(19) United States US 2008.0004288A1

(12) Patent Application Publication (10) Pub. No.: US 2008/0004288 A1 Santhakumar et al. (43) Pub. Date: Jan. 3, 2008

(54) INDAZOLE SULPHONAMIDE DERIVATIVES

(75) Inventors: Vijayaratnam Santhakumar, St. Laurent (CA); Miroslaw Tomaszewski, St. Laurent (CA)

Correspondence Address: ASTRAZENECA PHARMACEUTICALS LP GLOBAL INTELLECTUAL PROPERTY 18OO CONCORD PIKE

WILMINGTON, DE 19850-5437 (US)

(73) Assignee: ASTRAZENECA AB, Sodertalje (SE)

(21) Appl. No.: 11/718,736

(22) PCT Filed: Nov. 7, 2005

(86). PCT No.: PCT/SEOS/O1669

S 371(c)(1), (2), (4) Date: May 7, 2007

(30) Foreign Application Priority Data

Nov. 11, 2004 (SE).......................................... O4O2762-9

Publication Classification

(51) Int. Cl. A6II 3L/496 (2006.01) A6II 3 L/454 (2006.01) C07D 403/02 (2006.01) A6II 3 L/46 (2006.01)

(52) U.S. Cl. .................... 514/254.06; 514/406; 514/322: 544/371; 546/199: 548/362.5

(57) ABSTRACT

O (I) R 3 \ || R

Ni R2 N N M

y R8

Compounds of formula I or pharmaceutically acceptable salts thereof: Formula (I) wherein R', R, R and Rare as defined in the specification as well as salts and pharmaceu tical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

US 2008/0004288 A1

NDAZOLE SULPHONAMIDE DERVATIVES

BACKGROUND OF THE INVENTION

0001) 0002 The invention is related to therapeutic compounds which are CB receptor ligands, pharmaceutical composi tions containing these compounds, manufacturing processes thereof and uses thereof, and more particularly to com pounds that are CB receptoragonists. More particularly, the present invention is related to compounds that may be effective in treating pain, cancer, multiple Sclerosis, Parkin son's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiovas cular disorders.

0003 2. Discussion of Relevant Technology

1. Field of the Invention

0004 Pain management has been an important field of study for many years. It has been well known that cannab inoid receptor (e.g., CB receptor, CB receptor) ligands including agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CB and/or CB receptors. Generally, CB receptors are located predominately in the central nervous system, whereas CB receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system. 0005) While CB receptor agonists, such as A-tetrahy drocannabinol (A-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 undes ired side effects are known to be mediated by the CB receptors located in CNS. There are lines of evidence, however, Suggesting that CB1 agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile.

0006) Therefore, there is a need for new CB receptor ligands such as agonists, antagonists or inverse agonists that are useful in managing pain or treating other related Symp toms or diseases with reduced or minimal undesirable CNS side-effects.

DISCLOSURE OF THE INVENTION

0007. The present invention provides CB receptor ligands which are useful in treating pain and other related symptoms or diseases. Definitions

0008 Unless specified otherwise within this specifica tion, 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. 0009 “CB/CB receptors' means CB and/or CB receptors.

Jan. 3, 2008

0010. The term “C.” or "C group' used alone or as a prefix, refers to any group having m to n carbonatoms, 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” would refer to a chemical group having 1 to 6 carbon atoms, and having 0 to 6 multivalent heteroa toms selected from O, S, N and P.

0011. 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 "hydro carbon radical' or “hydrocarby1 used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon.

0012. 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.

0013 The term “alkylene' used alone or as suffix or prefix, refers to divalent straight or branched chain hydro carbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together.

0014. The term “alkenyl used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocar bon radical having at least one carbon-carbon double bond and comprising at least 2 up to about 12 carbon atoms.

0.015 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.

0016. 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.

0017. 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.

0018. 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.

0019. 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 charac ter, (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.

0020. 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).

0021. 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.

US 2008/0004288 A1

0022. 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, con taining 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. 0023 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 heteroa toms selected from N, O, P and S. 0024. 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). 0.025 The term "heterocyclic group.”heterocyclic moi ety.”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. 0026. The term "heterocyclyl used alone or as a suffix or prefix, refers a monovalent radical derived from a hetero cycle by removing one hydrogen from a carbon of a ring of the heterocycle. 0027. 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. 0028. 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. 0029. The term "heterocylcoalkyl used alone or as a suffix or prefix, refers to a heterocyclyl that does not have aromatic character.

0030 The term "heteroarylene' used alone or as a suffix or prefix, refers to a heterocyclylene having aromatic char acter.

0031. The term "heterocycloalkylene' used alone or as a suffix or prefix, refers to a heterocyclylene that does not have aromatic character.

0032. The term “six-membered used as prefix refers to a group having a ring that contains six ring atoms. 0033. The term “five-membered” used as prefix refers to a group having a ring that contains five ring atoms. 0034. 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. 0035 Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl pyra Zolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1.2,

Jan. 3, 2008

3-thiadiazolyl, 1.2.3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thia diazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4- thiadiazolyl, and 1,3,4-oxadiazolyl. 0036) 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. 0037 Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

0038. The term “substituted” used as a prefix refers to a structure, molecule or group, wherein one or more hydro gens are replaced with one or more C-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 het eroatoms include heterocyclyl, - NO. —OR, —Cl, —Br.

- NRC(=O)R, oxo (=O), imino (=NR), thio (=S), and oximino (=N OR), wherein each “R” is a Chydrocar byl. For example, substituted phenyl may refer to nitrophe nyl, pyridylphenyl, methoxyphenyl, chlorophenyl, ami nophenyl, etc., wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring.

0.039 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 “phe nyl substituted by nitro' refers to nitrophenyl. 0040. The term “optionally substituted” refers to both groups, structures, or molecules that are substituted and those that are not substituted.

0041 Heterocycle includes, for example, monocyclic heterocycles Such as: aziridine, oxirane, thirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, Sulfolane 2,3-dihydro furan, 2.5-dihydrofuran tetrahydrofuran, thiophane, piperi dine, 1.2.3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2.3-dihydropyran, tet rahydropyran, 1.4-dihydropyridine, 1,4-dioxane, 1,3-diox ane, dioxane, homopiperidine, 2.3.4.7-tetrahydro-1H azepine homopiperazine, 1,3-dioxepane, 4.7-dihydro-1,3- dioxepin, and hexamethylene oxide.

0042. In addition, heterocycle includes aromatic hetero cycles, 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-triaz ole, 1,3,4-thiadiazole, and 1.3,4-oxadiazole. 0043. Additionally, heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroiso quinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, Xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthala

US 2008/0004288 A1

Zine, 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. 0044) 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, diazabicyclo2.2.1]hep tane and 7-Oxabicyclo2.2.1]heptane. 0045 Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiranyl, aze tidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imida Zolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, Sulfolanyl. 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1.2.3,6-tetrahydro-pyridinyl, piper azinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl. 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridi nyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2.3.4.7-tetrahydro-1H-azepinyl, homopiperazinyl, 1.3-diox epanyl, 4.7-dihydro-1,3-dioxepinyl, and hexamethylene oxidyl. In addition, heterocyclyl includes aromatic hetero cyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl pyrazolyl, isothiazolyl, isox azolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxa diazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1.3.4 oxadiazolyl. 0046 Additionally, heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tet rahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzo furanyl, 2,3-dihydrobenzofuranyl, isobenzofuranyl, chrome nyl, chromanyl, isochromanyl, Xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, perimidinyl, phenan throlinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1.2- benzisoxazolyl, benzothiophenyl, benzoxazolyl, benzthiaz olyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl, and quino lizidinyl. 0047. In addition to the polycyclic heterocyclyls described above, heterocyclyl includes polycyclic heterocy clyls 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, diazabicy clo2.2.1]heptyl; and 7-Oxabicyclo2.2.1]heptyl. 0.048. 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. Exem plary alkoxy includes methoxy, ethoxy, propoxy, isopro poxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy. 0049. The term “aryloxy' used alone or as suffix or prefix, refers to radicals of the general formula —O—Ar", wherein —Ar' is an aryl.

Jan. 3, 2008

0050. The term “heteroaryloxy” used alone or as suffix or prefix, refers to radicals of the general formula —O—Ar", wherein —Ar' is a heteroaryl. 0051. 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. 0052 “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.

0053 Halogen includes fluorine, chlorine, bromine and iodine.

0054) “Halogenated,” used as a prefix of a group, means one or more hydrogens on the group is replaced with one or more halogens. 0055) 0056. 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.

0057) “Link,”“linked,” or “linking,” unless otherwise specified, means covalently linked or bonded.

“RT or “rt’ means room temperature.

0058 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.

0059 "Saturated carbon” means a carbon atom in a structure, molecule or group wherein all the bonds con nected 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 spatomic orbital hybridization.

0060 “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 spatomic orbital hybridization.

DESCRIPTION OF PREFERRED EMBODIMENTS

0061. In one aspect, the invention provides a compound of formula I, pharmaceutically acceptable salts thereof, diastereomers, enantiomers, or mixtures thereof:

O R3 V || N

R2 I \ M

y R8

US 2008/0004288 A1

wherein

0062) R' is selected from hydrogen, Coalkyl, Coalk enyl, Coalkynyl, Cocycloalkyl, Cascycloalkenyl, Cs-ocycloalkyl-C-alkyl, Cascycloalkenyl-C-alkyl, Casheteroaryl, Co-oaryl, Co-oaryl-Coalkyl, C-heterocy cloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxycar bonyl; wherein said Coalkyl, Coalkenyl, Coalkynyl, Cs-ocycloalkyl, Cascycloalkenyl, Calocycloalkyl-C- 6alkyl, Cascycloalkenyl-C-alkyl, C-sheteroaryl, Co-oaryl, Co-oaryl-C-galkyl, Cheterocycloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxycarbonyl used in defining R is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and NRR: with one or more Substituents selected from Calkyl, Calkenyl, halogen, Calkoxy, amino, cyano, OXO, nitro, hydroxy, Co-oaryl, Co-oaryl-C-alkyl, Cheterocyclyl and Cachet erocyclyl-C-alkyl;

0063 R’ is selected from hydrogen, Coalkyl, Coalk enyl, Coalkynyl, Cocycloalkyl, Cascycloalkenyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-C-alkyl, Casheteroaryl, Co-oaryl, Co-oalkyl-C-galkyl, Chetero cycloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxy carbonyl, wherein said Coalkyl, Coalkenyl, Coalky nyl, Clocycloalkyl, Cascycloalkenyl, Cocycloalkyl-C- 6alkyl, Cascycloalkenyl-C-alkyl, C-sheteroaryl, Co-oaryl, Co-oaryl-C-galkyl, Cheterocycloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxycarbonyl used in defining R is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and NRR: with one or more Substituents selected from Calkyl, Calkenyl, halogen, Calkoxy, amino, cyano, OXO, nitro, hydroxy, Co-oaryl, Co-oaryl-C-alkyl, Cheterocyclyl and Cachet erocyclyl-C-alkyl:

0064 optionally R' and R together with the N to which they are bound may form a 3-10 membered aromatic, heteroaromatic or heterocycloalkyl ring; wherein said aro matic, heteroaromatic or heterocycloalkyl ring is optionally Substituted by one or more groups independently selected from hydrogen, Cigalkyl, C2-galkenyl, C2-galkynyl, halo gen, amino, Cigalkoxy, Calkoxy-C-alkyl, Cigalkoxy carbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy,

0065 R is selected from hydrogen, halogen, amino, Coalkyl, C2-loalkenyl, C2-loalkynyl, Cs-locycloalkyl, Cs-ocycloalkyl-C-alkyl, Cascycloalkenyl-C-alkyl, Cheterocycloalkyl-C-alkyl, Cascycloalkenyl, RRN-, Casheteroaryl, Coaryl and Cheterocy cloalkyl, wherein said amino, Coalkyl, Coalkenyl, Coalkynyl, Calocycloalkyl, Calocycloalkyl-C-alkyl, Cascycloalkenyl-C-alkyl, Cheterocycloalkyl-Calkyl, Cascycloalkenyl, R'R''N , Casheteroaryl, Coaryl and Cheterocycloalkyl used in defining R is optionally sub stituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and NRRS;

0.066 wherein R and Rare independently selected from —H, Calkyl, Calkenyl, C2-alkynyl, and a divalent C-group that together with another divalent R or R may form a ring or a portion of a ring wherein said ring is

Jan. 3, 2008

optionally Substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl and hydroxy; and 0067 R is selected from Cocycloalkyl, Cascycloalk enyl, Calocycloalkyl-Coalkyl, Cascycloalkenyl-C- 6alkyl, Coaryl, Coaryl-Calkyl, Cheterocyclyl, Cheterocyclyl-Calkyl, Caryl-C(=O)—Calkyl, Cheterocyclyl-C(=O)—Calkyl, Cohydrocarby lamino, Coaryl-C(=O)—, or Cheterocyclyl C(=O)—, wherein said Cocycloalkyl, Cascycloalkenyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-Calkyl, Co-oaryl, Co-oaryl-C-galkyl, C-heterocyclyl, C-hetero cyclyl-C-alkyl, Caryl-C(=O)—Calkyl, Chetero cyclyl-C(=O)—Calkyl, Cohydrocarbylamino, Coaryl-C(=O)—, or Cheterocyclyl-C(=O)— used in defining R is optionally substituted by one or more groups selected from hydrogen, Calkyl, Calkenyl, halogen, Calkoxy, amino, cyano, oxo, nitro, hydroxy and NRR.

0068 Particularly, the compounds of the present inven tion are those of formula I, wherein

0069) R' is selected from hydrogen, Calkyl, Calk enyl, C2-alkynyl, Cocycloalkyl, Caecycloalkenyl, Cocycloalkyl-C-alkyl, Cascycloalkenyl-C-galkyl, phe nyl, phenyl-C alkyl, Cheterocyclyl, Cheterocyclyl Calkyl or Calkoxycarbonyl; wherein said Calkyl, Calkenyl, C2-alkynyl, Cocycloalkyl, Caecycloalk enyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-C- 6alkyl, phenyl, phenyl-C alkyl, Cheterocyclyl, Chet erocyclyl-C-alkyl or Calkoxycarbonyl used in defining R" is optionally substituted by one or more groups selected from halogen, Calkyl, Calkenyl, Calkoxy, amino, OXO, cyano, nitro, hydroxy, Co-oaryl, Co-oaryl-C alkyl, Cheterocyclyl, Cheterocyclyl-C, alkyl and —NR'R''. 0070 R is selected from hydrogen, Calkyl, Calk enyl, C2-alkynyl, Cocycloalkyl, Cecycloalkenyl, Cocycloalkyl-C-alkyl, Cascycloalkenyl-C-galkyl, phe nyl, phenyl-C alkyl, Cheterocyclyl, Cheterocyclyl Calkyl or Calkoxycarbonyl; wherein said Calkyl, C2-galkenyl, C2-galkynyl, Cocycloalkyl, Caecycloalk enyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-C- 6alkyl, phenyl, phenyl-C alkyl, Cheterocyclyl, Chet erocyclyl-C-alkyl or Calkoxycarbonyl used in defining R’ is optionally substituted by one or more groups selected from halogen, Calkyl, C2-alkenyl, Calkoxy, amino, OXO, cyano, nitro, hydroxy, Coaryl, Coaryl-Calkyl, Cheterocyclyl, Cheterocyclyl-C, alkyl and —NR'R''. 0.071) R' and R can form together with the N to which they are bound may form a 3-6 membered aromatic, het eroaromatic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally Sub stituted by one or more groups independently selected from hydrogen, Calkyl, Calkenyl, Calkynyl, halogen, amino, Calkoxy, Calkoxy-C alkyl, Calkoxycarbo nyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy:

0072 R is selected from hydrogen, halogen, amino, Calkyl, Calkenyl, C2-alkynyl, C-acycloalkyl, Calcy cloalkenyl, C-sheteroaryl, R'R''N-, Cacycloalkyl-C. 4alkyl, Caecycloalkenyl-Calkyl, phenyl, phenyl-C- 4alkyl, Cheterocyclyl or Cheterocyclyl-C alkyl; wherein said amino, Calkyl, C2-alkenyl, C2-galkynyl,

US 2008/0004288 A1

Cs-cycloalkyl, Cacycloalkenyl, C-sheteroaryl, R'R''N-, C-cycloalkyl-C alkyl, Caecycloalkenyl-C-alkyl, phe nyl, phenyl-C alkyl, Cheterocyclyl or Cheterocyclyl Calkyl used in defining R is optionally substituted by one or more groups selected from Calkyl, Calkenyl, halo gen, Calkoxy, amino, nitro, cyano, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, Cecycloalkyl-Calkyl, Chet erocyclyl, Cheterocyclyl-C-alkyl, and —NR'R''. 0073 wherein R and Rare independently selected from —H, Calkyl, Calkenyl, C2-alkynyl, and a divalent C group that together with another divalent R or R 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 0074 R is selected from Cecycloalkyl, C-cycloalkyl Calkyl, Caecycloalkenyl, Co-oaryl, phenyl, phenyl-C- 4alkyl, Cheterocyclyl or Cheterocyclyl-Calkyl: wherein said Cecycloalkyl, C-acycloalkyl-Calkyl, Caecycloalkenyl, Coaryl, phenyl, phenyl-Calkyl, Cheterocyclyl or Cheterocyclyl-Calkyl used in defining R is optionally substituted by one or more groups Selected from Calkyl, Calkoxy, halogen, cyano, amino, nitro, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, and NRR.

0075 More particularly, the compounds of the present invention are those of formula I,

0076) R' is selected from hydrogen, Calkyl, Calk enyl, C2-alkynyl, C-scycloalkyl, Caecycloalkenyl, Cascy cloalkenyl-C-alkyl, C-scycloalkyl-Calkyl, phenyl, phe nyl-Calkyl, Cheterocyclyl, Cheterocyclyl-Calkyl or Calkoxycarbonyl; wherein said Calkyl, Calkenyl, C2-galkynyl, Cascycloalkyl, Caecycloalkenyl, Cascy cloalkenyl-C-alkyl, C-scycloalkyl-Calkyl, phenyl, phe nyl-Calkyl, Cheterocyclyl, Cheterocyclyl-Calkyl or Calkoxycarbonyl used in defining R' is optionally Substituted with one or more groups selected from Calkyl, halogen, Calkoxy, amino, cyano, OXO. hydroxy, Calhet erocyclyl, Cheterocyclyl-Calkyl, Csaryl, Csaryl-C- 4alkyl;

0077 R’ is selected from hydrogen, Calkyl, Calk enyl, C2-alkynyl, Cascycloalkyl, Caecycloalkenyl, Cascy cloalkenyl-C-alkyl, C-scycloalkyl-Calkyl, phenyl, phe nyl-Calkyl, Cheterocyclyl, Cheterocyclyl-Calkyl or Calkoxycarbonyl; wherein said Calkyl, Calkenyl, C2-galkynyl, Cascycloalkyl, Caecycloalkenyl, Cascy cloalkenyl-C-alkyl, C-scycloalkyl-Calkyl, phenyl, phe nyl-Calkyl, Cheterocyclyl, Cheterocyclyl-Calkyl or C-3alkoxycarbonyl used in defining R is optionally Substituted with one or more groups selected from Calkyl, halogen, Calkoxy, amino, cyano, OXO. hydroxy, Calhet erocyclyl, Cheterocyclyl-Calkyl, Cosaryl, Co-saryl-C- 4alkyl;

0078) R' and R 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-triaz olyl, 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-di oxanyl, 1.3-dioxepanyl, 1,4-benzodioxanyl, 1,4-dihydropy ridinyl, 1,4-dioxanyl, 2.3.4.7-tetrahydro-1H-azepinyl, 2.3- dihydrobenzofuranyl, 2,3-dihydrofuranyl, 2,3-

Jan. 3, 2008

dihydropyranyl. 2,5-dihydrofuranyl, 4,7-dihydro-1,3- dioxepinyl, aZetidinyl, aziridinyl, benzofuranyl, chromanyl. chromenyl, dioxanyl, dioxolanyl, furazanyl, furyl, hexam ethylene homopiperazinyl, imidazolidinyl, indazolyl, indolizinyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naph thyridinyl, oxazolyl, oxetanyl, oxidyl, oxiranyl, phenox athiinyl, phthalazinyl, phenyl, piperazinyl, piperidinyl, puri nyl, pyranyl, pyrazinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, quinazolinyl quinolinyl, quinox alinyl sulfolanyl, tetrahydrofuranyl, tetrahydroisoquinoli nyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, thi anthrenyl, thiazolyl, thienyl, thietanyl, thiranyl. thiomorpholinyl, thiophanyl, thiopyranyl, triazinyl and Xan thenyl:

0079 wherein said 1.2.3,6-tetrahydro-pyridinyl, 1,2,3- oxadiazolyl, 1.2.3-thiadiazolyl, 1.2.3-triazolyl, 1,2,4-Oxa diazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiaz olyl, 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-1H-azepinyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrofuranyl, 2,3- dihydropyranyl. 2,5-dihydrofuranyl, 4,7-dihydro-1,3- dioxepinyl, aZetidinyl, aziridinyl, benzofuranyl, chromanyl. chromenyl, dioxanyl, dioxolanyl, furazanyl, furyl, hexam ethylene homopiperazinyl, imidazolidinyl, indazolyl, indolizinyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naph thyridinyl, oxazolyl, oxetanyl, oxidyl, oxiranyl, phenoxathi nyl, phthalazinyl, phenyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, quinazolinyl quinolinyl, quinoxalinyl Sulfola nyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydro pyranyl, tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thia Zolyl, thienyl, thietanyl, thiranyl, thiomorpholinyl, thiophanyl, thiopyranyl, triazinyl and Xanthenyl used in defining R' and R together is optionally substituted by one or more groups selected from Calkyl, Calkenyl, Calkynyl, hydrogen, halogen, amino, Calkoxy, Calkoxy-C-alkyl, Calkoxycarbonyl, carbonyl, car bamoyl, acetyl, acetylamino and hydroxy:

0080 R is selected from hydrogen, halogen, amino, Coalkyl, C2-galkenyl, C-cycloalkyl, C-cycloalkyl-C- 4alkyl, Cheterocyclyl or Cheterocyclyl-Calkyl wherein said amino, Calkyl, Calkenyl, Cecycloalkyl, Cecycloalkyl-C alkyl, Cheterocyclyl or Cheterocy clyl-C-alkyl used in defining R is optionally substituted with one or more groups selected from Calkyl, halogen, Calkoxy, methoxy, ethoxy, methyl, ethyl, hydroxy, Cheterocyclyl, Cheterocyclyl-C-alkyl and —NR'R''. 0081 wherein R and Rare independently selected from —H, C-alkyl, Calkenyl, Calkynyl, and a divalent Cagroup that together with another divalent R' or R 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

I0082 R is selected from phenyl, allyl, phenyl-C alkyl, Cecycloalkyl-Calkyl, Caecycloalkenyl-Calkyl, Cheterocycloalkyl, Cheterocycloalkyl-C alkyl, Co-oaryl, C-cycloalkyl, and Caecycloalkenyl, wherein said phenyl, phenyl-C alkyl, Cecycloalkyl-C alkyl, Caecycloalkenyl-Calkyl, C-heterocycloalkyl, Calhet

US 2008/0004288 A1

erocycloalkyl-C alkyl, Co-oaryl, Caecycloalkyl, and Cacycloalkenyl, used in defining R is optionally substi tuted by one or more groups selected from Calkyl, Calkoxy, halogen, amino, cyano, OXO, methoxy, ethoxy, methyl, ethyl, hydroxy, and NR'R''. 0.083 Most particularly, the compounds of the present invention are those of formula I, wherein I0084) R' is selected from hydrogen, methyl, ethyl, pro pyl. n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropy lmethyl, 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, cyclo hexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahy drothiophenyl, phenyl, phenylmethyl 2-phenylethyl, pyri midinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl used in defining R' is optionally sub stituted with one or more groups selected from Calkyl, halogen, Calkoxy, amino, cyano, oxo, hydroxy, pyrrolidi nyl and phenylmethyl; I0085) R is selected from hydrogen, methyl, ethyl, pro pyl. n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, cyclohexyl, cyclopropy lmethyl, 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, cyclo hexyl, cyclopropylmethyl, cyclohexylmethyl, tetrahy drothiophenyl, phenyl, phenylmethyl 2-phenylethyl, pyri midinyl, furanylmethyl, pyridinylmethyl, pyrazinylmethyl or methoxycarbonyl used in defining R is optionally sub stituted with one or more groups selected from Calkyl, halogen, Calkoxy, amino, cyano, oxo, hydroxy, pyrrolidi nyl and phenylmethyl; 0086) R' and R together with the N to which they are bound may form a group selected from cyclohexyl, 1.2.3, 6-tetrahydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl or morpholinyl; wherein said cyclohexyl, 1.2.3, 6-tetrahydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl or morpholinyl used in defining R' and R' together is optionally substituted by one or more groups Selected from Calkyl, C2-alkenyl, C2-alkynyl, hydrogen, halogen, amino, Calkoxy, Calkoxy-C-alkyl, Calkoxycarbonyl, carbonyl, carbamoyl, acetyl, acety lamino and hydroxy: 0087 R is selected from hydrogen, Cl, diethylamino, cyclohexylmethylamino, piperidinyl, morpholinyl, piperazi nyl, pyrrolidinyl, t-butyl, n-butyl, 2-methyl-2-butyl, isopen tyl, 2-methoxy-2-propyl, 2-hydroxyl-propyl, 1-methyl-pro pyl, 1,1-dimethyl-propyl, 1,1-dimethyl-3-buten-1-yl, ethyl, 2-propyl and NR'R'; wherein said diethylamino, cyclo hexylmethylamino, 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, 1,1-dimethyl-3-buten-1-yl, ethyl, 2-propyl and NR'R' used in defining R is optionally Substituted with one or more groups selected from hydrogen and methyl; 0088 wherein R and Rare independently selected from —H, C-alkyl, Calkenyl, Calkynyl, and a divalent

Jan. 3, 2008

Cagroup that together with another divalent R' or R 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 0089 R is selected from phenyl, allyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopen tyl, tetrahydropyranyl, tetrahydrofuranyl, 1-piperidinyl, N-methyl-2-piperidinyl and benzyl; wherein said phenyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclo hexyl, cyclopentyl, tetrahydropyranyl, tetrahydrofuranyl. 1-piperidinyl, N-methyl-2-piperidinyl and benzyl used in defining R is optionally substituted by one or more groups selected from Calkyl, Calkoxy, fluorine, chlorine, amino, cyano, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, and trifluoromethyl. 0090. 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 mix ture. The present invention includes any possible enanti omers, 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.

0091. 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.

0092. 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. 0093. Within the scope of the invention are also salts of the compounds of the formula I. Generally, pharmaceuti cally 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 com pound, 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 corre sponding 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 conven tional purification techniques. 0094. 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, fuma rate, maleate, tartrate, citrate, methaneSulphonate or p-tolu enesulphonate.

US 2008/0004288 A1

0.095 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 CB1 receptors. More particularly, the compounds of the invention exhibit selec tive activity as agonist of the CB1 receptors and are useful in therapy, especially for relief of various pain conditions Such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present inven tion are useful in other disease states in which dysfunction of the CB1 receptor is present or implicated. Furthermore, the compounds of the invention may be used to treat cancer, multiple Sclerosis, Parkinson's disease, Huntington's cho rea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiavascular disorders.

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

0097 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 applica tions such as positron emission tomography (PET).

0.098 Compounds of the invention are useful for the treatment of diarrhea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic dis order, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, pre mature ejaculation, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipa tion, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parlkinson'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.

0099 Compounds of the invention are useful as an anal gesic 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, anxiolyt ics, neuromuscular blockers and opioids.

0100 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.

0101. A further aspect of the invention is a method for the treatment of a subject Suffering from any of the conditions discussed above, whereby an effective amount of a com pound according to the formula I above, is administered to a patient in need of Such treatment.

Jan. 3, 2008

0102) Thus, the invention provides a compound of for mula I, or pharmaceutically acceptable salt or Solvate thereof, as hereinbefore defined for use in therapy. 0103) 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. 0104. In the context of the present specification, the term “therapy' also includes “prophylaxis' unless there are spe cific 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 com pound 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 contin ued therapy for chronic disorders. 0105 The compounds of the present invention are useful in therapy, especially for the therapy of various pain con ditions including, but not limited to: acute pain, chronic pain, neuropathic pain, acute pain, back pain, cancer pain, and visceral pain. 0106. In use for therapy in a warm-blooded animal such as a human, the compound of the invention may be admin istered in the form of a conventional pharmaceutical com position by any route including orally, intramuscularly, Subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.

0.107. In one embodiment of the invention, the route of administration may be orally, intravenously or intramuscu larly.

0108. The dosage will depend on the route of adminis tration, the severity of the disease, age and weight of the patient and other factors normally considered by the attend ing physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient. 0.109 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.

0.110) A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, Solubiliz ers, lubricants, Suspending agents, binders, or table disinte grating agents; it can also be an encapsulating material.

0111. 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. 0112 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.

US 2008/0004288 A1

0113 Suitable carriers are magnesium carbonate, mag nesium Stearate, talc, lactose, Sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, Sodium carboxymethyl cellu lose, a low-melting wax, cocoa butter, and the like. 0114. The 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.

0115 Tablets, powders, cachets, and capsules can be used as Solid dosage forms suitable for oral administration. 0116 Liquid form compositions include solutions, sus pensions, 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.

0117 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. 0118 Depending on the mode of administration, the pharmaceutical composition will preferably include from 0.05% to 99% w (percent 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.

0119) 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. 0120. Within the scope of the invention is the use of any compound of formula I as defined above for the manufacture of a medicament.

0121 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. 0122) 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.

0123. 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 com pound according to the formula I above, is administered to a patient in need of Such therapy. 0.124. 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.

Jan. 3, 2008

0.125 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. 0.126 Further, there is provided a pharmaceutical com position comprising a compound of Formula I, or a phar maceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the con ditions discussed above.

0127. In a further aspect, the present invention provides a method of preparing the compounds of the present inven tion.

0128. In one embodiment, the invention provides a pro cess for preparing a compound of Formula II, comprising of the step of

II R1 O 3 V || R

Ni R2 \ M

y R8

reacting a compound of formula III,

III

V O C

N R / \ M

y R8

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

I0129) R' is selected from hydrogen, Coalkyl, Coalk enyl, Coalkynyl, Cocycloalkyl, Cascycloalkenyl, Cocycloalkyl-C-alkyl, Cascycloalkenyl-C-alkyl, Casheteroaryl, Co-oaryl, Co-oaryl-C1-alkyl, C-heterocy cloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxycar bonyl; wherein said Coalkyl, C2-oalkenyl, Coalkynyl, Cocycloalkyl, Cascycloalkenyl, Cocycloalkyl-C- 6alkyl, Cascycloalkenyl-Coalkyl, C-sheteroaryl, Coaryl, Coaryl-Calkyl, Cheterocycloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxycarbonyl used in defining R is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and NR'R'; with one or more substituents selected from Caryl, Calkenyl, halo gen, Cigalkoxy, amino, cyano, Oxo, nitro, hydroxy, Co-oaryl, Co-oaryl-C-alkyl, Cheterocyclyl and Chet erocyclyl-C-alkyl;

US 2008/0004288 A1

0130 R is selected from hydrogen, Coalkyl, Coalk enyl, Coalkynyl, Cocycloalkyl, Cascycloalkenyl, Cs-ocycloalkyl-C-alkyl, Cascycloalkenyl-C-alkyl, C-sheteroaryl, Coaryl, Coaryl-C-alkyl, Cheterocy cloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxycar bonyl; wherein said Coalkyl, Coalkenyl, Coalkynyl, Cs-ocycloalkyl, Cascycloalkenyl, Calocycloalkyl-C- 6alkyl, Cascycloalkenyl-Coalkyl, C-sheteroaryl, Coaryl, Coaryl-C-alkyl, Cheterocycloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxycarbonyl used in defining R is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and NRR: with one or more Substituents selected from Calkyl, Calkenyl, halogen, Calkoxy, amino, cyano, OXO, nitro, hydroxy, Coaryl, Coaryl-C-alkyl, Cheterocyclyl and Chet erocyclyl-C-alkyl;

0131 optionally R' and R together with the N to which they are bound may form a 3-10 membered aromatic, heteroaromatic or heterocycloalkyl ring; wherein said aro matic, heteroaromatic or heterocycloalkyl ring is optionally Substituted by one or more groups independently selected from hydrogen, Calkyl, Calkenyl, C2-alkynyl, halo gen, amino, Cigalkoxy, Calkoxy-C-alkyl, Cigalkoxy carbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy,

0132) R is selected from hydrogen, halogen, amino, Coalkyl, C2-loalkenyl, C2-loalkynyl, Cocycloalkyl, Cs-ocycloalkyl-C-alkyl, Cascycloalkenyl-C-alkyl, Cheterocycloalkyl-C-alkyl, Cascycloalkenyl, RRN-, Casheteroaryl, Coaryl and Cheterocy cloalkyl, wherein said amino, Coalkyl, Coalkenyl, Coalkynyl, Calocycloalkyl, Calocycloalkyl-C-alkyl, Cascycloalkenyl-C-alkyl, Cheterocycloalkyl-C-alkyl, Cascycloalkenyl, R'R''N , C-sheteroaryl, Coaryl and Cheterocycloalkyl used in defining R is optionally sub stituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and NRRS;

0133) wherein R and Rare independently selected from —H, Calkyl, Calkenyl, C2-alkynyl, and a divalent C group that together with another divalent R or R 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

0134) R is selected from Cocycloalkyl, Cascycloalk enyl, Calocycloalkyl-Coalkyl, Cascycloalkenyl-C- 6alkyl, Coaryl, Coaryl-Calkyl, Cheterocyclyl, Cheterocyclyl-Calkyl, Caryl-C(=O)—C-alkyl, Cheterocyclyl-C(=O)—Calkyl, Cohydrocarby lamino, Coaryl-C(=O)—, or Cheterocyclyl C(=O)—, wherein said Cocycloalkyl, Cascycloalkenyl, Cs-ocycloalkyl-C-alkyl, Cascycloalkenyl-C-alkyl, Co-oaryl, Co-oaryl-Coalkyl, C-heterocyclyl, Chetero cyclyl-Calkyl, Caryl-C(=O)—Calkyl, Chetero cyclyl-C(=O)—Calkyl, Cohydrocarbylamino, Caryl-C(=O)—, or Cheterocyclyl-C(=O)— used in defining R is optionally substituted by one or more groups selected from hydrogen, Calkyl, Calkenyl, halogen, Calkoxy, amino, cyano, oxo, nitro, hydroxy and NRR.

Jan. 3, 2008

0.135 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):

O RCHY, N O -

DMF, 100 C.

N Y = Cl, Br N

M N H

O2 O

CS M N

2

NHNH2 Dioxan, 100 C. --

R8 = 4-Fluorophenyl 2,6-Dichlorophenyl phenyl 3-Chlorophenyl 2-Fluorophenyl 2-trifluoromethylphenyl

General Procedure 2 (Alkylation of Indazoles)

C C

8 \ NaH, RCHY, \ / DMF M He

N Y = Cl, Br y

R8 R = Phenyl, 4-Fluorophenyl

US 2008/0004288 A1 Jan. 3, 2008 10

General Procedure 3 (Synthesis of Pyrrolidinyl Indazoles) General Procedure 6 (Synthesis of Indazole Sulphonamides)

NH2 Br Br X

Y ? (1) Chlorosulfonic acid N N DCM N -- N - --

M Cs2CO3 M (2) Thionyl chloride N DMF, 100 C. N

V R O

R8 | X S RRNH 1. r2|Y 1.

C11 W. N EtN, DCE O N --- N /

N V

N R N O

N? RR2NN X S M ) O \

R8 M N R = 2,6-Dichlorophenyl

Phenyl R 3-Chlorophenyl 2-Trifluoromethylphenyl

R = 4-Fluorophenylmethyl 2,6-Dichlorophenylmethyl

O Phenylmethyl 3-Chlorophenylmethyl X = H, C1 t y pheny y \xis C ly 2-Fluorophenylmethyl 2-Trifluoromethylphenylmethyl N N N ylphenylmethy

H H H General Procedure 4 (Reductive Alkylation of Amino Inda- Phenyl Zoles) Allyl

General Procedure 7 (Amination of 3-chloro Indazole Sul u? phonamides)

NH2 N

O C N CHCHO N RR3N RRsNH, He N NaHBOAc), N / N Pd(OAc)

N DCM N O N NaOtBu, toluene

M N

R8 R8 R = 4-Fluorophenyl

2,6-Dichlorophenyl Phenyl tBuP 3-Chlorophenyl 110° C. 2-Fluorophenyl 2-Trifluoromethylphenyl F

O NRR RR2NN R4RS General Procedure 5 (Amination of 3-chloroindazoles) 7 N

O N

N? O

O

N N H

1.5 eq NaO'Bu RRSN = N 0.05 eq Pd(OAc) N 5 C D HN ) 0.1 eqNolan's ligand ) N N H H Xylene, reflux

R8 R8 R =Phenyl

4-Fluorolphenyl 0.136 Compounds of the present invention may be pre pared according to the synthetic routes as depicted in Schemes 1-3 using one or more methods disclosed herein.

US 2008/0004288 A1

-continued

Biological Evaluation

hCB and hCB Receptor Binding

0137 Human CB receptor from Receptor Biology (hCB1) or human CB receptor from BioSignal (hCB2) membranes are thawed at 37° C., passed 3 times through a 25-gauge blunt-end needle, diluted in the cannabinoid bind ing buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl, 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 ICs of the compounds of the inven tion at hCB and hCB are evaluated from 10-point dose response curves done with H-CP55,940 at 20000 to 2500 G. dpm per well (0.17-0.21 nM) in a final volume of 300 ul. The total and non-specific binding are determined in the absence and presence of 0.2 uM 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 har vester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl, 0.5 mg BSA 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 ul/well of MS-20 scintillation liquid.

hCB and hCB2 GTPYS Binding 0138 Human CB receptor from Receptor Biology (hCB1) or human CB receptor membranes (BioSignal) are thawed at 37° C., passed 3 times through a 25-gauge blunt-end needle and diluted in the GTPYS binding buffer (50 mM Hepes, 20 mMNaOH, 100 mMNaCl, 1 mM EDTA, 5 mM MgCl, pH 7.4, 0.1% BSA). The ECs and E of the compounds of the invention are evaluated from 10-point dose-response curves done in 300 ul with the appropriate amount of membrane protein and 100000-130000 dpm of GTPgS per well (0.11-0.14 nM). The basal and maximal stimulated binding is determined in absence and presence of 1 uM (hCB) or 10 uM (hCB1) Win 55,212-2 respectively. The membranes are pre-incubated for 5 minutes with 56.25 uM (hCB2) or 112.5uM (hCB) GDP prior to distribution in plates (15 uM (hCB) or 30 uM (hCB) GDP final). The

Jan. 3, 2008

O R,R.N.N. NRRs

S M

M N

R

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

H N HN

RRsN = N H N

plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifilters GF/B (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl, 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 ul/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 con centration of agonist. 0.139 Based on the above assays, the dissociation con stant (Ki) for a particular compound of the invention towards a particular receptor is determined using the fol lowing equation:

0140. Wherein ICs is the concentration of the compound of the invention at which 50% displacement has been observed; 0.141 rad) is a standard or reference radioactive ligand concentration at that moment; and 0.142 Kd is the dissociation constant of the radioactive ligand towards the particular receptor. 0.143 Using above-mentioned assays, the Ki towards human CB receptors for most compounds of the invention is measured to be in the range of 36-5700 nM. The Ki towards human CB receptors for most compounds of the invention is measured to be in the range of about 1.6-36 nM.

EXAMPLES

0144. The invention will further be described in more detail by the following Examples which describe methods whereby compounds of the present invention may be pre pared, purified, analyzed and biologically tested, and which are not to be construed as limiting the invention. 0145 Where retention time (t) values are provided the LC/MS conditions were as follows: column: Phenomenex

US 2008/0004288 A1

Synergy 4u Polar-RP 80A, 30x2.00 mm; 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-equilibration time: 0.5 min. at 10% B. Where capacity factor (k") 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, 1 mL/min, 40° C.

Example 1

3-chloro-1-(4-fluorobenzyl)-N,N-dipropyl-1H-inda Zole-5-sulfonamide

0146)

Step A. 3-chloro-1-(4-fluorobenzyl)-N,N-dipropyl 1H-indazole-5-sulfonamide

0147)

C \/ C 1

\ C \ M M N -- N --

F F

V/ C -S

0148. To a solution of alkyl-indazole (1 equiv.) in dichlo romethane (20 ml/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).

Jan. 3, 2008

The indazole-Sulfonic acid appears as brown oil that sepa rates from the solvent. The reaction was cooled to room temperature. Thionyl chloride (1 ml/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 con centrated in vacuo. The crude compound was dissolved in dichloroethane (20 ml/mmol 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 1 h). More dichloroethane was added and the organic phase was washed with a 1N aqueous HCl solution, saturated NaHCO, and brine, and was then dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography to provide the title com pound. After flash chromatography (dichloromethane to 1:99 methanol: dichloromethane), the title compound (20.22 g, 37%) was obtained as a white solid. 'H-NMR (CDOD): 5 ppm 0.77 (t, J=7.42 Hz, 6H), 1.45 (sextuplet, J=7.38 Hz, 4H), 2.98-3.02 (m, 4H), 5.52 (s. 2H), 6.96 (t, J=8.69 Hz, 2H), 7.23 (dd, J=8.40 Hz, 5.27 Hz, 2H), 7.69 (d. J=8.98 Hz, 1H), 7.73-7.76 (m. 1H), 8.04-8.05 (s, 1H). MS (ESI) (M+H)"=424.

Step B. 3-chloro-1-(4-fluorobenzyl)-1H-indazole

0149)

C C

YN N^N

0150. 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 0° C. The reaction mixture was stirred at 0°C. for 1 h. 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 1N aqueous HCl solution, saturated NaHCO, and brine, and was then dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography to provide the title compound. The title compound (2.10 g, 87%) was obtained as a white solid. 'H-NMR (CDC1): 8 ppm 5.50 (s, 2H), 6.99 (m, 2H), 7.21 (m, 3H), 7.31 (dt, J=8.59 Hz, 0.88 HZ, 1H), 7.40 (ddd, J=8.40 Hz, 6.93 Hz, 1.07 Hz, 1H), 7.69

US 2008/0004288 A1 14

(dt, J=8.10, 1.12 Hz, 1H). MS (ESI) (M+H)"=261. Anal. Calcd for CHCIFN: C, 64.50; H, 3.87; N, 10.75. Found: C, 64.92; H, 3.86; N, 10.78.

Example 2

1-(3-chlorophenyl)methyl-N-3-(dimethylamino )propyl)-3-(1-pyrrolidinyl)-1H-indazole-5-sulfona

mide

0151)

Y. n-1N1 \ \, N N

o Step A. 1-(3-chlorophenyl)methyl-N-3-(dimethy lamino)propyl)-3-(1-pyrrolidinyl)-1H-indazole-5-

NS

Sulfonamide

0152)

C N N M

N ---

C

O. O C \/ 1. C N N

M N

C

Jan. 3, 2008

-continued

Y- n1N1 in \ \, N N

C

0153. Following the same procedure as Example 1, Step A, the title compound (0.09 g, 52%) was obtained as a white solid. 'H NMR (400 MHz, CHLOROFORM-D) 8 ppm 1.86 (m. 2H)2.05 (m, 4H)2.52 (s, 6H)2.57 (m, 2H)2.72 (m, 2H) 3.06 (d. J=5.08 Hz, 2H)3.68 (d. J=6.44 Hz, 3H) 5.36 (s. 2H) 7.06 (m, 1H) 7.23 (m, 4H) 7.70 (m, 1H) 8.37 (s, 1H). MS (ESI) (M+H)"=476

Step B. 1-(3-chlorophenyl)methyl-3-(1-pyrrolidi nyl)-1H-indazole

0154)

NH2

\ M N

C

C \ M

N

C

0.155 1,4-dibromobutane (0.9 equiv) was added to a mixture of the amine (1 equiv.), DMF (5 mL/mmolamine) and CSCO (2 equiv.). The mixture was heated at 80 C 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 NaSO, filtered, concentrated in vacuo and the residue was purified by flash chromatography. The title compound (1.12 g, 72%) was obtained as pale brown oil. MS (ESI) (M+H)"=312.

US 2008/0004288 A1

Example 3

N-(cyclopropylmethyl)-3-(diethylamino)-1-(4-fluo rophenyl)methyl-N-propyl-1H-indazole-5-sulfona

mide

0156)

Step A. N-(cyclopropylmethyl)-3-(diethylamino)-1- (4-fluorophenyl)methyl-N-propyl-1H-indazole-5-

Sulfonamide

O157)

Su N N M N Her

F

O l u? N

1. C I \ M He

N

Jan. 3, 2008

-continued

Su W N

M N

F

0158. Following the same procedure as Example 1, Step A, the title compound (0.16 g. 68%) was obtained as a white solid. "H NMR (400 MHz, CHLOROFORM-D) 8 ppm 0.16 (m. 2H) 0.49 (m, 2H) 0.89 (m, 4H) 1.28 (m, 6H) 1.61 (m, 2H)3.07 (t, J=6.84 Hz, 2H)3.20 (m, 2H)3.59 (m, 4H) 5.37 (s. 2H) 6.98 (m, 2H) 7.17 (m, 3H) 7.64 (m. 1H) 8.30 (s, 1H). MS (ESI) (M+H)"=473

Step B. N.N-diethyl-1-(4-fluorophenyl)methyl)-1H indazol-3-amine

0159)

NH2 SJ

Y - O). M M N N

F F

0.160 Sodium triacetoxyborohydride (10 equiv) was added portionwise to a mixture of the amine (1 equiv.). 1,2-dichloroethane (15 mL/mmol amine), acetaldehyde (5 equiv.) and acetic acid (0.2 equiv.). The mixture was stirred at room temperature overnight. The reaction was then diluted with 2Maqueous NaOH, and the aqueous phase was extracted with CHCl (3x). The combined organic phases were dried over NaSO, filtered, and concentrated in vacuo to give products with >90% purity by LC/MS. The title compound (0.98 g. 92%) was obtained as pale brown oil. MS (ESI) (M+H)"=298.

US 2008/0004288 A1

Example 4

4-1-(2,6-dichlorophenyl)methyl-3-(diethy lamino)-1H-indazol-5-yl)sulfonyl-, 1-piperazinecar

boxylic acid, ethyl ester

0161)

N Y-- / \, N N

C

Step A. 4-1-(2,6-dichlorophenyl)methyl-3-(di ethylamino)-1H-indazol-5-yl)sulfonyl-, 1-piperazi

necarboxylic acid, ethyl ester

0162

N V -Cl V Or \, N

N

C

C

Jan. 3, 2008 16

-continued

C

0.163 Following the same procedure as Example 1, Step A, the title compound (0.18 g. 65%) was obtained as a white solid. "H NMR (400 MHz, CHLOROFORM-D) 8 ppm 1.19 (m, 9H) 2.59 (s, 3H) 3.00 (m, 3H) 3.54 (m, 6H) 4.07 (q, J=7.23 Hz, 2H) 5.65 (s, 2H) 7.25 (dd, J=8.89, 7.52 Hz, 1H) 7.38 (m, 3H) 7.62 (dd, J=8.98, 1.56 Hz, 1H) 8.20 (d. J=0.78 HZ, 1H). MS (ESI) (M+H)"=568.

Step B. 1-(2,6-dichlorophenyl)methyl-N,N-di ethyl-1H-indazol-3-amine

0164)

NH2 N

\ \ M M N N

C C

C C

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

US 2008/0004288 A1

Example 5

1-(4-fluorobenzyl)-3-(4-methylpiperazin-1-yl)-N,N- dipropyl-1H-indazole-5-sulfonamide

0166)

Step A. 1-(4-fluorobenzyl)-3-(4-methylpiperazin-1- yl)-N,N-dipropyl-1H-indazole-5-sulfonamide

0167)

V/ N 1. \

M N

F

0168 A solution of the chloroindazole sulphonamide (1 equiv.) in toluene (15 mL/mmol chloroindazole Sulphona mide) was placed in a N purged flask. NaOtBu (1.5 equiv.). 2-(di-tert-butylphosphino)biphenyl (0.1 equiv.), Pd(OAc), (0.05 equiv.) and the amine (10 equiv.) were added sequen

Jan. 3, 2008

tially, and the resulting mixture was heated at 110° C. until the chloroindazole was consumed (typically 8 h). The reac tion 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 com pound as the HCl salt. After flash chromatography (3:97 methanol:dichloromethane), the title compound (140 mg. 81%) was obtained as a pale yellow solid. 'H-NMR (CDOD): 8 ppm 0.83 (t, J=7.32 Hz, 6H), 1.51 (sext, J=7.42 Hz, 4H), 2.96 (s, 3H), 3.06 (m, 4H), 3.34 (m, 4H), 3.61 (m, 2H), 4.06 (m, 2H), 5.47 (m, 2H), 7.00 (m, 2H), 7.24 (m, 2H), 7.62 (m. 1H), 7.71 (m, 1H), 8.21 (m, 1H). MS (ESI) (M+H)"=488; k': 4.6. Anal. Calcd for CHFNOS+1.7 HC1+0.4 C.H.O. (dioxane): C, 54.63; H, 6.40; N, 11.97. Found: C, 54.76; H, 6.73; N, 12.01.

Step B. 3-chloro-1-(4-fluorobenzyl)-N,N-dipropyl 1H-indazole-5-sulfonamide

0169

C \/ C 1.

\ C \ M M N He- N

F F

W C N1

0170 Following the same procedure as Example 1, Step A, after flash chromatography (dichloromethane to 1:99 metharnol:dichloromethane), the title compound (2.22 g, 37%) was obtained as a white solid. 'H-NMR (CDOD): 8 ppm 0.77 (t, J=7.42 Hz, 6H), 1.45 (sextuplet, J=7.38 Hz, 4H), 2.98-3.02 (m, 4H), 5.52 (s. 2H), 6.96 (t, J=8.69 Hz, 2H), 7.23 (dd, J=8.40 Hz, 5.27 Hz, 2H), 7.69 (d. J=8.98 Hz, 1H), 7.73-7.76 (m. 1H), 8.04-8.05 (s, 1H). MS (ESI) (M+H)"=424.

US 2008/0004288 A1 Jan. 3, 2008 19

J=1.17 Hz, 1H). MS (ESI) (M+H)"=501. Anal. Calcd for CHFNOS+0.6 HCl: C, 62.06; H, 7.25: N, 10.72. -continued Found: C, 61.99: H 7.02: N, 10.62. O O Ol s s s s s \/ H

Example 8 N-11 N 1-(4-fluorobenzyl)-N,N-dipropyl-1H-indazole-5- N

Sulfonamide N

0177)

O. O

\/ H 1. F

N \ N^

0179 To a solution of 3-chloro-1-(4-fluorobenzyl)-N,N- dipropyl-1H-indazole-5-sulfonamide (484. Omol) in DMSO (343 Ol. 4.8 mmol) and THF (2.5 ml) at -20°C. was added a solution of potassium tert-butoxide (379 mg, 3.4 mmol) in THF (5 ml) at -20° C. Air was bubbled into the reaction

F mixture for 15 minutes. The reaction was quenched with a 5% KHSO aqueous Solution. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 30-80% CHCN in HO) to provide the TFA salt of the title compound as a colourless oil.

O O C 'H-NMR (CDC1): 8 ppm 0.87 (t, J-7.32 Hz, 6H), 1.56 V/ (sextuplet, J=7.32 Hz, 4H), 3.06-3.10 (m, 4H), 5.59 (s. 2H),

N N 6.98-7.03 (m, 2H), 7.18-7.22 (m, 2H), 7.42 (d. J=8.79 Hz, N DMSO, KOtBus THF 1H), 7.74 (dd, J=8.88 Hz, 1.66 Hz, 1H), 8.17 (s, 1H), 8.29

N^ -20° C. (d. J=0.98 Hz, 1H). MS (ESI) (M+H)"-390.

0180. The following exemplify some of the compounds of the present invention that were made according to the schemes and methods described above. These compounds

1-(4-fluorobenzyl)-N,N-dipropyl-1H-indazole-5- Sulfonamide

0178)

were found to be active towards the human CB receptor F based on the test results of using one or more assays

described above.

Observed

Example Mass

No. Structure (MH-H) tr (min)

461 2.03

US 2008/0004288 A1 20

-continued

Example

10 \- ou

11

12

13

Observed Mass

(MH+) tr. (min)

489 2.14

459 1.99

487 1.89

523 2.21

Jan. 3, 2008

US 2008/0004288 A1

Example

14

15

16

17

-continued

Structure

21

Observed Mass

(MH-H) tr (min)

519 2.03

529 2.14

445 1.93

485 2.06

Jan. 3, 2008

US 2008/0004288 A1

Example No.

18

19

-continued

Structure

22

Observed

Mass

(MH-H) tr (min)

473 2.09

499 1.98

475 1.86

Jan. 3, 2008

US 2008/0004288 A1

Example

21

22

23

24

-continued

Structure

23

Observed Mass

(MH+) tr. (min)

429 1.83

443 1.93

487 1.94

459 1.99

Jan. 3, 2008

US 2008/0004288 A1 24

-continued

Example No. Structure

25

26

27

Cl

Observed

Mass

(MH-H) tr (min)

473 2.03

543 2.17

545 1.78

Jan. 3, 2008

US 2008/0004288 A1

Example

28

29

30

31

-continued

Structure

25

Observed Mass

(MH+)

561

495

493

435

tR (min)

2.16

2.08

1.79

2.16

Jan. 3, 2008

US 2008/0004288 A1 26

-continued

Example No. Structure

32

Cl

33

34

35

Observed Mass

(MH+) tr. (min)

521 2.09

523 2.16

543 1.71

419 1.54

Jan. 3, 2008

US 2008/0004288 A1

Example No.

36

37

38

39

27

-continued

Structure

Observed

Mass

(MH-H) tr (min)

407 1.53

40S 1.51

40S 148

473 1.86

Jan. 3, 2008

US 2008/0004288 A1 28

-continued

Example No. Structure

40 ) \- O

so v \) N

Y-N-1- ^ \, N N

41

42

C N-N

is

Observed Mass

(MH+) tr. (min)

391 1.38

433 1.89

S86 1.73

421 1.31

Jan. 3, 2008

US 2008/0004288 A1

Example No.

44

45

46

47

-continued

Structure

N \-N V /

N N

29

Observed

Mass

(MH-H) tr (min)

485 2.09

483 1.78

419 1.57

379 1.37

Jan. 3, 2008

US 2008/0004288 A1

Example No.

48

49

50

51

30

-continued

Structure

\ , V

^ O N N N N

F

N1

Observed

Mass

(MH-H) tr (min)

488 1.43

538 1.64

393 1.42

441 1.58

Jan. 3, 2008

US 2008/0004288 A1 Jan. 3, 2008 31

-continued

Observed

Example Mass

No. Structure (MH-H) tr (min)

52 509 2.12

- N21 O

\-N N \ \,

C

C

53 525 2.03

l u? Y. Chiral

y^ - O \ \-N N \ \,

C

C

S4 481 2.01

- sy O \ \-N N M \,

C

C

55 543 1.96

J 1 N r O

C

C

US 2008/0004288 A1

Example No.

56

57

58

59

C

C

C

-continued

Structure

32

Observed

Mass

(MH-H) tr (min)

495 2.09

479 2.01

509 2.14

573 2.33

Jan. 3, 2008

US 2008/0004288 A1 33

-continued

Example No. Structure

60 N

J t N N n

r \- 21 N \,

C

C

61

N l l N a- \ 1. N

N \, O C

C

62

N l N

N 21 \- lu N \, F

C

C

63

N J

N 2 \, 1. N

C o1 C

Observed

Mass

(MH-H) tr (min)

571 1.64

535 2.23

563 2.23

561 2.06

Jan. 3, 2008

US 2008/0004288 A1

Example No.

64

65

66

67

-continued

Structure

C

34

Observed

Mass

(MH-H) tr (min)

533 1.73

S46 1.66

493 2.09

507 1.91

Jan. 3, 2008

US 2008/0004288 A1 35

-continued

Observed

Example Mass

No. Structure (MH-H) tr (min)

68 523 2.28

- N2 O

\-N N M \,

C

C

69 Q 539 2.31

- N21 O \ \, --- N M \,

C

C

70 l S49 2.01

- F N2 O

\ xO N M \, C

C

71 522 2.04

C

C

Jan. 3, 2008

US 2008/0004288 A1

Example No.

72

73

74

75

C

C

C

-continued

Structure

N

N e- \ 1. N N \,

C

Su N e \ 1. N N \,

C

Su a \ 1 N

\, C

Su N 21 \, 1. N N \,

36

Observed

Mass

(MH-H) tr (min)

518 1.58

483 2.04

607 1.94

497 2.04

Jan. 3, 2008

US 2008/0004288 A1

Example No.

76

77

78

79

C

C

C

C

37

-continued

Structure

N

e- y-O. \,

C

Su Y-->

N \, C

Su \- - y’s O

C

SJ N n

\-N 2 N \,

C

Observed

Mass

(MH-H) tr (min)

551 2.06

483 2.03

523 2.21

518 1.53

Jan. 3, 2008

US 2008/0004288 A1

Example No.

81

82

83

C

C

N

N

J

38

-continued

Structure

N

21

N

x-r- N \, C

J \-N

N \, C

J e O

Y-N-1-1 C

V O

Observed

Mass

(MH-H) tr (min)

497 2.03

531 2.06

485 1.79

545 2.04

Jan. 3, 2008

US 2008/0004288 A1 39

-continued

Observed

Example Mass

No. Structure (MH-H) tr (min)

84 591 2.08

N l

N21 O N O \, { N \,

C

C O N

85 l 509 2.19

N l

N2 O \, 1 Ol N M \,

C

C

86 483 2.06

N l

N2 O N \, S n-1N \,

C

C

87 Chiral 538 1.69

l N - r O

Jan. 3, 2008

US 2008/0004288 A1

Example No.

88

89

90

91

-continued

Structure

40

Observed

Mass

(MH-H) tr (min)

600 1.74

577 1.93

539 2.24

553 1.99

Jan. 3, 2008

US 2008/0004288 A1

Example No.

92

93

94

95

41

-continued

Observed

Mass

Structure (MH-H) tr (min)

538 1.81

J O N ls r N21 O

\ \, 1. Nu N \,

C

C

575 2.12

N l

N21 O N O W \,-\, n-1 O

C

C

535 2.01

- N2 O \ \-N N V

O F C

C

l 60S 2.04 N u?

N21 O \ \-N N \,

C 1. C O

Jan. 3, 2008

US 2008/0004288 A1

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

3 V || R

Ni M

y wherein

R" is selected from hydrogen, Coalkyl, Coalkenyl, Coalkynyl, Clocycloalkyl, Cascycloalkenyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-C-alkyl, Casheteroaryl, Co-oaryl, Co-oaryl-C6alkyl, Chet erocycloalkyl, Calkoxycarbonyl; wherein said Coalkyl, Coalk enyl, Coalkynyl, Calocycloalkyl, Cascycloalkenyl, Cocycloalkyl-C-alkyl, Cascycloalkenyl-C-alkyl, Casheteroaryl, Co-oaryl, Co-oaryl-C6alkyl, Chet erocycloalkyl, Cigalkoxycarbonyl used in defining R is optionally Substituted by one or more groups selected from halo gen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and NR'R'': with one or more substituents Selected from Calkyl, Calkenyl, halogen, C-galkoxy, amino, cyano, OXO, nitro, hydroxy, Coaryl, Coaryl-C-alkyl, Cheterocyclyl and Cheterocyclyl-Calkyl;

R is selected from hydrogen, Coalkyl, Coalkenyl, Coalkynyl, Clocycloalkyl, Cascycloalkenyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-C-alkyl, Casheteroaryl, Co-oaryl, Co-oaryl-C6alkyl, Chet erocycloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxycarbonyl; wherein said Coalkyl, Coalk enyl, Coalkynyl, Calocycloalkyl, Cascycloalkenyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-C-alkyl, Casheteroaryl, Co-oaryl, Co-oaryl-C6alkyl, Chet erocycloalkyl, Cheterocycloalkyl-C-alkyl or Cigalkoxycarbonyl used in defining R is optionally Substituted by one or more groups selected from halo gen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and NR'R'; with one or more substituents selected from Calkyl, Calkenyl, halogen, C-galkoxy, amino, cyano, OXO, nitro, hydroxy, Co-oaryl, Co-oaryl-C-alkyl, C-heterocyclyl and Cheterocyclyl-Calkyl;

optionally R' and R together with the N to which they are bound may form a 3-10 membered aromatic, heteroaro matic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally Substituted by one or more groups independently Selected from hydrogen, Calkyl, Calkenyl, C2-galkynyl, halogen, amino, Calkoxy, Cigalkoxy Calkyl, Calkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy:

R is selected from hydrogen, halogen, amino, Coalkyl, C-loalkenyl, C2-loalkynyl, Calocycloalkyl, Cs-ocy

Cheterocycloalkyl-Calkyl or

Cheterocycloalkyl-Calkyl or

42 Jan. 3, 2008

cloalkyl-C-alkyl, Cascycloalkenyl-C-alkyl, Cheterocycloalkyl-C-alkyl, Cascycloalkenyl, RRN , Casheteroaryl, Co-oaryl and Cheterocy cloalkyl, wherein said amino, Coalkyl, Coalkenyl, Coalkynyl, Clocycloalkyl, Cs-ocycloalkyl-C- 6alkyl, Cascycloalkenyl-Calkyl, Cheterocy cloalkyl-C-alkyl, Cascycloalkenyl, R'R''N-, Casheteroaryl, Co-oaryl and Cheterocycloalkyl used in defining R is optionally substituted by one or more groups selected from halogen, cyano, nitro, meth oxy, ethoxy, methyl, ethyl, hydroxy, and —NRR:

wherein R* and Rare independently selected from -H, Calkyl, Calkenyl, Calkynyl, and a divalent C-group that together with another divalent R' or R 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

R is selected from Csocycloalkyl, Cascycloalkenyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-Calkyl, Co-oaryl, Co-oaryl-C-alkyl, Cheterocyclyl, Cheterocyclyl-Calkyl, Coaryl-C(=O)—C. 6alkyl, Cheterocyclyl-C(=O)—Calkyl, Cohy drocarbylamino, Coaryl-C(=O)—, or Cheterocy clyl-C(=O)—, wherein said Cocycloalkyl, Cascycloalkenyl, Clocycloalkyl-Coalkyl, Cascy cloalkenyl-Calkyl, Coaryl, Coaryl-Calkyl, Cheterocyclyl, Cheterocyclyl-Coalkyl, Coaryl-C(=O)—Calkyl, Cheterocyclyl C(=O)—C-alkyl, Cohydrocarbylamino, Coaryl-C(=O)—, or Cheterocyclyl-C(=O)— used in defining R is optionally substituted by one or more groups selected from hydrogen, Calkyl, Calkenyl, halogen, Calkoxy, amino, cyano, OXo, nitro, hydroxy and NR'R''.

2. A compound as claimed in claim 1, wherein R" is selected from hydrogen, Coalkyl, Calkenyl,

C2-galkynyl, Cs-ocycloalkyl, Caecycloalkenyl, Cocycloalkyl-C-alkyl, Cascycloalkenyl-Coalkyl, phenyl, phenyl-Calkyl, Cheterocyclyl, Chet erocyclyl-C-alkyl or Calkoxycarbonyl; wherein said Calkyl, Calkenyl, C2-alkynyl, Cocy cloalkyl, Caecycloalkenyl, Clocycloalkyl-Coalkyl, Cascycloalkenyl-Calkyl, phenyl, phenyl-C alkyl, Cheterocyclyl, Cheterocyclyl-Calkyl O Calkoxycarbonyl used in defining R' is optionally Substituted by one or more groups selected from halo gen, Calkyl, C2-alkenyl, Calkoxy, amino, OXo, cyano, nitro, hydroxy, Coaryl, Coaryl-Calkyl, Cheterocyclyl, Cheterocyclyl-Calkyl and NRR:

R is selected from hydrogen, C-alkyl, Calkenyl, C2-galkynyl, Cs-ocycloalkyl, Caecycloalkenyl, Cocycloalkyl-C-alkyl, Cascycloalkenyl-Coalkyl, phenyl, phenyl-Calkyl, Cheterocyclyl, Chet erocyclyl-C-alkyl or Calkoxycarbonyl; wherein said Coalkyl, C2-alkenyl, C2-alkynyl, Calocy cloalkyl, Caecycloalkenyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-C-alkyl, phenyl, phenyl-Calkyl, Cheterocyclyl, Cheterocyclyl-Calkyl O Caalkoxycarbonyl used in defining R is optionally Substituted by one or more groups selected from halo

US 2008/0004288 A1

gen, C-4alkyl, C2-alkenyl, Calkoxy, amino, oxo, cyano, nitro, hydroxy, Co-oaryl, Co-oaryl-C-alkyl, Coheterocyclyl, Cheterocyclyl-Calkyl and NRR:

R" and R can form together with the N to which they are bound may form a 3-6 membered aromatic, heteroaro matic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally Substituted by one or more groups independently selected from hydrogen, Calkyl, Calkenyl, C2-alkynyl, halogen, amino, Calkoxy, Calkoxy Calkyl, Calkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy:

R is selected from hydrogen, halogen, amino, Calkyl, C2-alkenyl, C2-galkynyl, C-acycloalkyl, Cacycloalk enyl, C-sheteroaryl, R'R''N , Cacycloalkyl-C- 4alkyl, Cacycloalkenyl-Calkyl, phenyl, phenyl-C. 4alkyl, Cheterocyclyl or Cheterocyclyl-Calkyl; wherein said amino, Calkyl, Calkenyl, C-alky nyl, Cs-cycloalkyl, Cacycloalkenyl, C-sheteroaryl, RRN-, C-acycloalkyl-C-alkyl, Cacycloalkenyl Calkyl, phenyl, phenyl-Calkyl, Cheterocyclyl or Cs-heterocyclyl-C-alkyl used in defining R is optionally substituted by one or more groups selected from C-alkyl, C2-alkenyl, halogen, Calkoxy, amino, nitro, cyano, oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, Cecycloalkyl-C-alkyl, Cheterocy clyl, Cheterocyclyl-C-alkyl, and NR'R'':

wherein R and Rare independently selected from -H, Calkyl, C2-alkenyl, Coalkynyl, and a divalent C-group that together with another divalent R' or R 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

R is selected from C-acycloalkyl, C-acycloalkyl-C- 4alkyl, Calocycloalkenyl, Co-oaryl, phenyl, phenyl-C- 4alkyl, Cheterocyclyl or Cheterocyclyl-Calkyl; wherein said Cecycloalkyl, C-cycloalkyl-Calkyl, Calocycloalkenyl, Co-oaryl, phenyl, phenyl-C-alkyl, Cheterocyclyl or Cheterocyclyl-C alkyl used in defining R is optionally substituted by one or more groups selected from Calkyl, Calkoxy, halogen, cyano, amino, nitro. Oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, and NR'R''.

3. A compound as claimed claim 1, wherein R" is selected from hydrogen, Calkyl, Calkenyl,

C2-alkynyl, Cascycloalkyl, Cacycloalkenyl, Cascy cloalkenyl-Coalkyl, C-scycloalkyl-Calkyl, phenyl, phenyl-Calkyl, Cheterocyclyl, Cheterocyclyl Calkyl or Calkoxycarbonyl; wherein said Coalkyl, C2-alkenyl, C2-alkynyl, C-scycloalkyl, Calocycloalkenyl, Cascycloalkenyl-Coalkyl, Cascy cloalkyl-Calkyl, phenyl, phenyl-Calkyl, Chet erocyclyl, C-heterocyclyl-Calkyl or Calkoxy carbonyl used in defining R' is optionally substituted with one or more groups selected from Calkyl, halogen, Calkoxy, amino, cyano, oxo, hydroxy, Coheterocyclyl, Cheterocyclyl-Calkyl, Csaryl, Co-saryl-C-alkyl:

R is selected from hydrogen, C-alkyl, Calkenyl, C2-alkynyl, Cascycloalkyl, Cacycloalkenyl, Cascy

43 Jan. 3, 2008

cloalkenyl-C-alkyl, C-scycloalkyl-C alkyl, phenyl, phenyl-C alkyl, Cheterocyclyl, Cheterocyclyl Calkyl or Calkoxycarbonyl; wherein said C-calkyl, Calkenyl, C-calkynyl, C-scycloalkyl, Calocycloalkenyl, Cascycloalkenyl-Coalkyl, C-scy cloalkyl-Calkyl, phenyl, phenyl-Calkyl, Chet erocyclyl, Cheterocyclyl-Calkyl or Calkoxy carbonyl used in defining R is optionally substituted with one or more groups selected from Calkyl, halogen, Calkoxy, amino, cyano, oxo, hydroxy, Coheterocyclyl, C-heterocyclyl-Calkyl, Csaryl, Co-saryl-C-alkyl:

R" and R 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-1H-azepinyl, 2,3-dihydrobenzofura nyl, 2,3-dihydrofuranyl, 2,3-dihydropyranyl, 2,5-dihy drofuranyl, 4.7-dihydro-1,3-dioxepinyl, azetidinyl, aziridinyl, benzofuranyl, chromanyl, chromenyl, dioxanyl, dioxolanyl, furazanyl, furyl, hexamethylene homopiperazinyl, imidazolidinyl, indazolyl, indoliz inyl, isobenzofuranyl, isochromanyl, isoindolinyl, iso quinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naph thyridinyl, oxazolyl, oxetanyl, oxidyl, oxiranyl, phenoxathinyl, phthalazinyl, phenyl, piperazinyl, pip eridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, quinazolinyl quinolinyl, quinoxalinyl sulfolanyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydro quinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thienyl, thietanyl, thiranyl, thiomorpholinyl, thiophanyl, thi opyranyl, triazinyl and Xanthenyl:

wherein said 1.2.3,6-tetrahydro-pyridinyl, 1.2.3-oxadiaz olyl, 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiaz olyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, 1,3,4-oxadiaz olyl, 1,3,4-thiadiazolyl, 1.3,4-triazolyl, 1,3-dioxanyl, 1,3-dioxepanyl, 1,4-benzodioxanyl, 1,4-dihydropyridi nyl, 1,4-dioxanyl. 2.3.4.7-tetrahydro-1H-azepinyl, 2.3- dihydrobenzofuranyl. 2,3-dihydrofuranyl, 2,3-dihydro pyranyl. 2.5-dihydrofuranyl, 4,7-dihydro-1,3- dioxepinyl, azetidinyl, aziridinyl, benzofuranyl, chromanyl, chromenyl, dioxanyl, dioxolanyl, furaza nyl, furyl, hexamethylene homopiperazinyl, imidazo lidinyl, indazolyl, indolizinyl, isobenzofuranyl, isoch romanyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolyl, oxetanyl, oxidyl, oxiranyl, phenoxathinyl, phthalazi nyl, phenyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyrro lidinyl, quinazolinyl quinolinyl, quinoxalinyl sulfola nyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tet rahydropyranyl, tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thienyl, thietanyl, thiranyl, thio morpholinyl, thiophanyl, thiopyranyl, triazinyl and Xanthenyl used in defining R' and R together is option ally substituted by one or more groups selected from Calkyl, C2-alkenyl, C2-alkynyl, hydrogen, halo gen, amino, Calkoxy, Calkoxy-C-alkyl, Calkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy:

US 2008/0004288 A1

R is selected from hydrogen, halogen, amino, C-alkyl, C2-galkenyl, C-cycloalkyl, C-cycloalkyl-Calkyl, Cheterocyclyl or Cheterocyclyl-Calkyl wherein said amino, Calkyl, Calkenyl, C-acycloalkyl, C-cycloalkyl-C alkyl, C-heterocyclyl or Chet erocyclyl-Calkyl used in defining R is optionally Substituted with one or more groups selected from Coalkyl, halogen, C-2alkoxy, methoxy, ethoxy, methyl, ethyl, hydroxy, Cheterocyclyl, Chetero cyclyl-C-alkyl and NR'R'':

wherein R* and Rare independently selected from -H, Calkyl, Calkenyl, Calkynyl, and a divalent Cagroup that together with another divalent R' or R 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-Calkyl, Cecycloalkyl-Calkyl, Caecycloalkenyl-Calkyl, Cheterocycloalkyl, Cheterocycloalkyl-Calkyl, Co-oaryl, Caecycloalkyl, and Cacycloalkenyl, wherein said phenyl, phenyl-Calkyl, C-cycloalkyl Calkyl, Cacycloalkenyl-C-alkyl, C-heterocy cloalkyl, Cheterocycloalkyl-Calkyl, Coaryl, Cecycloalkyl, and Caecycloalkenyl, used in defining R is optionally substituted by one or more groups Selected from Calkyl, Calkoxy, halogen, amino, cyano, Oxo, methoxy, ethoxy, methyl, ethyl, hydroxy, and NRR.

4. A compound as claimed in claim 1, wherein R" is selected from hydrogen, methyl, ethyl, propyl.

n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, cyclohexyl, cyclo propylmethyl, cyclohexylmethyl, tetrahydrothiophe nyl, 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, cyclopropylm ethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl 2-phenylethyl, pyrimidinyl, furanylm ethyl, pyridinylmethyl, pyrazinylmethyl or methoxy carbonyl used in defining R' is optionally substituted with one or more groups selected from Calkyl, halogen, Cisalkoxy, amino, cyano, OXO, hydroxy, pyr rolidinyl and phenylmethyl;

R is selected from hydrogen, methyl, ethyl, propyl, n-butyl, t-butyl, n-pentyl, t-pentyl, hexyl, propenyl, butenyl, cycloproply, cyclopentyl, cyclohexyl, cyclo propylmethyl, cyclohexylmethyl, tetrahydrothiophe nyl, 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, cyclopropylm ethyl, cyclohexylmethyl, tetrahydrothiophenyl, phenyl, phenylmethyl 2-phenylethyl, pyrimidinyl, furanylm ethyl, pyridinylmethyl, pyrazinylmethyl or methoxy carbonyl used in defining R is optionally substituted with one or more groups selected from Calkyl, halogen, Cisalkoxy, amino, cyano, OXO, hydroxy, pyr rolidinyl and phenylmethyl;

44 Jan. 3, 2008

tetrahydropyridinyl, piperidinyl, pyrrolidinyl, pyrroli nyl, piperazinyl or morpholinyl; wherein said cylco hexyl, 1.2.3,6-tetrahydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl or morpholinyl used in defining R' and R together is optionally sub stituted by one or more groups selected from Calkyl, C2-alkenyl, C2-alkynyl, hydrogen, halogen, amino, Calkoxy, Calkoxy-C-2alkyl, Cisalkoxycarbonyl, carbonyl, carbamoyl, acetyl, acetylamino and hydroxy:

R is selected from hydrogen, Cl, diethylamino, cyclo hexylmethylamino, piperidinyl, morpholinyl, piperazi nyl, pyrrolidinyl, t-butyl, n-butyl, 2-methyl-2-butyl, isopentyl, 2-methoxy-2-propyl, 2-hydroxyl-propyl. 1-methyl-propyl, 1,1-dimethyl-propyl, 1,1-dimethyl-3- buten-1-yl, ethyl, 2-propyl and NR'R'; 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-pro pyl, 1,1-dimethyl-3-buten-1-yl, ethyl 2-propyl and —NRR used in defining R is optionally substituted with one or more groups selected from hydrogen and methyl;

wherein R* and Rare independently selected from -H, Calkyl, Calkenyl, Calkynyl, and a divalent Cagroup that together with another divalent R' or R 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

R is selected from phenyl, allyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, tet rahydropyranyl, tetrahydrofuranyl, 1-piperidinyl, N-methyl-2-piperidinyl and benzyl; wherein said phe nyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl. cyclohexyl, cyclopentyl, tetrahydropyranyl, tetrahy drofuranyl, 1-piperidinyl, N-methyl-2-piperidinyl and benzyl used in defining R is optionally substituted by one or more groups selected from Calkyl, Calkoxy, fluorine, chlorine, amino, cyano, OXo, methoxy, ethoxy, methyl, ethyl, hydroxy, and trifluo romethyl.

5. A compound selected from: 1-(3-chlorophenyl)methyl-N-3-(dimethylamino)pro

pyl-3-(1-pyrrolidinyl)-1H-indazole-5-sulfonamide, N-(cyclopropylmethyl)-3-(diethylamino)-1-(4-fluo rophenyl)methyl-N-propyl-1H-indazole-5-sulfona mide, N-(cyclopropylmethyl)-1-(2,6-dichlorophenyl )methyl-3-(diethylamino)-N-propyl-1H-indazole-5- Sulfonamide, 3-(diethylamino)-1-(4- fluorophenyl)methyl-N,N-dipropyl-1H-indazole-5- sulfonamide, 4-1-(2,6-dichlorophenyl)methyl-3- (diethylamino)-1H-indazol-5-yl)sulfonyl). 1-piperazinecarboxylic acid, ethyl ester, 1-(4-fluo robenzyl)-3-(4-methylpiperazin-1-yl)-N,N-dipropyl 1H-indazole-5-sulfonamide, 1-(4-fluorobenzyl)-3-pip eridin-1-yl-N,N-dipropyl-1H-indazole-5 sulfonamide, 3-(cyclohexylmethyl)amino-1-(4-fluorobenzyl)-N,N- dipropyl-1H-indazole-5-Sulfonamide, and pharmaceu tically acceptable salts thereof.

6-7. (canceled) 8. A method for the treatment of anxiety disorders in a

warm-blooded animal, comprising the step of administering to said animal in need of Such treatment a therapeutically effective amount of a compound according to claim 1.

R" and R together with the N to which they are bound may form a group selected from cylcohexyl, 1.2.3,6-

US 2008/0004288 A1 45

9. A method for the treatment of cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's dis ease, gastrointestinal disorders and cardiovascular disorders in a warm-blooded animal, comprising the step of admin istering to said animal in need of Such treatment a thera peutically effective amount of a compound according to claim 1.

10. A pharmaceutical composition comprising a com pound according to claim 1 and a pharmaceutically accept able 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 claim 1.

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

II 3 V || R

N R2 | \

M

y R8

comprising the step of reacting a compound of formula III,

III RI V O N C N R / \

M N

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

R" is selected from hydrogen, Coalkyl, Coalkenyl, Coalkynyl, Clocycloalkyl, Cascycloalkenyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-C-alkyl, Casheteroaryl, Co-oaryl, Co-oaryl-C6alkyl, Chet erocycloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxycarbonyl; wherein said Coalkyl, Coalk enyl, Coalkynyl, Calocycloalkyl, Cascycloalkenyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-C-alkyl, Casheteroaryl, Co-oaryl, Co-oaryl-C6alkyl, Chet erocycloalkyl, Cheterocycloalkyl-Calkyl or Cigalkoxycarbonyl used in defining R is optionally Substituted by one or more groups selected from halo gen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and NR'R'; with one or more substituents selected from Calkyl, Calkenyl, halogen, C-galkoxy, amino, cyano, OXO, nitro, hydroxy, Coaryl, Coaryl-C-alkyl, Cheterocyclyl and Cheterocyclyl-Calkyl;

R is selected from hydrogen, Coalkyl, Coalkenyl, Coalkynyl, Clocycloalkyl, Cascycloalkenyl,

Jan. 3, 2008

Cocycloalkyl-C-alkyl, Cascycloalkenyl-Coalkyl, Casheteroaryl, Co-oaryl, Co-oaryl-C-galkyl, Chet erocycloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxycarbonyl; wherein said Coalkyl, Coalk enyl, Coalkynyl, Calocycloalkyl, Cascycloalkenyl, Cocycloalkyl-Calkyl, Cascycloalkenyl-Calkyl, Casheteroaryl, Co-oaryl, Co-oaryl-C-galkyl, Chet erocycloalkyl, Cheterocycloalkyl-C-alkyl or Calkoxycarbonyl used in defining R is optionally Substituted by one or more groups selected from halo gen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and NR'R'; with one or more substituents selected from Calkyl, Calkenyl, halogen, C-galkoxy, amino, cyano, OXO, nitro, hydroxy, Co-oaryl, Co-oaryl-C-alkyl, C-heterocyclyl and Cheterocyclyl-C-alkyl:

optionally R' and R together with the N to which they are bound may form a 3-10 membered aromatic, heteroaro matic or heterocycloalkyl ring; wherein said aromatic, heteroaromatic or heterocycloalkyl ring is optionally Substituted by one or more groups independently Selected from hydrogen, Calkyl, Calkenyl, C2-galkynyl, halogen, amino, Calkoxy, Cigalkoxy Calkyl, Calkoxycarbonyl, carbonyl, carbamoyl. acetyl, acetylamino and hydroxy:

R is selected from hydrogen, halogen, amino, Coalkyl, C-loalkenyl, C2-oalkynyl, Calocycloalkyl, Cs-ocy cloalkyl-C-alkyl, Cascycloalkenyl-C-alkyl, Cheterocycloalkyl-C-alkyl, Cascycloalkenyl, RRN , C-sheteroaryl, Coaryl and Cheterocy cloalkyl, wherein said amino, Coalkyl, Coalkenyl, Coalkynyl, Cocycloalkyl, Cocycloalkyl-C- 6alkyl, Cascycloalkenyl-Coalkyl, C-heterocy cloalkyl-C-alkyl, Cascycloalkenyl, R'R''N-, Casheteroaryl, Co-oaryl and Cheterocycloalkyl used in defining R is optionally substituted by one or more groups selected from halogen, cyano, nitro, meth oxy, ethoxy, methyl, ethyl, hydroxy, and —NR'R'':

wherein R* and Rare independently selected from -H, Calkyl, Calkenyl, Calkynyl, and a divalent C-group that together with another divalent R' or R 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

R is selected from Cocycloalkyl, Cascycloalkenyl, Cocycloalkyl-C-alkyl, Cascycloalkenyl-Coalkyl, Coaryl, Coaryl-C-alkyl, Cheterocyclyl, Cheterocyclyl-Calkyl, Coaryl-C(=O)—C. 6alkyl, Cheterocyclyl-C(=O)—Calkyl, Chy drocarbylamino, Coaryl-C(=O)—, or Cheterocy clyl-C(=O)—, wherein said Cocycloalkyl, Cascycloalkenyl, Cocycloalkyl-Calkyl, Cascy cloalkenyl-C6alkyl, Co-oaryl, Co-oaryl-Coalkyl, Cheterocyclyl, Cheterocyclyl-Calkyl, Coaryl-C(=O)—Calkyl, Cheterocyclyl C(=O)—C-alkyl, Cohydrocarbylamino, Coaryl-C(=O)—, or Cheterocyclyl-C(=O)— used in defining R is optionally substituted by one or more groups selected from hydrogen, Calkyl, C2-galkenyl, halogen, Calkoxy, amino, cyano, OXo, nitro, hydroxy and - NRR.

k k k k k