO₂; -CN; carbamoyl; sulphamoyl; C_1-6alkyl; Ci-δhaloalkyl; Ci_6alkoxy; Ci-δhaloalkoxy; C₂-6alkenyl; C₂-6alkynyl; Ci_6alkanoyl; Ci_6alkanoyloxy; Λ/-(Ci-6alkyl)amino; Λ/,Λ/-(Ci.6alkyl) _ncarbamoyl wherein n is 0-2; Ci_-6alkylS(O)_a wherein a is 0 to 2; Ci_-6alkoxycarbonyl; TV-(C i_-6alkyl)sulphamoyl; Λ/,Λ/-(Ci.6alkyl)₂Sulphamoyl; Ci-6alkylsulphonylamino; 5- or 6-membered heterocyclyl; and a 5- or 6-membered heteroaryl containing at least one nitrogen atom;

R⁸ is selected from halo; Ci_₆alkyl; Ci-_δhaloalkyl; Ci_₆alkoxy; C₂-₆alkenyl; C₂-₆alkynyl; C_3-6carbocyclyl; Ci_-6alkyl-O-; Ci_-6haloalkyl-O-; C_3-4 cycloalkyl-O-;

Ci-δhaloalkyl-S-; and C^carbocyclyl-S-;

R⁹ is selected from C_2-6alkyl; Ci_-6fluoroalkyl; Ci_-4alkoxyalkyl-Ci_-4 alkyl; C_3-6cyanoalkyl; C_2-6alkenyl; C_2-6alkynyl; C_3-7carbocyclyl; C_3-8carbocyclylalkyl; C_3-8carbocyclylalkynyl; C₂-6 fluoroalkylsulfonyl; C₂-6alkylsulfanyl; C₂-6 alkoxy; Ci-δfluoroalkoxy; C_3-6alkylsulfonyl; C_3-6alkylsulfinyl; phenyl; as well as a pharmaceutically acceptable salt or optical isomer thereof, or a salt of said optical isomer.

2. A compound according to claim 1, wherein

Y is selected from H; -NH₂; -OH; and -NHSO₂CH₃;

R¹ is selected from H; and C_1-6alkyl;

R² is selected from H; C_1-6alkyl; Ci-ofluoroalkyl; C_3-7cycloalkyl; Ci_₆alkanoyl;

Ci_-6 hydroxyalkyl; Ci_-6alkanesulfonyl; C_6-i₂arylalkyl; phenyl; and pyridinyl; R³ is H or Ci-ealkyl;

R⁴ and R⁵ is each and independently selected from H and

R⁶ and R⁷ is each and independently selected from H; hal

Ci-δfluoroalkoxy;

-OCF₃; and pyrimidine;

R⁸ is selected from halo; C_1-6alkyl; and C_1-6alkoxy; and R⁹ is selected from C₂-₆alkyl; C₂-₆haloalkyl; C₃_₆Cyanoalkyl; C₂-₆alkoxy; and C2-6haloalkoxy.

3. A compound according to claim 2, wherein Y is OH.

4. A compound according to claim 2, wherein Y is H.

5. A compound according to claim 2, wherein Y is NH2.

6. A compound according to claim 2, wherein Y is

7. A compound according to any one of claims 1-6, wherein R¹ is hydrogen or methyl..

8. A compound according to any one of claims 1-7, wherein R² is selected from benzyl; phenyl; pyridinyl; hydrogen; methyl; ethyl; cyclopropyl; i-propyl; -CH₂-CH₂-OH; -CH₂-CH₂-O-CH₃; -CH₂-CH₂-CH₂-F; and -SO₂-CH₃.

9. A compound according to any one of claims 1-8, wherein R³ is hydrogen or methyl.

10. A compound according to any one of claims 1-9, wherein R⁴ is hydrogen or methoxy.

11. A compound according to any one of claims 1-0, wherein R⁵ is hydrogen.

12. A compound according to any one of claims 1-11, wherein R⁶ is selected from hydrogen; methoxy; and -OCF₃.

13. A compound according to any one of claims 1-12, wherein R⁷ is selected from hydrogen; chloro; and pyrimidine.

14. A compound according to any one of claims 1-3, wherein R⁸ is selected from methoxy; ethoxy; methyl; and chloro.

15. A compound according to any one of claims 1-14, wherein R⁹ is selected from phenyl; butyl; i-butyl; -0-CH-(CH₂F)₂;. -C-(CH₃)₂-CN; -(CH₂)_3-F; CF₃; -0-CF₃; -0-CH₂-CH₂-CF₃; -CH₂-CH₂-C-(CH₃)(F₂); -CH₂-C-(CH₃)₂-F; (CH₃)₂-CH-O-; -C-(CH₃)₂-O-CH₃; and -0-CH-CF₃.

16. A compound according to claim 15, wherein R⁹ is bonded to the phenyl ring at para- position in relation to R⁸.

17. A compound according to any one of the preceding claims, selected from any one of:

• 2-Benzyl-4-(5-tert-butyl-2-methoxyphenyl)-5,7-dimethoxy-l,2,3,4- tetrahydroisoquinolin-4-ol; • 4-{5-[2-fluoro-l-(fluoromethyl)ethoxy]-2-methoxyphenyl}-2-methyl-l,2,3,4- tetrahydroisoquinolin-4-ol;

• 2-Benzyl-4-(5-tert-butyl-2-methoxyphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-cyclopropyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 2-Benzyl-4-(5-isopropoxy-2-methoxyphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol; • 2-Benzyl-4-(5-tert-butyl-2-methoxyphenyl)-3 -methyl- 1 ,2,3,4-tetrahydroisoquinolin-4- ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-8-chloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4- ol;

• 4-(5-tert-Butyl-2-methoxy-phenyl)-2-benzyl-7-trifluoromethoxy-l,2,3,4-tetrahydro- isoquinolin-4-ol;

• 2-Benzyl-4-(5-tert-butyl-2-ethoxyphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol; • 2-Benzyl-4-(2-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-l,2,3,4- tetrahydroisoquinolin-4-ol;

• 2-Benzyl-4-(5-butyl-2-methylphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-[5-(3-Fluoropropyl)-2-methoxyphenyl]-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol; • 4-(5-tert-Butyl-2-methoxyphenyl)- 1 ,2-dimethyl- 1 ,2,3 ,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2,3-dimethyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-ethyl-5,7-dimethoxy-l,2,3,4- tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-isopropyl-5,7-dimethoxy-l, 2,3,4- tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-5,7-dimethoxy-2-(2-methoxyethyl)-l,2,3,4- tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-5,7-dimethoxy-2-(pyridin-4-yl)-l,2,3,4- tetrahydroisoquinolin-4-ol; • 4-(5-tert-Butyl-2-methoxyphenyl)-2-(pyridin-4-yl)-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-ethyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 2-[3-(2-Ethyl-4-hydroxy - 1 ,2,3,4-tetrahydroisoquinolin-4-yl)-4-methoxyphenyl]-2- methylpropanenitrile;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-(3-fluoropropyl)-l,2,3,4-tetrahydroisoquinolin-4- ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-5,7-dimethoxy-2-methyl- 1,2,3,4- tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-7-trifluoromethoxy-l,2,3,4-tetrahydro- isoquinolin-4-ol; • 4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 2-Ethyl-4-(2-methyl-5-trifluoromethylphenyl)-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(2-Methoxy-5-(trifluoromethoxy)phenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-4- ol; • 2-(3 -(4-Hy droxy-2 -methyl- 1 ,2,3,4-tetrahydroisoquinolin-4-yl)-4-methoxyphenyl)-2- methylpropanenitrile; • 2-(3-(4-Hydroxy-l,2,3,4-tetrahydroisoqumolm-4-yl)-4-methoxyphenyl)-2- methylpropanenitrile;

• 4-(5-Butyl-2-methoxyphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-[5-(3,3-Difluorobutyl)-2-methoxyphenyl]-2-methyl-l,2,3,4-tetrahydroisoquinolin-4- ol;

• 4-(5-tert-Butyl-2-chlorophenyl)-2 -methyl- 1, 2, 3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-Isopropoxy-2-methoxyphenyl)-2 -methyl- l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-3-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-ethoxyphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol; • 4-(2-Methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-2-methyl-l,2,3,4- tetrahydroisoquinolin-4-ol;

• 4-(5-Butyl-2-methylphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinoline;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-amine; • N-(4-(5-tert-Butyl-2-methoxyphenyl)-2-methyl-l ,2,3,4-tetrahydroisoqumolin-4- yl)methanesulfonamide;

• 4-(5-tert-Butyl-2-methoxyphenyl)-2-(methylsulfonyl)-l,2,3,4-tetrahydroisoqumolin-4- ol;

• 4-(2-Methoxy-5-((3 ,3 j3j-trifluoro-propoxy)-phenyl)-7-trifluoromethoxy- 1,2,3,4- tetrahydro-isoquinolin-4-ol;

• 4-[2-Methoxy-5-(l-methoxy-l-methyl-ethyl)-phenyl]-7-trifluoromethoxy- 1,2,3,4- trtrahydroisoquinolin-4-ol;

• 4-[5-(3-Fluoro-3-methyl-butyl)-2-methoxy-phenyl]-2-methyl-l,2,3,4-tetrahydro- isoquinolin-4-ol; • 4-[5-(3-fluoro-3-methyl-butyl)-2-methoxy-phenyl]-l,2,3,4-tetra-hydro-isoquinolin-4- ol;

• 2-Benzyl-4-(4-methoxy-biphenyl-3-yl)-l,2,3,4-tetrahydro-isoquinolin-4-ol;

• 4-(5-tert-Butyl-2-methoxy-phenyl)-2-hydroxy-ethyl-l,2,3,4-tetrahydroisoquinolin-4-ol;

• 2-Benzyl-8-bromo-4-(5-tert-butyl-2-methoxy-phenyl)-l,2,3,4-tetrahydro-isoquinolin-4- ol; • 2-Benzyl-4-(5-tert-butyl-2-methoxy-phenyl)-8-pyrimidin-5-yl-l,2,3,4-tetrahydro- isoquinolin-4-ol;

• 4-[5-(2-Fluoro-2-methyl-propyl)-2-methoxy-phenyl]-7-methoxy-l,2,3,4-tetrahydro- isoquinolin; and • 2-Methyl-4-[5-(2-Fluoro-2-methyl-propyl)-2-methoxy-phenyl]-7-methoxy-l,2,3,4- tetrahydro-isoquinolin.

18. A compound according to any one of the preceding claims, for use in therapy.

19. Use of a compound according to any one of claims 1-17, for the manufacture of a medicament for use in the treatment of a pain disorder.

20. A method for the treatment of a pain disorder, whereby a compound according to any one of claims 1-17 is administered to a subject in need of such pain treatment.

21. A compound according to any one of claims 1-17, for use in the treatment of a pain disorder.

22. A compound selected from

7-Trifluoromethoxy-2,3-dihydro-4(lH)-isoquinolinone;

8-Chloro-2,3-dihydro-4(lH)-isoquinolinone; and 2-Benzyl-l-methyl-2,3-dihydro-4(lH)-isoquinolinone.

Box No. I! Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)

This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:

1- [3 Claims Nos.: 20 because they relate to subject matter not required to be searched by this Authority, namely:

Claim 20 relates to a method for treatment of the human or animal body by surgery or by therapy, as well as diagnostic

2- Q] Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically:

3. Q] Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).

Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet)

This International Searching Authority found multiple inventions in this international application, as follows:

1. r~] AS all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims.

2. Qj As all searchable claims could be searched without effort justifying an additional fees, this Authority did not invite payment of any additional fees.

3. [^""J AS only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.:

4. Qj NO required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.:

Remark on Protest Q] The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee. Qj The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation. Q] No protest accompanied the payment of additional search fees.

Form PCT/ISA/210 (continuation of first sheet (2)) (July 2008) Box II . 1 methods, see PCT rule 39.1(iv). Nevertheless, a search has been made for this claim. The search has been directed to the technical content of the claim.

Form PCT/ISA/210 (extra sheet) (July 2008)