WO2006052190A1 - Indazole sulphonamide derivatives - Google Patents

Abstract

Compounds of formula I or pharmaceutically acceptable salts thereof: Formula (I) wherein R1, R2, R3 and R8 are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

Description

INDAZOLE SULPHONAMIDE DERIVATIVES

BACKGROUND OF THE INVENTION 1. Field of the invention

The invention is related to therapeutic compounds which are CB₁ receptor ligands, pharmaceutical compositions containg these compounds, manufacturing processes thereof and uses thereof, and more particularly to compounds that are CB₁ receptor agonists. More particularly, the present invention is related to compounds that may be effective in treating pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiavascular disorders.

2. Discussion of Relevant Technology Pain management has been an important field of study for many years. It has been well known that cannabinoid receptor (e.g., CB₁ receptor, CB₂ receptor) ligands including agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CB₁ and/or CB₂ receptors. Generally, CB₁ receptors are located predominately in the central nervous system, whereas CB₂ receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system.

While CB₁ receptor agonists, such as Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and anadamide, are useful in anti-nociception models in animals, they tend to exert undesired CNS side-effects, e.g., psychoactive side effects, the abuse potential, drug dependence and tolerance, etc. These undesired side effects are known to be mediated by the CB₁ receptors located in CNS. There are lines of evidence, however, suggesting that CB 1 agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile. Therefore, there is a need for new CB₁ receptor ligands such as agonists, antagonists or inverse agonists that are useful in managing pain or treating other related symptoms or diseases with reduced or minimal undesirable CNS side-effects.

DISCLOSURE OF THE INVENTION The present invention provides CB₁ receptor ligands which are useful in treating pain and other related symptoms or diseases.

Definitions Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version

5.09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada. "CB₁ZCB₂ receptors" means CBj and/or CB₂ receptors. 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, and having 0 to n multivalent heteroatoms selected from O, S, N and P, wherein m and n are 0 or positive integers, and n>m. For example, "C_1-6" would refer to a chemical group having 1 to 6 carbon atoms, and having 0 to 6 multivalent heteroatoms selected from O, S, N and P.

The term "hydrocarbon" used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms. The term "hydrocarbon radical" or "hydrocarbyl" used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon.

The term "alkyl" used alone or as a suffix or prefix, refers to monovalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms. Unless otherwise specified, "alkyl" general includes both saturated alkyl and unsaturated alkyl.

The term "alkylene" used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together. 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 least 2 up to ^:about 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 at least 2 up to about 12 carbon atoms.

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

The term "cycloalkenyl" used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms. The term "cycloalkynyl" used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon triple bond and comprising about 7 up to about 12 carbon atoms.

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

The term "non-aromatic group" or "non-aromatic" used alone, as suffix or as prefix, refers to a chemical group or radical that does not containing a ring having aromatic character (e.g., 4n + 2 delocalized electrons). The term "arylene" used alone or as suffix or prefix, refers to a divalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, which serves to links two structures together.

The term "heterocycle" used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s). Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or unfused. Fused rings generally refer to at least two rings share two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character. The term "heteroalkyl" used alone or as a suffix or prefix, refers to a radical formed as a result of replacing one or more carbon atom of an alkyl with one or more heteroatoms selected from N, O, P and S.

The term "heteroaromatic" used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring- containing structure or molecule has an aromatic character (e.g., 4n + 2 delocalized electrons). The term "heterocyclic group," "heterocyclic moiety," "heterocyclic," or

"heterocyclo" used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.

The term "heterocyclyl" used alone or as a suffix or prefix, refers a monovalent radical derived from a heterocycle by removing one hydrogen from a carbon of a ring of the heterocycle.

The term "heterocyclylene" used alone or as a suffix or prefix, refers to a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to links two structures together.

The term "heteroaryl" used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character, wherein the radical of the heterocyclyl is located on a carbon of an aromatic ring of the heterocyclyl.

The term "heterocylcoalkyl" used alone or as a suffix or prefix, refers to a heterocyclyl that does not have aromatic character.

The term "heteroarylene" used alone or as a suffix or prefix, refers to a heterocyclylene having aromatic character.

The term "heterocycloalkylene" used alone or as a suffix or prefix, refers to a heterocyclylene that does not have aromatic character.

The term "six-membered" used as prefix refers to a group having a ring that contains six ring atoms. The term "five-membered" used as prefix refers to a group having a ring that contains five ring atoms.

A five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, O and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl. A six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.

Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term "substituted" used as a prefix refers to a structure, molecule or group, wherein one or more hydrogens are replaced with one or more

Q.^hydrocarbon groups, or one or more chemical groups containing one or more heteroatoms selected from N, O, S, F, Cl, Br, I, and P. Exemplary chemical groups containing one or more heteroatoms include heterocyclyl, -NO₂, -OR, -Cl, -Br, -I, -F, -CF₃, -C(O)R, -C(O)OH, -NH₂, -SH, -NHR₃ -NR₂, -SR, -SO₃H, -SO₂R, -S(O)R, - CN, -OH, -C(O)OR₅ -C(O)NRa, -NRC(O)R, oxo (O), imino (=NR), thio (=S), and oximino (=N-OR), wherein each "R" is a C_Mahydrocarbyl. For example, substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring. The term "substituted" used as a suffix of a first structure, molecule or group, followed by one or more names of chemical groups refers to a second structure, molecule or group, which is a result of replacing one or more hydrogens of the first structure, molecule or group with the one or more named chemical groups. For example, a "phenyl substituted by nitro" refers to nitrophenyl. The term "optionally substituted" refers to both groups, structures, or molecules that are substituted and those that are not substituted.

Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5- dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-lH^~-azepine homopiperazine, 1,3-dioxepane, 4,7- dihydro-l,3-dioxepin, and hexamethylene oxide.

In addition, heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazole, tetrazole, 1,2,3- thiadiazole, 1,2,3-oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4- triazole, 1,3,4-thiadiazole, and 1,3,4- oxadiazole.

Additionally, heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3 -dihydrobenzo furan, isobenzo furan, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2- benzisoxazole, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine.

In addition to the polycyclic heterocycles described above, heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.

Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro- pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3- dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-l/i-azepinyl, homopiperazinyl, 1,3- dioxepanyl, 4,7-dihydro-l,3-dioxepinyl, and hexamethylene oxidyl.

In addition, heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.

Additionally, heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4- benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3- dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, perimidinyl, plienanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl, and quinolizidinyl.

In addition to the polycyclic heterocyclyls described above, heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1Jheptyl.

The term "alkoxy" used alone or as a suffix or prefix, refers to radicals of the general formula — O-R, wherein -R is selected from a hydrocarbon radical. Exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy.

The term "aryloxy" used alone or as suffix or prefix, refers to radicals of the general formula -O-Ar, wherein -Ar is an aryl. The term "heteroaryloxy" used alone or as suffix or prefix, refers to radicals of the general formula -O-Ar¹, wherein -Ar' is a heteroaryl.

The term "amine" or "amino" used alone or as a suffix or prefix, refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbon radical. " Acyl" used alone, as a prefix or suffix, means -C(=O)-R, wherein -R is an optionally substituted hydrocarbyl, hydrogen, amino or alkoxy. Acyl groups include, 'for example, acetyl, propionyl, benzoyl, phenyl acetyl, carboethoxy, and dimethylcarbamoyl. Halogen includes fluorine, chlorine, bromine and iodine.

"Halogenated," used as a prefix of a group, means one or more hydrogens on the group is replaced with one or more halogens.

¹¹RT" or "rt" means room temperature. A first ring group being "fused" with a second ring group means the first ring and the second ring share at least two atoms therebetween.

"Link," "linked," or "linking," unless otherwise specified, means covalently linked or bonded.

When a first group, structure, or atom is "directly connected" to a second group, structure or atom, at least one atom of the first group, structure or atom forms a chemical bond with at least one atom of the second group, structure or atom.

"Saturated carbon" means a carbon atom in a structure, molecule or group wherein all the bonds connected to this carbon atom are single bond. In other words, there is no double or triple bonds connected to this carbon atom and this carbon atom generally adopts an sp³ atomic orbital hybridization.

"Unsaturated carbon" means a carbon atom in a structure, molecule or group wherein at least one bond connected to this carbon atom is not a single bond. In other words, there is at least one double or triple bond connected to this carbon atom and this carbon atom generally adopts a sp or sp² atomic orbital hybridization.

Description of Preferred Embodiments

In one aspect, the invention provides a compound of formula I, pharmaceutically acceptable salts thereof, diastereomers, enantiomers, or mixtures thereof:

I wherein

R¹ is selected from hydrogen, Q.ioalkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C₄-₈cycloalkenyl, Ca-iocycloalkyl-Cμ_δalkyl, C_4-8cycloalkenyl- C_1-6alkyl, C_3-5heteroaryl, C₆-ioaryl, C₆.₁₀aryl-C_1-6alkyl, C₃.₆heterocycloa.kyl, C_{3- 6}heterocycloallcyl-Ci_₆alkyl or Ci_-6alkoxycarbonyl; wherein said C_1-10alkyl₅ C_{2- l}oalkenyl, C_2-10allcynyl, C_3-10cycloalkyl, C_4-8CyClOaIlCeIIyI, C_3-iocycloalkyl-Ci_-6alkyl, C_4-8cycloalkenyl-C_1-6alkyl, C_3-5heteroaryl, Cβ-ioaryl, C_6-ioaryl-C_1-6alkyl, C_{3- 6}heterocycloalkyl, C_3-6heterocycloalkyl-C_1-6alkyl or C_1-6alkoxycarbonyl used in defining R² is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; with one or more substituents selected from C^aUcyl, C_2-6alkenyl, halogen, Q.βalkoxy, amino, cyano, oxo, nitro, hydroxy, Co-ioaryl, C_6-1oaryl-C_1-6alkyl, C_3-6heterocyclyl and C_{3- ό}heterocyclyl-Ci-βalkyl;

R² is selected from hydrogen, C_1-1OaIlCyI, Ca-ioalkenyl, C_2-ioalkynyl, C_3-10cycloalkyl, C_4-scycloalkenyl, Q.iocycloalkyl-d-_δalkyl, C_4-scycloalkenyl- C_1-6alkyl, C_3-5heteroaryl, C_6-1oaryl, C_6-1OaIyI-C_{1 -6}alkyl, C_3-6heterocycloalkyl, C_{3- 6}heterocycloalkyl-C_1-6alkyl or C_1-6alkoxycarbonyl; wherein said Q.ioalkyl, C₂, ₁₀alkenyl, C2-i_Oalkynyl, C_3-1ocycloaU<yl, C₄.₈cycloalkenyl,

C_4-8Cy cloalkenyl-d-βalkyl, C_3-5heteroaryl, C_6-1oaryl, C_6-10aryl-C_1-6alkyl, C_{3- 6}heterocycloalkyl, C₃.₆heterocycloalkyl-C_1-6alkyl or C_1-6alkoxycarbonyl used in defining R² is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; with one or more substituents selected from C_1-6alkyl, C_2-6alkenyl, halogen, C^alkoxy, amino, cyano, oxo, nitro, hydroxy, C_6-10aryl, C_6-1oaryl-d -6alkyl, C_3-6heterocyclyl and C_{3- 6}heterocy cly 1-C 1 _-6alkyl; optionally R¹ and R² together with the N to which they are bound may form a 3-10 membered aromatic, heteroaromatic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally substituted by one or more groups independently selected from hydrogen, Chalky!, C_2-6alkenyl, C_2-6alkynyl, halogen, amino, C^alkoxy, C_1-6alkoxy-C_1-6alkyl, d.₆alkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy; R³ is selected from hydrogen, halogen, amino, C_1-10alkyl, C_2-1oalkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-1ocycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl-C₁.₆alkyl, C_3-6heterocycloalkyl-Ci_-6alkyl, C_4-8cycloalkenyl, R⁴R⁵N-, C_3-5heteroaryl, C₆.₁₀aryl and C_3-6heterocycloalkyl, wherein said amino, C_1-1OaIlCyI, C_2-10alkenyl, C_2-ioalkynyl, C_3- iocycloalkyl, Cs.iocycloalkyl-d-_όalkyl, C_4-8cycloahcenyl-C_1-6alkyl, C_3-6heterocycloalkyl-C_1-6alkyl, C4.₈cycloalken.yl, R⁴R⁵N-, C_3-5heteroaryl, C₆.₁₀aryl and Cs-eheterocycloalkyl used in defining R³ is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; wherein R⁴ and R⁵ are independently selected from -H, C_1-6alkyl, C_2-6alkenyl,

C_2-6alkynyl, and a divalent C_1-6group that together with another divalent R⁴ or R⁵ may form a ring or a portion of a ring wherein said ring is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl and hydroxy; and R⁸ is selected from C_3-10cycloalkyl, C_4-scycloalkenyl, C^iocycloalkyl-Cu

₆alkyl, C_4-8cycloalkenyl-C_1-6alkyl, C_6-10aryl, C_6-10aryl-Ci_-6alkyl, C_3-6heterocyclyl, C₃. ₆heterocyclyl-C_1-6alkyl, C_6-10aryl-C(=O)-C_1-6alkyL C_3-6heterocyclyl-C(=O)-C_1-6alkyl, C_1-10hydrocarbylamino, C_6-1oaryl-C(=0)-, or C_3-6heterocyclyl-C(=0)-; wherein said

C_4-8cycloalkenyl, C_3-10cycloalkyl-Ci.₆alkyl, C_4-8cycloalkenyl- C^alkyl, C₆.ioaryl, C_ό-ioaryl-Cuealkyl, C₃.₆heterocyclyl, C₃.₆heterocyclyl-C_1-6alkyl, C_6-1oaryl-C(=0)-C_1-6alkyl, C_3-6heterocyclyl-C(=O)-Ci_-6alkyl, Ci.iohydrocarbylamino, C_6-10aryl-C(=O)-, or C₃.₆heterocyclyl-C(=O)- used in defining R⁸ is optionally substituted by one or more groups selected from hydrogen, Ci.₆alkyl, C_2-6alkenyl, halogen, C^alkoxy, amino, cyano, oxo, nitro, hydroxy and -NR⁴R⁵.

Particularly, the compounds of the present invention are those of formula I, wherein

R¹ is selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C₂_₆alkynyl, C_3-1ocycloalkyl, C_4-6cycloalkenyl, C_3-10cycloalkyl-Ci_-6alkyl, C_4-scycloalkenyl- Ci_-6alkyl, phenyl, ρhenyl-C_1-4alkyl, C^eheterocyclyl, C_3-6heterocyclyl-C_1-6alkyl or C_1-4alkoxycarbonyl; wherein said Ci.₆alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C₄.₆cycloalkenyl, C₃.₁₀cycloalkyl-Ci_-6aUcyl, C_A-scycloalkenyl-Q-ealkyl, phenyl, phenyl-C_1-4alkyl, C^heterocyclyl, C_3-6heterocyclyl-C₁.₆alkyl or Ci.₄alkoxycarbonyl used in defining R¹ is optionally substituted by one or more groups selected from halogen, C^alkyl, C_2-4alkenyl, C_1-4alkoxy, amino, oxo, cyano, nitro, hydroxy, C_6- ioaryl, C_6-10aryl-C_1-4alkyl, C₃.₆heterocyclyl, Cs^heterocyclyl-Q^alkyl and -NR⁴R⁵;

R² is selected from hydrogen, Ci.₆alkyl, C₂.₆alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_4-6cycloalkenyl,

C₄.₈cycloalkenyl- C_1-6alkyl, phenyl, phenyl-C_1-4alkyl, C_3-6heterocyclyl, C_3-6heterocyclyl-C_1-6alkyl or Ci_-4alkoxycarbonyl; wherein said C_1-6alkyl, C₂_₆alkenyl, C_2-6alkynyl, C^ocycloalkyl, C_4-6cycloalkenyl, C_3-1ocycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl-C_1-6alkyl, phenyl, phenyl-Ci_-4alkyl, C_3-6heterocyclyl, C_3-6heterocyclyl-Ci.₆alkyl or C_1-4alkoxycarbonyl used in defining R² is optionally substituted by one or more groups selected from halogen, C_1-4alkyl, C_2-4alkenyl, Cj_-4alkoxy, amino, oxo, cyano, nitro, hydroxy, C_{6- 10}aryl, Cό-ioaryl-C_Malkyl, C^heterocyclyl, C_3-6heterocyclyl-Ci_-4alkyl and -NR⁴R⁵; R¹ and R² can form together with the N to which they are bound may form a 3-6 membered aromatic, heteroaromatic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally substituted by one or more groups independently selected from hydrogen, C^aUcyl, C_2-4alkenyl, C_2-4alkynyl, halogen, amino, C_1-4alkoxy, C_1-4alkoxy-Ci_-4alkyl, C_1-4alkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy;

R³ is selected from hydrogen, halogen, amino, C_1-6alkyl, C_2-6alkenyl, C_{2- 6}alkynyl, C_3-6cycloalkyl, C_4-6cycloalkenyl, C_3-5heteroaryl, R⁴R⁵N-, C₃,₆cycloalkyl-Ci. ₄alkyl, C₄.6cycloalkenyl-Ci_-4alkyl, phenyl, phenyl-C_1-4alkyl, C_3-6heterocyclyl or C_{3- 6}heterocyclyl-C_1-4alkyl; wherein said amino, Q^alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6CyClOaIlCyI, C₄.₆cycloalkenyl, C_3-5heteroaryl, R⁴R⁵N-, C_3-6cycloalkyl-C_1-4alkyl, C_4-6cycloalkenyl-C_1-4alkyl, phenyl, phenyl-C_1-4alkyl, C_3-6heterocyclyl or C_{3- 6}heterocyclyl-C_1-4alkyl used in defining R³ is optionally substituted by one or more groups selected from Ci_-4alkyl, C_2-4alkenyl, halogen, C_1-4alkoxy, amino, nitro, cyano, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, Q-ecycloalkyl-Q-ealkyl, C_{3- 6}heterocyclyl, Cs-eheterocyclyl-d-ealkyl, and -NR⁴R⁵; wherein R⁴ and R⁵ are independently selected from -H, C_1-4alkyl, C_2-6alkenyl, C_2-6alkynyl, and a divalent C_1-6group that together with another divalent R⁴ or R⁵ may form a ring or a portion of a ring wherein said ring is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl and hydroxy; and

R⁸ is selected from C₃.₆cycloalkyl, C_3-6cycloalkyl-Ci.₄alkyl, C_4-6cycloalkenyl, C_6-1oaryl, phenyl, phenyl-C_1-4alkyl, C₃.₆heterocyclyl or C₃.₆heterocyclyl-C_1-4alkyl; wherein said C_3-6cycloalkyl, C_3-6CyClOaIlCyI-C_{1 -4}alkyl, C_4-6cycloalkenyl, C_6-1oaryl, phenyl, phenyl-C_1-4alkyl, C_3-6heterocyclyl or Ca-eheteroeyclyl-Ci^alkyl used in defining R⁸ is optionally substituted by one or more groups selected from Ci_-4alkyl, Q^alkoxy, halogen, cyano, amino, nitro, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵.

More particularly, the compounds of the present invention are those of formula I,

R¹ is selected from hydrogen, C_1-6alkyL C_2-4alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, C_4-6cycloalkenyl, C_4-8cycloalkenyl-C_1-6alkyl, C₃.₈cycloallcyl-C_1-4alkyl, phenyl,

C_3-6heterocyclyl, C_3-6heterocyclyl-Ci_-4alkyl or Ci_-2alkoxycarbonyl; wherein said Ci_-6alkyl, C₂.₄alkenyl, C_2-6alkynyl, C₃.scycloalkyl, C_4-6cycloalkenyl, C_4-8cycloalkenyl-C_1-6alkyl, C_3-8cycloalkyl-C_1-4alkyl, phenyl, phenyl- C_1-4alkyl, C₃.₆heterocyclyl, C_3-6heterocyclyl-Ci_-4alkyl or C_1-2alkoxycarbonyl used in defining R¹ is optionally substituted with one or more groups selected from Q^alkyl, halogen, C^alkoxy, amino, cyano, oxo, hydroxy, C_3-6heterocyclyl, C_3-6heterocyclyl- C_1-4alkyl, C_6-8aryl, C6-8aryl-C_1-4alkyl; R² is selected from hydrogen, C_1-6alkyl, C₂-₄alkeiiyl, C_2-6alkynyl,

C_3-8CyClOaIlCyI, C_4-6cycloalkenyl, C_4-8cycloalkenyl-C₁-₆alkyl, C₃.₈cycloalkyl-C_1-4alkyl, phenyl, phenyl-C₁,₄alkyl, C₃_₆heterocyclyl, C_3-6heterocyclyl-C_1-4alkyl or C_1-2alkoxycarbonyl; wherein said C_1-6alkyl, C₂.₄alkenyl, C_2-6alkynyl, C_3-scycloalkyl, C_4-6cycloalkenyl, C_4-8cycloalkenyl-C_1-6alkyl, C₃.₈cycloalkyl-C_1-4alkyl, phenyl, phenyl- C_1-4alkyl, Cs-όheterocyclyl, C_3-6heterocyclyl-Ci_-4alkyl or Ci_-2alkoxycarbonyl used in defining R² is optionally substituted with one or more groups selected from C_1-4alkyl, halogen, C_1-4alkoxy, amino, cyano, oxo, hydroxy, C_3-6heterocyclyl, C_3-6heterocyclyl- C_1-4alkyl, C_6-saryl, C₆.₈aryl-C_1-4alkyl;

R¹ and R² together with the N to which they are bound may form a group selected from 1,2,3,6-tetrahydro-pyridinyl, 1,2,3-oxadiazolyl, 1,2,3- thiadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4- triazolyl, 1,3,4- oxadiazolyl, 1,3,4-thiadiazolyl, 1,3,4-triazolyl, 1,3-dioxanyl, 1,3-dioxepanyl, 1,4-benzodioxanyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 2,3,4,7- tetrahydro-lH-azepinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuranyl, 2,3- dihydropyranyl, 2,5-dihydrofuranyl, 4,7-dihydro-l,3-dioxepinyl, azetidinyl, aziridinyl, benzofuranyl, chromanyl, chromenyl, dioxanyl, dioxolanyl, furazanyl, furyl, hexamethylene homopiperazinyl, imidazolidinyl, indazolyl, indolizinyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolyl, oxetanyl, oxidyl, oxiranyl, phenoxathiinyl, phthalazinyl, phenyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, quinazolinyl quinolinyl, quirioxalinyl sulfolanyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thienyl, thietanyl, thiranyl, thiomorpholinyl, thiophanyl, thiopyranyl, triazinyl and xanthenyl; wherein said 1,2,3,6-tetrahydro-pyridinyl, 1,2,3-oxadiazolyl, 1,2,3- thiadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4- triazolyl, 1,3,4- oxadiazolyl, 1,3,4-thiadiazolyl, 1,3,4-triazolyl, 1,3-dioxanyl, 1,3-dioxepanyl, 1,4-benzodioxanyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 2,3,4,7- tetrahydro-lH-azepinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuranyl, 2,3- dihydropyranyl, 2,5-dihydrofuranyl, 4,7-dihydro-l,3-dioxepinyl, azetidinyl, aziridinyl, benzofuranyl, chromanyl, chromenyl, dioxanyl, dioxolanyl, furazanyl, furyl, hexamethylene homopiperazinyl, imidazolidinyl, indazolyl, indolizinyl, isobenzofuranyl,. isochromanyl, isoindolinyl, isoqtiinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolyϊ, oxetanyl, oxidyl, oxiranyl, phenoxathiinyl, phthalazinyl, phenyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, quinazolinyl quinolinyl, quinoxalinyl sulfolanyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thienyl, thietanyl, thiranyl, thiomorpholinyl, thiophanyl, thiopyranyl, triazinyl and xanthenyl used in defining R¹ and R² together is optionally substituted by one or more groups selected from C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, hydrogen, halogen, amino, C_{1- 4}alkoxy, C_1-4alkoxy-C_1-2alkyl, C_1-3alkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy;

R³ is selected from hydrogen, halogen, amino, C_1-6alkyl, C_2-6alkenyl, C_3-6CyClOaIlSyI, C₃,₆cycloalkyl-C_1-4alkyl, C_3-6heterocyclyl or C_3-6heterocyclyl-C_1-4alkyl wherein said amino, C_1-6alkyl, C_2-6alkenyl, C_3-6cycloalkyl, C₃.6cycloalkyl-C_1-4alkyl, C_3-6heterocyclyl or C^heterocyclyl-C_Malkyl used in defining R³ is optionally substituted with one or more groups selected from Ci.₆alkyl, halogen,

methoxy, ethoxy, methyl, ethyl, hydroxy, C_3-6heterocyciyl, C₃.₆heterocyclyl-C_1-6alkyl and -NR⁴R⁵; wherein R⁴ and R⁵ are independently selected from -H, C_1-3alkyl, C₂.₄alkenyl,

C_2-4alkynyl, and a divalent C_1-4group that together with another divalent R⁴ or R⁵ may form a ring or a portion of a ring; wherein said ring is optionally substituted by one or more groups selected from methoxy, ethoxy, methyl, ethyl and hydroxy; and

R is selected from phenyl, allyl, phenyl-C_1-4alkyl, C₃.₆cycloalkyl-C_1-4alkyl, C_4-6cycloalkenyl-C_1-4alkyl, Cs-_όheterocycloalkyl, Cs._δheterocylcoalkyl-C_ϊ^alkyl, C_6- ioaryl, C_3-6CyClOaIlCyI₅ and C_4-6cycloalkenyl, wherein said phenyl, phenyl-Ci_-4alkyl, C_3-6Cy cloalkyl-C_1-4alkyl, C_4-6cycloalkenyl-C_1-4allcyl, C^heterocycloalkyl, C_{3- 6}heterocylcoalkyl-C_1-4alkyl, C_6-1oaryl, C_3-6cycloalkyl, and C_4-6cycloalkenyl, used in defining R⁸ is optionally substituted by one or more groups selected from C_1-4alkyl, d^alkoxy, halogen, amino, cyano, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵.

Most particularly, the compounds of the present invention are those of formula I, wherein R is selected from hydrogen, methyl, ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, buteήyl, cyclopropyl, cyclopentyl. eyclohexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl, 2-phenylethyl, pyrimidinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl; wherein the ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, eyclohexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl, 2-phenylethyl, pyrimidinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl used in defining R¹ is optionally substituted with one or more groups selected from C_1-3alkyl, halogen, C_1-3alkoxy, amino, cyano, oxo, hydroxy, pyrrolidinyl and phenylmethyl;

R is selected from hydrogen, methyl, ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, eyclohexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl, 2-phenylethyl, pyrimidinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl; wherein the ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydrothiopheriyl, phenyl, phenylmethyl, 2-phenylethyl, pyrimidinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl used in defining R² is optionally substituted with one or more groups selected from Ci_-3alkyl, halogen, Ci.₃alkoxy, amino, cyano, oxo, hydroxy, pyrrolidinyl and phenylmethyl; R¹ and R² together with the N to which they are bound may form a group selected from cylcohexyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl or morpholinyl; wherein said cylcohexyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl or morpholinyl used in defining R¹ and R² together is optionally substituted by one or more groups selected from C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, hydrogen, halogen, amino, C_1-4alkoxy, C_1-4alkoxy-C_1-2alkyl, Q^alkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy;

R³ is selected from hydrogen, Cl, diethylamino, cyclohexylmethylamino, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, t-butyl, n-butyl, 2-methyl-2- butyl, isopentyl, 2-methoxy-2-propyl, 2-hydroxyl-propyl, 1-methyl-propyl, 1,1- dimethyl-propyl, l,l-dimethyl-3-buten-l-yl, ethyl, 2-propyl and -NR⁴R⁵; wherein said diethylamino, cyclohexylmethylamino, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, t-butyl, n-butyl, 2-methyl-2-butyl, isopentyl, 2-methoxy- 2-proρyl, 2-hydroxyl-propyl, 1-methyl-propyl, 1,1-dimethyl-propyl, l,l-dimethyl-3- buten-1-yl, ethyl, 2-propyl and -NR⁴R⁵ used in defining R³ is optionally substituted with one or more groups selected from hydrogen and methyl; wherein R⁴ and R⁵ are independently selected from -H, Cϊ_-3alkyl, C₂.₄alkenyl, C_2-4alkynyl, and a divalent C_1-4group that together with another divalent R⁴ or R⁵ may form a group selected from morpholinyl and piperazinyl; wherein said morpholinyl and piperazinyl is optionally substituted by one or more groups selected from methoxy, ethoxy, methyl, ethyl and hydroxy; and R⁸ is selected from phenyl, allyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, tetrahydrofuranyl, 1- piperidinyl, N-methyl-2-piperidinyl and benzyl; wherein said phenyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, tetrahydrofuranyl, 1-piperidinyl, N-methyl-2-piperidinyl and benzyl used in defining R⁸ is optionally substituted by one or more groups selected from C_1-4alkyl, C_1-4alkoxy, fluorine, chlorine, amino, cyano, oxb, methoxy, ethoxy, methyl, ethyl, hydroxy, and trifluoromethyl.

It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I. The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.

It will also be appreciated that certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes. The present invention includes any geometrical isomer of a compound of Formula I. It will further be understood that the present invention encompasses tautomers of the compounds of the formula I.

It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of the formula I.

Within the scope of the invention are also salts of the compounds of the formula I. Generally, pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCl or acetic acid, to afford a physiologically acceptable anion. It may also be possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as^' a calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.

In one embodiment, the compound of formula I above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate. We have now found that the compounds of the invention have activity as pharmaceuticals, in particular as modulators or ligands such as agonists, partial agonists, inverse agonist or antagonists of CBl receptors. More particularly, the compounds of the invention exhibit selective activity as agonist of the CBl receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pairi caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction of the CBl receptor is present or implicated. Furthermore, the compounds of the invention may be used to treat cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiavascular disorders.

Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.

Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).

Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive - Ig - compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.

Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.

Also within the scope of the invention is the use of any of the compounds according to the formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.

A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby ari effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment.

Thus, the invention provides a compound of formula I, or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.

In a further aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The term "therapeutic" and "therapeutically" should be contrued accordingly. The term "therapy" within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders. The compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, acute pain, back pain, cancer pain, and visceral pain. In use for therapy in a warm-blooded animal such as a human, the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasaliy, intraperitoneal^, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.

In one embodiment of the invention, the route of administration may be orally, intravenously or intramuscularly.

The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient. For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid and liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents; it can also be an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound of, the invention, or the active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like. Tlie term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as sdϊid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or water propylene glycol solutions of. the active compounds may be liquid preparations suitable for parenteral administration. ^• Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

Depending on the mode of administration, the pharmaceutical composition will preferably include from 0.05% to 99%w (per cent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition.

A therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.

Within the scope of the invention is the use of any compound of formula I as defined above for the manufacture of a medicament.

Also within the scope of the invention is the use of any compound of formula I for the manufacture of a medicament for the. therapy of pain.

Additionally provided is the use of any compound according to Formula I for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, acute pain, back pain, cancer pain, and visceral pain.

A further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such therapy.

Additionally, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. Particularly, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.

Further, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.

In a further aspect, the present invention provides a method of preparing the compounds of the present invention. In one embodiment, the invention provides a process for preparing a compound of Formula II, comprising of the step of

II

reacting a compound of formula III,

ra with a compound OfR⁴R⁵NH to form the compound of formula III, wherein R¹ is selected from hydrogen, Ci.iQalkyl, C_2-10alkenyl, C_2-10alkynyl,

C_3-1ocycloalkyl, C_4-scycloalkenyl, Cs-iocycloalkyl-Ci-galkyl, C_4-8cycloalkenyl- Ci.ealkyl, C_3-5heteroaryl, C_6-i₀aryl, C_6-10aryl-Ci_-6alkyl, Cs-isheterocycloalkyl, C_{3- 6}heterocycloalkyl-C_1-6alkyl or Ci_-6alkoxycarbonyl; wherein said C^oalkyl, C_{2- 10}alkenyl, C_2-loalkynyl, C_3-10cycloalkyl, C_4-8cycloalkenyl, C₃.i₀cycloalkyl-Ci_-6alkyl, C_4-8cyc loalkeny 1-C₁.₆alkyl₃ C_3-5heteroaryl, C_6-1oaryl, C_δ-ioaryi-Q.galkyl, C₃,

₆heterocycloalkyl, C_3-6heterocycloalkyl-C_1-6alkyl or C_1-6alkoxycarbonyl used in defining R² is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; with one or more substituents selected from Ci_-6alkyl, C₂-₆alkenyl, halogen, C_1-6alkoxy, amino, cyano, oxo, nitro, hydroxy, C_6-1oaryl, C_6-10aryl-Ci_-6alkyl, C_3-6heterocyclyl and C_{3- 6}heterocy clyl-C i _-6alkyl;

R² is selected from hydrogen, C_1-10alkyl, C_2-1oalkenyl, C_2-10alkynyl, C_3-1ocycloalkyl, C4-scycloalkenyl,

C_4-8cycloalkenyl- C_1-6alkyl, C₃.₅heteroaryl, C_ό-^aryl, C_6-10aryl-C_1-6alkyl, Cs-oheterocycloalkyl, C_3- βheterocycloalkyl-Ci-όalkyl or C_1-6alkoxycarbonyl; wherein said

C_2- ioalkenyl, C_2-1oalkynyl, C_3-1OCyClOaIlCyI, C_4-8cycloalkenyl, Cs-iocycloalkyl-d-βalkyl, C_4-8cycloalkenyl-C_1-6alkyl, C_3-5heteroaryl, C₆.₁₀aryl, C_6-10aryl-C_1-6alkyl, C_{3- 6}heterocycloalkyl,

or Cμgalkoxycarbonyl used in defining R² is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; with one or more substituents selected from

amino, cyano, oxo, nitro, hydroxy, C_6-10aryl, C_ό-ioaryl-Q-_όalkyl, C_3-6heterocyclyl and C_{3- 6}heterocyclyl-C_1-6alkyl; optionally R¹ and R² together with the N to which they are bound may form a 3-10 membered aromatic, heteroaromatic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally substituted by one or more groups independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C₂.₆alkynyl, halogen, amino, C_1-6alkoxy, Q.galkoxy-Ci-όalkyl, C_1-6alkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy;

R³ is selected from hydrogen, halogen, amino, Ci.₁₀alkyl, C_2-i₀alkenyl, C_2-ioalkynyl, C_3-10cycloalkyl, C_3-1ocycloalkyl-C_1-6alkyl, C_4-scycloalkenyl-Ci_-6alkyl, Cs.eheterocycloalkyl-Cμgallcyl, C_4-scycloalkenyL R⁴R⁵N-, C_3-5heteroaryl, C_6-10aryl and Cs._δheterocycloalkyl, wherein said amino, Cuioalkyl, C_2-1oalkenyl, C_2-1oalkynyl, C_3- iocycloalkyl, C_3-1ocycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl-C_1-6alkyl, Cs-eheterocycloalkyl-Q-fjalkyl, C_4-scycloalkenyl, R⁴R⁵N-, C_3-5heteroaryl, C₆.ioaryl and Q-eheterocycloalkyl used in defining R³ is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; wherein R⁴ and R⁵ are independently selected from — H, Ci_-6alkyl, C₂.₆alkenyl, C_2-6alkynyl, and a divalent Ci.₆group that together with another divalent R⁴ or R⁵ may form a ring or a portion of a ring wherein said ring is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethox}/, methyl, ethyl and hydroxy; and

R⁸ is selected from C_3-10CyClOaIlCyI, C_4-8cycloalkenyl, C_3-1ocycloalkyl-Ci. ₆alkyl,

C_{3- 6}heterocyclyl-C_1-6alkyl, C₆₄₀aryl-C(=O)-C_1-6alkyl, C_3-6heterocyclyl-C(=O)-C_1-6alkyl, C_Mohydrocarbylamino,

or C_3-6heterocyclyl-C(=O)-; wherein said C_3-1ocycloalkyl, C_4-8cycloalkenyl, C_3-1ocycloalkyl-C₁_₆alkyl, C_4-8cycloalkenyl-

C_1-6alkyl, C_6-1oaryl, C_6-10aryl-C_1-6alkyl, Q._δheterocyclyl, Qj-eheterocyclyl-Ci-ealkyl, C_6-i₀aryl-C(=O)-C_1-6alkyl, C_3-6heterocyclyl-C(=O)-Ci_-6alkyl, C_1-10hydrocarbylamino, C₆-ioaryl-C(=0)-, or C_3-6heterocyclyl-C(=O)- used in defining R⁸ is optionally substituted by one or more groups selected from hydrogen, Ci_-6alkyl, C_2-6alkenyl, halogen, C_1-6alkoxy, amino, cyano, oxo, nitro, hydroxy and -NR⁴R⁵. Further embodiments of the invention provide a process for preparing the compounds of the invention according to the synthetic routes depicted in the general procedures below:

General Procedure 1 (Synthesis of amino indazoles):

4-Fluorophenyl 2,6-Dichlorophenyl phenyl

3-Chlorophenyi 2-Fluorophenyl 2-trifluoromethylphe

General procedure 2 (Alkylation of indazoles)

Phenyl, 4-Fluorophenyl

General Procedure 3 (Synthesis of pyrrolidinyl indazoles)

2,6-Dichlorophenyl Phenyl

3-Chlorophenyl 2-Trifluoromethylphenyl

General Procedure 4 (Reductive alkylation of amino indazoles) 4-Fiuorophenyl 2,6-Dichlorophenyl Phenyl

3-Chlorophenyl 2-Fluorophenyl 2-Trifluoromeihylphenyl

General Procedure 5 (Amination of 3-chloroindazoles)

R⁸ = Phenyl

4-Fluorolphenyl

General Procedure 6 (Synthesis of indazole sulphonamides)

R = 4-Fuorophenylmethyt 2,6-Dichlorophenyimethyi Phenytmethyl 3-Chlorophenylmethyl

2-Fluorophenylmetriyl 2-Trifiuoromethyfphenyfmethyl Phenyl AIIyI

General Procedure 7 (Amination of 3-chloro indazole sulphonamides)

Compounds of the present invention may be prepared according to the synthetic routes as depicted in Schemes 1-3 using one or more methods disclosed herein. Scheme 1.

Ra 2,6-Dichlorophenyl Phenyl

3-Chlorophenyl 2-Trifluoromethylphenyl

Scheme 2.

R = 4-Fluorophenylmethyl 2,6-Dichlorophenylmethyl Phenylmethyl R₁R₂NH, 3-Chlorophenylmethyl Et₃N, DCE 2-Fluorophenylmethyl 2-Trifluoromethylphenylmethyl

Phenyl

AIIyI

R = 4-Fluorophenylmethyl 2,6-Dichlorophenylmethyl Phenylmethyl 3-Chlorophenylmethyl 2-Fluorophenylmethyl 2-Trifluoromethylphenylmethyl Phenyl AIIyI •

Biological Evaluation hCBi and I1CB₂ receptor binding

Human CB₁ receptor from Receptor Biology (hCBl) or human CB₂ receptor from BioSignal (hCB2) membranes are thawed at 37 ⁰C, passed 3 times through a 25- gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl₂, and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed in 96-well plates. The IC₅₀ of the compounds of the invention at 11CB₁ and hCB₂ are evaluated from 10-point dose-response curves done with ³H-CP55,940 at 20000 to 25000 dpm per well (0.17- 0.21 nM) in a final volume of 300 μl. The total and non-specific binding are determined in the absence and. presence of 0.2 μM of HU210 respectively. The plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters GF/B (presoaked in 0.1% polyethyleneimine) with the Tomtec or Packard harvester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl₂, 0.5 mg BSA pH 7.0). The filters are dried for 1 hour at 55 ⁰C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid.

hCBi and JiCB₂ GTPγS binding

Human CBi receptor from Receptor Biology (hCBl) or human CB₂ receptor membranes (BioSignal) are thawed at 37 ⁰C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTPγS binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl₂, pH 7.4, 0.1% BSA). The EC₅₀ and E_maχ of the compounds of the invention are evaluated from 10-point dose- response curves done in 300μl with the appropriate amount of membrane protein and 100000-130000 dpm of GTPg³⁵S per well (0.11 -0.14 nM). The basal and maximal stimulated binding is determined in absence and presence of 1 μM (hCB₂) or 10 μM (hCBi) Win 55,212-2 respectively. The membranes are pre-incubated for 5 minutes with 56.25 μM (hCB2) or 112.5 μM (!1CB₁) GDP prior to distribution in plates (15 μM (hCB₂) or 30 μM QxCBi) GDP final). The plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifϊlters GF/B (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl₂, 50 mM NaCl, pH 7.0). The filters are dried for 1 hour at 55 °C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid. Antagonist reversal studies are done in the same way except that (a) an agonist dose-response curve is done in the presence of a constant concentration of antagonist, or (b) an antagonist dose-response curve is done in the presence of a constant concentration of agonist. Based on the above assays, the dissociation constant (Ki) for a particular compound of the invention towards a particular receptor is determined using the following equation:

Ki = IC₅₀/(l+[rad]/Kd),

Wherein IC_5O is the concentration of the compound of the invention at which 50% displacement has been observed;

[rad] is a standard or reference radioactive ligand concentration at that moment; and

Kd is the dissociation constant of the radioactive ligand towards the particular receptor. Using above-mentioned assays, the Ki towards human CB₁ receptors for most compounds of the invention is measured to be in the range of 36-5700 nM. The Ki towards human CB₂ receptors for most compounds of the invention is measured to be in the range of about 1.6-36 nM.

EXAMPLES

The invention will further be described in more detail by the following Examples which describe methods whereby compounds of the present invention may be prepared, purified, analyzed and biologically tested, and which are not to be construed as limiting the invention. Where retention time (t_R) values are provided the LC/MS. conditions were as follows: column: Phenomenex Synergy 4u Polar-RP 8OA, 30 X 2.00mm; mobile phase A: 0.1% TFA in water, B: 0.1% TFA in acetonitrile; gradient: 90:10 (A/B) linear to 5:95 (A/B) in 2.25 min., hold for 0.75 min., re-equilibratiori time: 0.5 min. at 10%B. Where capacity factor (k¹) provided, the LC/MS conditions were as follows: column: Zorbax C-18; mobile phase: A - 0.05% TFA in water, B - 0.05% TFA in acetonitrile; gradient: 10-95% B, lmL/min, 40° C.

Example 1 3-chloro-l-(4-fluorobenzyl)-iV_rΛ^?-dipropyl-lJ?-indazole-5-sulfonamide

Step A. 3-chIoro-l-(4-fluoroben2yI)-i\yV-dipropyl-liϊ-indazole-5-sulfonamide

To a solution of alkyl-indazole (1 equiv.) in dichloromethane (20ml/mmol indazole) was added chlorosulfonic acid (5 equiv.). The reaction mixture was heated at reflux until all of the indazole had been consumed (typically 7h). The indazole-sulfonic acid appears as brown oil that separates from the solvent. The reaction was cooled to room temperature. Thionyl chloride (lml/mmol indazole) was added. The reaction was stirred at room temperature until all of the indazole-sulfonic acid (brown oil) had been consumed (typically overnight). The reaction mixture was poured slowly onto a mixture of crushed ice and water. The aqueous was extracted with dichloromethane (2x). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude compound was dissolved in dichloroethane (20nύ7mmol indazole). Triethylamine (1 equiv.) was added, followed by the amine (1 equiv.)- The reaction mixture was stirred at room temperature until all of the sulfonyl chloride had been consumed (typically Ih). More dichloroethane was added and the organic phase was washed with a IN aqueous HCl solution, saturated NaHCO₃, and brine, and was then dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography to provide the title compound. After flash chromatography (dichloromethane to 1:99 methanol: dichloromethane), the title compound (2.22g, 37%) was obtained as a white solid. ¹H-NMR (CD₃OD): δ ppm 0.77 (t, J=7.42 Hz, 6 H), 1.45 (sextuplet, J=7.38 Hz, 4 H), 2.98-3.02 (m, 4 H), 5.52 (s, 2 H)₇ 6.96 (t, J=8.69 Hz, 2 H), 7.23 (dd, J=8.40 Hz, 5.27 Hz, 2 H), 7.69 (d, J=8.98 Hz, 1 H), 7.73-7.76 (m, 1 H), 8.04-8.05 (s, 1 H). MS (ESI) (M+H)⁺ = 424.

Step B. 3-chloro-l-(4-fluorobenzyl)-lH-indazole

A 60% suspension of NaH in mineral oil (1.1 equiv.) was added portionwise to a solution of the indazole (1 equiv.) in DMF (4 mL/mmol indazole) at O⁰C. The reaction mixture was stirred at O⁰C for Ih. The halide (1.1 equiv.) was added. The reaction was allowed to warm to room temperature and was stirred until all of the indazole had been consumed (typically overnight). The reaction was quenched by pouring it slowly onto iced water. The solvent was partially evaporated and the mixture was diluted with EtOAc The phases were separated and the organic phase was washed with a IN aqueous HCl solution¹, saturated NaHCO₃, and brine, and was then dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography to provide the title compound. The title compound (2.1Og, 87%) was obtained as a white solid. ¹H-NMR (CDCl₃): δ ppm 5.50 (s, 2 H), 6.99 (m, 2 H), 7.21 (m, 3 H), 7.31 (dt, J=8.59 Hz, 0.88 Hz, 1 H)₅ 7.40 (ddd, J=8.40 Hz, 6.93 Hz, 1.07 Hz, 1 H), 7.69 (dt, J=8.10, 1.12 Hz, 1 H). MS (ESI) (M+H)⁺ = 261. Anal Calcd for Ci₄H₁₀ClFN₂: C, 64.50; H₅ 3.87; N₅ 10.75. Found: C, 64.92; H, 3.86; N₅ 10.78.

Example 2 l-[(3-chlorophenyl)methyl]-N-[3-(dimethylamino)propyl]-3-(l- pyrrolidinyl)-lH-indazole-5~sulfonamide

Step A. l-[(3-chloropIienyl)methyl]-Λ^?-[3-(dimethylamino)propyl]-3-(l- pyrrolidinyl)-lH-indazole-5-sulfonamide

Following the same procedure as Example 1, Step A, the title compound (0.09g, 52%) was obtained as a white solid. IH NMR (400 MHz, CHLOROFORM-D) δ ppm 1.86 (m, 2 H) 2.05 (m, 4 H) 2.52 (s, 6 H) 2.57 (m, 2 H) 2.72 (m₇ 2 H) 3.06 (d, J=5.08 Hz, 2 H) 3.68 (d, J=6.44 Hz, 3 H) 5.36 (s, 2 H) 7.06 (m, 1 H) 7.23 (m, 4 H) 7.70 (m, 1 H) 8.37 (s, 1 H). MS (ESI) (M+H)⁺ = 476

Step B. l-[(3-chlorophenyl)methyl]-3-(l-pyrrolidinyl)-li3-indazole

1,4-dibromobutane (0.9 equiv) was added to a mixture of the amine (1 equiv.), DMF (5 mL/mmol amine) and CS₂CO₃ (2equiv.). The mixture was heated at 8OC overnight. The reaction mixture was concentrated in vacuo; the residue was taken in dichloromethane and washed with brine (3x). The organic phases were dried over Na₂SO₄, filtered, concentrated in vacuo and the residue was purified by flash chromatography. The title compound (1.12g, 72%) was obtained as pale brown oil. MS (ESI) (M+H)⁺ = 312.

Example 3

N-(cyclopropyImethyl)-3~(diethyϊamino)-l-[(4-fluorophenyl)πiethyl]-iV-propyl- lH-indazole-5-sulfonamide

Step A. iV-(cyclopropylmethyl)-3-(diethylamino)-l-[(4-fluorophenyl)methyl]-iV- propyl-lJΪ-indazole-5-sulfonamide

Following the same procedure as Example 1, Step A, the title compound (O.lόg, 68%) was obtained as a white solid. IH NMR (400 MHz, CHLOROFORM-D) δ ppm 0.16 (m, 2 H) 0.49 (m, 2 H) 0.89 (m, 4 H) 1.28 (m, 6 H) 1.61 (m, 2 H) 3.07 (t, J=6.84 Hz, 2 H) 3.20 (m, 2 H) 3.59 (m, 4 H) 5.37 (s, 2 H) 6.98 (m, 2 H) 7.17 (m, 3 H) 7.64 (m, 1 H) 8.30 (s, 1 H). MS (ESI) (M+H)⁺ = 473

Step B. i\VV-diethyl-l-[(4-fluorophenyl)methyl]-lH-indazoI-3-amine

Sodium triacetoxyborohydride (10 equiv) was added portionwise to a mixture of the amine (1 equiv.), 1,2-dichloro ethane (15 mL/mmol amine), acetaldehyde (5equiv.) and acetic acid (0.2equiv.). The mixture was stirred at room temperature overnight.

The reaction was then diluted with 2M aqueous NaOH, and the aqueous phase was extracted with CH₂Cl₂ (3x). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated in vacuo to give products with >90% purity by LC/MS.

The title compound (0.98g, 92%) was obtained as pale brown oil. MS (ESI) (M+H)⁺ =

298.

Example 4

4-[ [1- [(2,6-dichlorophenyl)methyl] -3-(diethylamino)-lfl-indazol-5-yl] sulf onyl] -, 1-piperazinecarboxylic acid, ethyl ester

Step A. 4-[[l-[(2,6-dichlorophenyl)methyl]-3-(diethylamino)-lJ3^r-indazol-5- yl]sulfbnyl]~, 1-piperazinecarboxylic acid, ethyl ester

Following the same procedure as Example 1, Step A, the title compound (0.18g, 65%) was obtained as a white solid. IH NMR (400 MHz, CHLOROFORM-D) δ ppm 1.19 (m, 9 H) 2.59 (s, 3 H) 3.00 (m, 3 H) 3.54 (m, 6 H) 4.07 (q, J=7.23 Hz₅ 2 H) 5.65 (s, 2 H) 7.25 (dd, J=8.89, 7.52 Hz, 1 H) 7.38 (m, 3 H) 7.62 (dd, J=8.98, 1.56 Hz, 1 H) 8.20 (d, J=0.78 Hz, 1 H). MS (ESI) (M+H)⁺ = 568.

Step B. l-[(2,6-dichlorophenyl)methyl]-ΛyV-diethyl-lJΪ-mdazol-3-arame

Following the same procedure as Example 3, Step B, the title compound (0.77g, 86%) was obtained as a pale brown solid. MS (ESI) (M+H)⁺ = 348.

Example 5 l-(4-fluorobenzyl)-3-(4-methylpiperazin-l-yl)-N//-dipropyl-lJϊ-indazole-5- sulfonamide

Step A. l-(4-fluorobenzyl)-3-(4-methyIpiperazin-l-yl)-iVyV-dipropyl-lH- indazole-5-sulfonamide

A solution of the chloroindazole sulphonamide (1 equiv.) in toluene (15 mL/mmol chloroindazole sulphonamide) was placed in a N₂ purged flask. NaOtBu (1.5 equiv.), 2-(di-tert-butylphosρhino)biρhenyl (0.1 equiv.), Pd(OAc)₂ (0.05 equiv.) and the amine (10 equiv.) were added sequentially, and the resulting mixture was heated at 110⁰C until the chloroindazole was consumed (typically 8 h). The reaction was then cooled and concentrated in vacuo. The crude product was purified by silica gel column chromatography. The free base of the title compound was obtained as crystals from methanol. A solution of HCl in diethylether (3 equiv.) was added to a solution of the free base in dichloromethane (20 ml/mmol). The solution was stirred at room temperature for 15 minutes and concentrated in vacuo. The residue was dissolved in dioxan and lyophylized to yield the title compound as the HCl salt. After flash chromatography (3:97 methanol: dichloromethane), the title compound (140mg, 81%) was obtained as a pale yellow solid. ¹H-NMR (CD₃OD): δ ppm 0.83 (t, J=7.32 Hz, 6 H), 1.51 (sext, J=7.42 Hz, 4 H), 2.96 (s, 3 H), 3.06 (rn, 4 H), 3.34 (m, 4 H), 3.61 (m, 2 H), 4.06 (m, 2 H), 5.47 (m, 2 H), 7.00 (m, 2 H), 7.24 (m, 2H), 7.62 (m, 1 H), 7.71 (m, 1 H), 8.21 (m, 1 H). MS (ESI) (M+H)⁺ =488; k': 4.6. Anal. Calcd for C₂₅H₃₄FN₅O₂S + 1.7 HCl + 0.4 C₄H₈O₂ (dioxane): C, 54.63; H, 6.40; N, 11.97. Found: C, 54.76; H, 6.73; N, 12.01.

Step B . 3-chloro-l-(4-fluoroben2yl)-i\yV-dipropyl-ljH-indazole-5-sulfonamide

Following the same procedure as Example 1, Step A, after flash chromatography

(dichloromethane to 1:99 methanol: dichloromethane), the title compound (2.22g, 37%) was obtained as a white solid. ¹H-NMR (CD₃OD): δ ppm 0.77 (t, J=7.42 Hz, 6 H), 1.45 (sextuplet, J=7.38 Hz, 4 H), 2.98-3.02 (m, 4 H), 5.52 (s, 2 H), 6.96 (t, 0 J=8.69 Hz, 2 H), 7.23 (dd, J=8.40 Hz, 5.27 Hz, 2 H), 7.69 (d, J=8.98 Hz, 1 H), 7.73-7.76 (m, 1 H), 8.04-8.05 (s, 1 H). MS (ESI) (M+H)⁺ = 424.

Example 6 5 l-(4-fluorobenzyI)-3-piperidin-l-yI-7VyV-dipropyl-lH-indazole-5-sulfonamide

l-(4-fluorobenzyl)-3-piperidin-l-yl-iV_;iN-dipropyl-lZr-indazole-5-sulfonamide

Following the Example 5, step A, after flash chromatography (3:97 methanol: dichloromethane), the title compound (32mg, 25%) was obtained as a pale pink solid. ¹H-NMR (CD₃OD): δ ppm 0.83 (t, J=7.42 Hz, 6 H), 1.52 (sextuplet, J=7.46Hz, 4 H), 1.67-1.77 (m, 2 H), 1.85-1.96 (m, 4 H), 3.05-3.09 (m, 4 H), 3.55-3.65 (m, 4 H), 5.54 (s, 2 H), 6.98-7.04 (m, 2 H), 7.24-7.30 (m, 2 H), 7.65-7.74 (m, 1 H), 7.75-7.78 (m, 1 H), 8.32-8.33 (m, 1 H). MS (ESI) (M+H)⁺ =473. Anal. Calcd for C₂₅H₃₃FN₄O₂S + 0.5 HCl + 0.3 C₄H₈O₂ (dioxane): C, 60.83; H, 7.00; N, 10.83. Found: C, 60.88; H, 6.98; N, 10.86.

Example 7

3-[(cyclohexylmethyl)amino]-l-(4-fluorobenzyl)-Λ^r _:)Λ'-dipiOpyi-l//-indazole-5- sulfonamide

3- [(cyclohexylmethyl) amino] -l-(4-fluor ob enzyl)-JV,iV-dipr opyl-lH-indazole-5- sulfonamide

Following the general procedure 5, step A, after flash chromatography (5:95 methanol: dichloromethane), the title compound (74 mg, 55%) was obtained as a pale yellow solid. ¹H-NMR (CD₃OD): δ ppm 0.83 (t, J=7.42 Hz, 6 H), 1.00 (ddd, J=23.43 Hz, 12.11 Hz, 2.93 Hz, 2 H), 1.13-1.32 (m, 3 H), 1.52 (sextuplet, J=7.46 Hz, 4 H), 1.63-1.77 (m, 4 H), 1.77-1.84 (m, 2 H), 3.05-3.09 (m, 4 H), 3.17-3.26 (m, 2 H), 5.42 (s, 2 H), 6.99-7.05 (m, 2 H), 7.22-7.26 (m, 2 H), 7.64-7.72 (m, 1 H), 7.93 (dd, J=8.98 Hz, 1.37 Hz, 1 H), 8.51 (d, J=1.17 Hz, 1 H). MS (ESI) (M+H)⁺ =501. Anal. Calcd for C₂₇H₃₇FN₄O₂S + 0.6 HCl: C, 62.06; H, 7.25; N, 10.72. Found: C, 61.99; H, 7.02; N, 10.62. Example 8 l-(4-fluorobenzyl)-iV₎Λ'-dipropyl-lJΪ-mdazole-5-sulfonamide

l-(4-fluorobenzyl)-iNyV-dipropyl-lJ3^r-indazole-5-sulfonamide

To a solution of 3-chloro-l-(4-fluoroben2yl)-iV,N-diproρyHH-indazole-5- sulfonamide (484Dmol) in DMSO (343Dl, 4.8mmol) and THF (2.5ml) at -2O⁰C was added a solution of potassium fert-butoxide (379mg, 3.4mmol) in THF (5ml) at - 2O⁰C. Air was bubbled into the reaction mixture for 15 minutes. The reaction was quenched with a 5% KHSO₄ aqueous solution. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 30-80% CH₃CN in H₂O) to provide the TFA salt of the title compound as a colourless oil. ¹H-NMR (CDCl₃): δ ppm 0.87 (t, J=7.32 Hz, 6 H), 1.56 (sextuplet, J=7.32 Hz, 4 H), 3.06-3.10 (m, 4 H), 5.59 (s, 2 H), 6.98-7.03 (m, 2 H), 7.18-7.22 (m, 2 H), 7.42 (d, J=8.79 Hz, 1 H), 7.74 (dd, J=8.88 Hz, 1.66 Hz, 1 H), 8.17 (s, 1 H), 8.29 (d, J=0.98 Hz, 1 H). MS (ESI) (M+H)⁺ = 390.

The following exemplify some of the compounds of the present invention that were made according to the schemes and methods described above. These compounds were found to be active towards the human CBj receptor based on the test results of using one or more assays described above.

Claims

What is claimed is:

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

wherein

R¹ is selected from hydrogen, C_1-loalkyl, C_2-i₀alkenyl, C_2-i₀alkynyl, C_3-10cycloalkyl, C₄.₈cycloalkenyl, C_3-10cycloalkyl-C_1-6alkyl, C_4-scycloalkenyl- C_1-6alkyl, C_3-5heteroaryl, C_6-10aryl, C_6-10aryl-C_1-6alkyl, Cs-_όheterocycloalkyl, C_{3- 6}heterocycloalkyl-Ci_-6alkyl or C_1-6alkoxycarbonyl; wherein said C_1-10alkyl, C_2-

₁₀alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_4-gcycloalkenyl, C_3-10cycloalkyl-C₁.₆alkyl, C_4-8cycloalkenyl-C_1-6alkyl, C_3-5heteroaryl, C_6-i₀aryl, C_6-10aryl-C_1-6alkyl, C_{3- 6}heterocycloalkyl, C_3-6heterocycloalkyl-C_1-6alkyl or C_1-6alkoxycarbonyl used in defining R² is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; with one or more substituents selected from C_halky!, C_2-6alkenyl, halogen, C_1-6alkoxy, amino, cyano, oxo, nitro, hydroxy, C_δ-ioaryl, C_6-10aryl-C_1-6alkyl, C_3-6heterocyclyl and C_{3- 6}heterocyclyl-C_1-6alkyl;

R² is selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_4-8cycloalkenyl, C_3-1ocycloalkyl-C_1-6alkyl, C_4-scycloalkenyl- C_1-6alkyl, C_3-5heteroaryl, C_6-10aryl, C_6-10aryl-C_1-6alkyl, C^eheterocycloalkyl, C_{3- 6}heterocycloalkyl-C_1-6alkyl or C_1-6alkoxycarbonyl; wherein said C_1-10alkyl, C_{2- 10}alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_4-8cycloalkenyl, C_3-10cycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl-C₁.₆alkyl, C_3-5heteroaryl, C_6-1oaryl, C_6-10aryl-C_1-6alkyl, C_{3- 6}heterocycloalkyl, C_3-6heterocycloalkyl-C_1-6alkyl or Ci_-6alkoxycarbonyl used in defining R² is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; with one or more substituents selected from C_1-6alkyl, C_2-6alkenyl, halogen, C_1-6alkoxy, amino, cyano, oxo, nitro, hydroxy, C_6-1oaryl, C_6-10aryl-C_1-6alkyl, C_3-6heterocyclyl and C₃. ₆heterocy cly 1-C _{\ -6}alkyl; optionally R¹ and R² together with the N to which they are bound may form a 3-10 membered aromatic, heteroaromatic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally substituted by one or more groups independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_{2- 6}alkynyl, halogen, amino, Ci_-6alkoxy, C_1-6alkoxy-Ci.₆alkyl, Ci.ealkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy;

R³ is selected from hydrogen, halogen, amino, Ci..₁₀alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-1ocycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl-C_1-6alkyl,

C₃,₆heterocycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl, R⁴R⁵N-, C_3-5heteroaryl, C_6-10aryl and Q-eheterocycloalkyl, wherein said amino, Ci-ioalkyl, C_2-1oalkenyl, C₂-i₀alkynyl, C_{3- 10}cycloalkyl, C_3-1ocycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl-C_1-6alkyl, C₃.₆heterocycloalkyl-Ci_-6alkyl, C_4-scycloalkenyl, R⁴R⁵N-, C_3-5heteroaryl, C_6-10aryl and C₃.6heterocycloalkyl used in defining R³ is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; wherein R⁴ and R⁵ are independently selected from -H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and a divalent C_1-6group that together with another divalent R or R⁵ may form a ring or a portion of a ring wherein said ring is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl and hydroxy; and

R⁸ is selected from C_3-10cycloalkyl, C_4-8cycloalkenyl, C_3-I0CyClOaUCyI-C_{1- 6}alkyl, C₄.₈cycloalkenyl-C_1-6alkyl, C_6-10aryl, C_6-10aryl-C_1-6alkyl, C^heterocyclyl, C_{3- 6}heterocyclyl-Ci_-6alkyl, C_6-10aryl-C(=O)-C_1-6alkyl, C_3-6heterocyclyl-C(=O)-C_1-6alkyl, C_1-10hydrocarbylamino,

or C_3-6heterocyclyl-C(=O)-; wherein said C_3-1ocycloaU_yl, C_4-scycloalkenyl, Cs-_Kjcycloalkyl-d-_όalkyl, C_4-8cycloalkenyl- C_1-6alkyl, C_6-10aryl, C^oaryl-Q-ealkyl, C^eheterocyclyl, C_3-6heterocyclyl-C_1-6alkyl, C_6-Ioaryl-C(=0)-Ci.₆alkyl, C_3-6heterocyclyl-C(=O)-Ci_-6alkyl, C_Mohydrocarbylamino, C_6-10aryl-C(=O)-, or C_3-6heterocyclyl-C(=O)- used in defining R⁸ is optionally substituted by one or more groups selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, halogen, Ci_-6alkoxy, amino, cyano,- oxo, nitro, hydroxy and -NR⁴R⁵.

2. A compound as claimed in claim 1, wherein

R¹ is selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_4-6cycloalkenyl, C_3-10cycloalkyl-C₁.₆alkyl, C_4-8Cy cloalkenyl- C_1-6alkyl, phenyl, ρhenyl-C_1-4alkyl, C_3-6heterocyclyl, C_3-6heterocyclyl-C_1-6alkyl or C_1-4alkoxycarbonyl; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-1ocycloalkyl, C_4-6cy cloalkenyl, C_3-10cycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl-C_1-6alkyl, phenyl, phenyl-C_1-4alkyl, C_3-6heterocyclyl, C_3-6heterocyclyl-C_1-6alkyl or C_1-4alkoxycarbonyl used in defining R¹ is optionally substituted by one or more groups selected from halogen, C_1-4alkyl, C_2-4alkenyl, C_1-4alkoxy, amino, oxo, cyano, nitro, hydroxy, C_{6- 10}aryl, C_6-10aryl-C_1-4alkyl, C_3-6heterocyclyl, C_3-6heterocycly]-C_1-4alkyl and -NR⁴R⁵;

R is selected from hydrogen, C_1-6alkyl, C₂.₆alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_4-6Cy cloalkenyl,

C_4-8cycloalkenyl- C_1-6alkyl, phenyl, phenyl-Ci_-4alkyl₃ Cs-_όheterocyclyl, C₃-₆heterocyclyl-C_1-6alkyl or Ci_-4alkoxycarbonyl; wherein said C_1-6alkyl, C₂-₆alkenyl, C_2-6alkynyl, C_3-1ocycloaIkyl, C_4-6cycloalkenyl, C_3-10cycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl-C_1-6alkyl, phenyl, phenyl-C_1-4alkyl, C^heterocyclyl, Q.eheterocyclyl-Ci._όalkyl or C_1-4alkoxycarbonyl used in defining R² is optionally substituted by one or more groups selected from halogen, C_1-4alkyl, C_2-4alkenyl, C_1-4alkoxy, amino, oxo, cyano, nitro, hydroxy, C_6- ioaryl, C_6-10aryl-C_1-4alkyl, C_3-6heterocyclyl, C_3-6heterocyclyl-C_1-4alkyl and -NR⁴R⁵; R¹ and R² can form together with the N to which they are bound may form a

3-6 membered aromatic, heteroaromatic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally substituted by one or more groups independently selected from hydrogen, C_1-4alkyl, C_2-4alkenyl, C_{2- 4}alkynyl, halogen, amino, C_1-4alkoxy, C_1-4alkoxy-Ci.₄alkyl, C_1-4alkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy;

R³ is selected from hydrogen, halogen, amino, C_1-6alkyl, C2_-6alkenyl, C_{2- 6}alkynyl, C_3-6cycloalkyl, C_4-6cycloalkenyl, C_3-5heteroaryl, R⁴R⁵N-, C₃.₆cycloalkyl-Ci. ₄alkyl, C_4-6cycloalkenyl-C_1-4alkyl, phenyl, phenyl-C_1-4alkyl, C_3-6heterocyclyl or C_{3- 6}heterocyclyl-C_1-4alkyl; wherein said amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C₃.₆cycloalkyl, C_4-6cycloalkenyl, C_3-5heteroaryl, R⁴R⁵N-, C_3-6cycloalkyl-C_1-4alkyl, C_4-6cycloalkenyl-C_1-4alkyl, phenyl, phenyl-C_1-4alkyl, C_3-6heterocyclyl or C_{3- 6}heterocyclyl-C_1-4alkyl used in defining R³ is optionally substituted by one or more groups selected from C_1-4alkyl, C_2-4alkenyl, halogen, C_1-4ElIcOXy, amino, nitro, cyano, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, Q-_όCycloalkyl-Q-ealkyl, C_{3- 6}heterocyclyl, C_3-6heterocyclyl-C_1-6alkyl, and -NR⁴R⁵; wherein R⁴ and R⁵ are independently selected from -H₃ C_1-4alkyl, C_2-6alkenyl, C_2-6alkynyl, and a divalent C_1-6group that together with another divalent R⁴ or R⁵ may form a ring or a portion of a ring wherein said ring is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl and hydroxy; and

R⁸ is selected from C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-4alkyl, C_4-6cycloalkenyl, C_6-10aryl, phenyl, phenyl-C_1-4alkyl, C^heterocyclyl or C_3-6heterocyclyl-C_1-4alkyl; wherein said C_3-6cycloalkyl, C_3-6cycloalkyl-Ci_-4alkyl, C_4-6cycloalkenyl, C_6-10aryl, phenyl, phenyl-C_1-4alkyl, C_3-6heterocyclyl or C_3-6heterocyclyl-C_1-4alkyl used in defining R⁸ is optionally substituted by one or more groups selected from Q^alkyl, C_1-4alkoxy, halogen, cyano, amino, nitro, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵. .

3. A compound as claimed claim 1, wherein

R¹ is selected from hydrogen, C^alkyl, C_2-4alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, C₄.₆cycloalkenyl, C_4-scyclpalkenyl-C_1-6alkyl₅ C₃.scycloalkyl-Ci_-4alkyl,

phenyl, phenyl-C_1-4alkyl, C^eheterocyclyl, Cs.eheterocyclyl-Ci^alkyl or C_1-2alkoxycarbonyl; wherein said C_1-6alkyl, C_2-4alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, C_4-6cycloalkenyl, C_4-8cycloalkenyl-C_1-6alkyl, C_3-8cycloalkyl-C_1-4alkyl, phenyl, phenyl- C_1-4alkyl, Cs-oheterocyclyl, C_3-6heterocyclyl-C_1-4alkyl or C_1-2alkoxycarbonyl used in defining R¹ is optionally substituted with one or more groups selected from C_1-4alkyl, halogen, C_1-4alkoxy, amino, cyano, oxo, hydroxy, Cs-_όheterocyclyl, C_3-6heterocyclyl- C_1-4alkyl, C_6-8aryl, C_6-8aryl-C_1-4alkyl;

R² is selected from hydrogen, Q._δalkyl, C_2-4alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, C_4-6cycloalkenyl, C_4-8cycloalkenyl-C_1-6alkyl, C_3-8cycloalkyl-C_1-4alkyl, phenyl, phenyl-C_1-4alkyl, Q-_όheterocyclyl, C₃.₆heterocyclyl-C_1-4alkyl or C_1-2alkoxycarbonyl; wherein said Ci_-6alkyl, C_2-4alkenyl, C_2-6alkynyl, Cs-scycloalkyl, C_4-6cycloalkenyl, Gi-scycloalkenyl-Ci-βalkyl, C_3-8cycloalkyl-C_1-4alkyl, phenyl, phenyl- C_1-4alkyl, Cs-βheterocyclyl, C_3-6heterocyclyl-C_1-4alkyl or C_1-2alkoxycarbonyl used in defining R² is optionally substituted with one or more groups selected from C_1-4alkyl, halogen, Ci_-4alkoxy, amino, cyano, oxo, hydroxy, C₃_₆heterocyclyl, C_3-6heterocyclyl- C₁^aIlCyI, C_6-8aryl, C_6-8aryl-C_1-4alkyl;

R¹ and R² together with the N to which they are bound may form a group selected from 1,2,3,6-tetrahydro-pyridinyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, 1,3,4- oxadiazolyl, 1,3,4-thiadiazolyl, 1,3,4-triazolyl, 1,3-dioxanyl, 1,3-dioxepanyl, 1,4- benzodioxanyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 2,3,4,7-tetrahydro-l/f-azepinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuranyl, 2,3-dihydropyranyl, 2,5- dihydrofuranyl, 4,7-dihydro-l,3-dioxepinyl, azetidinyl, aziridinyl, benzofuranyl, chromanyl, chromenyl, dioxanyl, dioxolanyl, furazanyl, furyl, hexamethylene homopiperazinyl, imidazolidinyl, indazolyl, indolizinyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolyl, oxetanyl, oxidyl, oxiranyl, phenoxathiinyl, phthalazinyl, phenyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, quinazolinyl quinolinyl, quinoxalinyl sulfolanyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thienyl, thietanyl, thiranyl, thiomorpholinyl, thiophanyl, thiopyranyl, triazinyl and xanthenyl; wherein said 1,2,3,6-tetrahydro-pyridinyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, 1,3,4- oxadiazolyl, 1,3,4-thiadiazolyl, 1,3,4-triazolyl, 1,3-dioxanyl. 1,3-dioxepanyl, 1,4- benzodioxanyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 2,3,4 J-tetrahydro-1/f-azepinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuranyl,.2,3-dihydropyranyl, 2,5- dihydrofuranyl, 4,7-dihydro-l,3-dioxepinyl, azetidinyl, aziridinyl, benzofuranyl, chromanyl, chromenyl, dioxanyl, dioxolanyl, furazanyl, furyl, hexamethylene homopiperazinyl, imidazolidinyl, indazolyl, indolizinyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolyl, oxetanyl, oxidyl, oxiranyl, phenoxathiinyl, phthalazinyl, phenyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, quinazolinyl quinolinyl, quinoxalinyl sulfolanyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thienyl, thietanyl, thiranyl, thiomorpholinyl, thiophanyl, thiopyranyl, triazinyl and xanthenyl used in defining R¹ and R² together is optionally substituted by one or more groups selected from C₁.₄a.kyl, C₂.₄alkenyl, C₂. ₄alkynyl, hydrogen, halogen, amino, C_1-4alkoxy, Ci.₄alkoxy-Ci_-2alkyl, Ci_-3alkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy; R³ is selected from hydrogen, halogen, amino, C_1-6alkyl, C_2-6alkenyl, C_3-6CyClOaIlCyI, C_3-6cycloalkyl-C_1-4alkyl, C₃.₆heterocyclyl or C_3-6heterocyclyl-C_1-4alkyl wherein said amino, C_1-6alkyl, C₂.₆alkenyl, C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-4alkyl, C₃.₆heterocyclyl or C_3-6heterocyclyl-C_1-4alkyl used in defining R³ is optionally substituted with one or more groups selected from C_1-6alkyl, halogen, Ci_-2alkoxy, methoxy, ethoxy, methyl, ethyl, hydroxy, C_3-6heterocyclyl, C^eheterocyclyl-Q-ealkyl and -NR⁴R⁵; wherein R⁴ and R⁵ are independently selected from -H, Ci_-3alkyl, C_2-4alkenyl, C_2-4alkynyl, and a divalent C^group that together with another divalent R⁴ or R⁵ may form a ring or a portion of a ring; wherein said ring is optionally substituted by one or more groups selected from methoxy, ethoxy, methyl, ethyl and hydroxy; and R^s is selected from phenyl, allyl, phenyl-C_1-4alkyl, C_3-6cycloalkyl-Ci_-4alkyl,

C_4-6cycloalkenyl-C_1-4alkyl, Q-_όheterocycloalkyl, C_3-6heterocylcoalkyl-Ci_-4alkyl, C_{6- 10}aryl, C_3-6Cy cloalkyl, and C_4-6cycloalkenyl, wherein said phenyl, phenyl-C_1-4alkyl, C_3-6cycloalkyl-C_1-4alkyl, C_4-6cycloalkenyl-C_1-4alkyl, Q-eheterocycloalkyl, C_3-

C_6-10aryl, C_3-6cycloalkyl, and C_4-6cycloalkenyl, used in defining R⁸ is optionally substituted by one or more groups selected from Ci_-4alkyl, Ci-₄alkoxy, halogen, amino, cyano, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵.

4. A compound as claimed in claim 1, wherein R¹ is selected from hydrogen, methyl, ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl, 2-phenylethyl, pyrimidinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl; wherein the ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl, 2-phenylethyl, pyrimidinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl used in defining R¹ is optionally substituted with one or more groups selected from C_1-3alkyl, halogen, C_1-3alkoxy, amino, cyano, oxo, hydroxy, pyrrolidinyl and phenylmethyl;

R² is selected from hydrogen, methyl, ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl, 2-phenylethyl, pyrimidinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl; wherein the ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl, 2-phenylethyl, pyrimidinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyi or methoxycarbonyl used in defining R² is optionally substituted with one or more groups selected from C_1-3alkyl, halogen, C_1-3alkoxy, amino, cyano, oxo, hydroxy, pyrrolidinyl and phenylmethyl;

R¹ and R² together with the N to which they are bound may form a group selected from cylcohexyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl or morpholinyl; wherein said cylcohexyl, 1,2,3,6- tetrahydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl or morpholinyl used in defining R¹ and R² together is optionally substituted by one or more groups selected from C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, hydrogen, halogen, amino, C_{1- 4}alkoxy, C_1-4alkoxy-C_1-2alkyl, C_1-3alkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy;

R³ is selected from hydrogen, Cl, diethylamino, cyclohexylmethylamino, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, t-butyl, n-butyl, 2-methyl-2-butyl, isopentyl, 2-methoxy-2-propyl, 2-hydroxyl-propyl, 1-methyl-propyl, 1,1-dimethyl- propyl, l,l-dimethyl-3-buten-l-yl, ethyl, 2-propyl and -NR⁴R⁵; wherein said diethylamino, cyclohexylmethylamino, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, t-butyl, n-butyl, 2-methyl-2-butyl, isopentyl, 2-methoxy-2-propyl, 2- hydroxyl-propyl, 1-methyl-propyl, 1,1-dimethyl-propyl, l,l-dimethyl-3-buten-l-yl, ethyl, 2-propyl and -NR⁴R⁵ used in defining R³ is optionally substituted with one or more groups selected from hydrogen and methyl; wherein R⁴ and R⁵ are independently selected from -H, Ci_-3alkyl, C_2-4alkenyl, C_2-4alkynyl, and a divalent C_1-4group that together with another divalent R⁴ or R⁵ may form a group selected from morpholinyl and piperazinyl; wherein said morpholinyl and piperazinyl is optionally substituted by one or more groups selected from methoxy, ethoxy, methyl, ethyl and hydroxy; and

R⁸ is selected from phenyl, allyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, tetrahydrofuranyl, 1- piperidinyl, N-methyl-2-piperidinyl and benzyl; wherein said phenyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, tetrahydrofuranyl, 1 -piperidinyl, N-methyl-2-piperidinyl and benzyl used in defining R⁸ is optionally substituted by one or more groups selected from C_1-4alkyl, C_1-4alkoxy, fluorine, chlorine, amino, cyano, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, and trifluoromethyl.

5. A compound selected from: l-[(3-chlorophenyl)methyl]-iV-[3-(dimethylamino)propyl]-3-(l-pyrrolidinyl)- lH-indazole-5-sulfonamide₃ N-(cyclopropylmethyl)-3-(diethylamino)-l-[(4- fluorophenyl)methyl]-iV-propyl-lif-indazole-5 -sulfonamide, iV-(cycloproρylmethyl)- l-[(2,6-dichlorophenyl)methyl]-3-(diethylamino)-Λ'^'-propyl-liϊ-mdazole-5- sulfonamide, 3-(diethylamino)-l-[(4-fluorophenyl)methyl]-N,Λ^?-dipropyl-lH- indazole-5 -sulfonamide, 4- [[ 1 - [(2,6-dichlorophenyl)memyl]-3 -(diethylamino)- IH- indazol-5-yl]sulfonyl]-, 1-piperazinecarboxylic acid, ethyl ester, l-(4-fiuorobenzyl)-3- (4-methylpiperazin- 1 -yl)-iV,./V-diρropyl- lH-indazole-5-sulfonamide, 1 -(4- fiuorobenzyl)-3-piperidin- 1 -yl-ΛζiV-dipropyl- lH-indazole-5 sulfonamide, 3- [(cyclohexylmethyl)amino]-l-(4-fluorobenzyl)-iV,iV-dipropyl-lH-mdazole-5- sulfonamide, and pharmaceutically acceptable salts thereof.

6. A compound according to any one of claims 1-5 for use as a medicament.

7. The use of a compound according to any one of claims 1-5 in the manufacture of a medicament for the therapy of pain.

8. The use of a compound according to any one of claims 1 -5 in the manufacture of a medicament for the treatment of anxiety disorders.

9. The use of a compound according to any one of claims 1 -5 in the manufacture of a medicament for the treatment of cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, gastrointestinal disorders and cardiavascular disorders.

10. A pharmaceutical composition comprising a compound according to any one of claims 1-5 and a pharmaceutically acceptable carrier.

11. A method for the therapy of pain in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of claims 1-5.

12. A method for preparing a compound of formula II,

II

comprising the step of reacting a compound of formula III,

III with a compound OfR⁴R⁵NH to form the compound of formula III, wherein

R¹ is selected from hydrogen, C_1-10alkyl, C_2-1oalkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_4-8cycloalkenyl, C_3-1ocycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl- C_1-6alkyl, C_3-5heteroaryl, C_6-10aryl, C_6-10aryl-C_1-6alkyl, Cs-_όheterocycloalkyl, C_{3- ό}heterocycloalkyl-Q.ealkyl or C_1-6alkoxycarbonyl; wherein said C_1-1QaUCyI, C_{2- 10}alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_4-8cycloalkenyI₅ C_3-1ocycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl-C_1-6alkyl, C_3-5heteroaryl, C_6-i₀aryl, C₆.i₀aryl-C_1-6alkyl, C_{3- 6}lieterocycloalkyl, C_3-6heterocycloalkyl-C_1-6alkyl or Cμ_δalkoxycarbonyl used in defining R² is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; with one or more substituents selected from C^alkyl, C_2-6alkenyl, halogen, C_1-6alkoxy, amino, cyano, oxo, nitro, hydroxy, C_6-10aryl,

₆heterocyclyl-Ci_-6alkyl;

R² is selected from hydrogen, C^oalkyl, C_2-i₀alkenyl, Ca-^alkynyl, C_3-10cycloalkyl, C_4τ8cycloalkenyl,

C_4-8cycloalkenyl- C_1-6alkyl, C_3-5heteroaryl, C6_-10aryl, C_6-10aryl-C_1-6alkyl, C^heterocycloalkyl, C_{3- 6}heterocycloalkyl-C_1-6alkyl or Ci_-6alkoxycarbonyl; wherein said C_1-10alkyl, C_{2- 10}alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_4-8cycloalkenyl,

C_4-8cycloalkenyl-C_1-6alkyl, C_3-5heteroaryl, C_6-10aryl, C_6-10aryl-C_1-6alkyl, C_{3- 6}heterocycloalkyl, Q-eheterocycloalkyl-Q-ealkyl or C_1-6alkoxycarbonyl used in defining R² is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; with one or more substituents selected from C_1-6alkyl, C_2-6alkenyl, halogen, Ci_-6alkoxy, amino, cyano, oxo, nitro, hydroxy, C_6-10aryl, C_6-1OaIyI-C_{1 -6}alkyl, C₃.₆heterocyclyl and C_3- όheterocyclyl-Ci.ealkyl; optionally R¹ and R² together with the N to which they are bound may form a 3-10 membered aromatic, heteroaromatic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally substituted by one or more groups independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, amino, C_1-6alkoxy, C_1-6alkoxy-C_1-6alkyl, C_1-6alkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy;

R³ is selected from hydrogen, halogen, amino, C_1-10alkyl, C_2-1oalkenyl, C_2-10alkynyl, C_3-1ocycloalkyl, C_Mocycloalkyl-Cμealkyl, C_4-8cycloalkenyl-C_1-6alkyl, C_3-6heterocycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl, R⁴R⁵N-, C_3-5heteroaryl, C_6-1oaryl and C^heterocycloalkyl, wherein said amino, Q.ioalkyl, C_2-10alkenyl, C_2-1oalkynyl, C_{3- 10}cycloalkyl, Cs-iocycloalkyl-d-_όalkyl, C_4-8cycloalkenyl-C_1-6alkyl, C_3-6heterocycloalkyl-C_1-6alkyl, C₄:₈cycloalkenyl, R⁴R⁵N-, C_3-5heteroaryl, C_6-10aryl and C^_όheterocycloalkyl used in defining R³ is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and -NR⁴R⁵; wherein R⁴ and R⁵ are independently selected from -H, C_1-6allcyl, C_2-6alkenyl, C_2-6alkynyl, and a divalent C_1-6group that together with another divalent R⁴ or R⁵ may form a ring or a portion of a ring wherein said ring is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl and hydroxy; and

R⁸ is selected from C_3-10cycloalkyl, C_4-8cycloalkenyl, C_3-10CyClOaIkVl-C_{1- 6}alkyl, C_4-8cycloalkenyl-C_1-6alkyl, C_6-1oaryl, C_6-1oaryl-C_1-6alkyl, C_3-6heterocyclyl, C_3- eheterocyclyl-Q-ealkyl, C_6-10aryl-C(=O)-C_1-6alkyl, C_3-6heterocyclyl-C(=O)-C_1-6alkyl, C_1-10hydrocarbylamino, C_6-10aryl-C(=O)-, or C_3-6heterocyclyl-C(=O)-; wherein said C_3-1ocycloalkyl, C_4-8cycloalkenyl, C_3-1ocycloalkyl-C_1-6alkyl, C_4-8cycloalkenyl- Ci_-6alkyl, C_6-10aryl, C_6-10aryl-C_1-6alkyl, C^eheterocyclyl, Cs-oheterocyclyl-Ci-ealkyl, C₆-ioaryl-C(=0)-C_1-6alkyl, C_3-6heterocyclyl-C(=O)-C_1-6alkyl, Ci-iohydrocarbylamino, C_6-10aryl-C(=O)-, or C_3-6heterocyclyl-C(=O)- used in defining R⁸ is optionally substituted by one or more groups selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, halogen, C_1-6alkoxy, amino, cyano, oxo, nitro, hydroxy and -NR⁴R⁵.