WO2008098025A1

WO2008098025A1 - Arylsulfonamide compounds which modulate the cb2 receptor

Info

Publication number: WO2008098025A1
Application number: PCT/US2008/053117
Authority: WO
Inventors: David Thomson; Doris Riether; Renee M. Zindell; Eugene Richard Hickey; Monika Ermann; James Edward Jenkins; Innocent Mushi; Malcolm Taylor; Patricia Amouzegh; Edward Walker
Original assignee: Boehringer Ingelheim International Gmbh; Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority date: 2007-02-08
Filing date: 2008-02-06
Publication date: 2008-08-14

Abstract

Compounds are provided which bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, the compounds having the general formula (I) and the formula (IA) wherein, R1, R2, R3, R4, R5, R6, R7, R8 and X have the meanings given in the specification, and the preparation and use thereof. The compounds are valuable CB2 receptor modulators.

Description

Arylsulfonamide Compounds Which Modulate The CB2 Receptor

APPLICATION DATA

This application claims benefit to US provisional application serial no. 60/888,830 filed February 8, 2007.

BACKGROUND OF THE INVENTION

1. TECHNICAL FIELD

The present invention relates to novel compounds which modulate the CB2 receptor and their use as medicaments.

2. BACKGROUND INFORMATION

Cannabinoids are a group of about 60 distinct compounds found in Cannabis sativa (also know as marijuana) with cannabinol, cannabidiol and Δ⁹-tetrahydrocannabinol (THC) being the most representative molecules. The therapeutic usage of Cannabis can be dated back to ancient dynasties of China and includes applications for various illnesses ranging from lack of appetite, emesis, cramps, menstrual pain, spasticity to rheumatism. The long history of Cannabis use has led to the development of several pharmaceutical drugs. For example, Marinol and Cesamet which are based on THC and its analogous nabilone, respectively, are used as anti-emetic and appetite stimulant. Despite of the clinical benefits, the therapeutic usage of cannabis is limited by its psychoactive effects including hallucination, addiction and dependence. Mechoulam R, ed. Cannabinoids as Therapeutic Agents, Boca Raton, FL; CRC Press, 1986 provides a review of the medicinal use of cannabis.

The physiological effects of cannabinoids are mediated by at least two G-protein coupled receptors, CBl and CB2. Autoradiographic studies have demonstrated that CBl receptors are expressed primarily in the central nervous system, specifically in the cerebral cortex, hippocampus, basal ganglia and cerebellum. They are also found in the reproductive system and other peripheral tissues including that of the immune system, but to a lesser degree. CBl receptors regulate the release of neurotransmitters from the pre-synaptic neurons and are believed to mediate most of the euphoric and other central nervous system effects of cannabis, such as THC-induced ring-catalepsy, hypomobility, and hypothermia, which were found to be completely absent in mice with a deletion of the CBl gene (Zimmer et al., Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CBl receptor knockout mice. Proc Natl Acad Sci U S A. (1999) 96:5780-5785.)

CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. It is estimated that the expression level of CB2 in the immune cells is about 10 to 100 times higher than CBl . Within the immune system, CB2 is found in various cell types, includung B cells, NK cells, monocytes, microglial cells, neutrophils, T cells, dentritic cells and mast cells, suggesting that a wide range of immune functions can be regulated through CB2 modulators (Klein et al., The cannabinoid system and immune system. J Leukoc Biol (2003) 74:.486-496). This is supported by the finding that the immunomodulatory effect of THC is absent in CB2 deficient mice mice (Bicklet et al., Immunomodulation by cannabinoid is absent in mice deficient for the cannabinoid CB2 receptor. Eur J Pharmacol (2000) 396:141- 149). CB2 selective ligands have been developed and tested for their effects in various imflammatory settings. For example, in animal models of inflammation, CB2 selective agonists, inverse agonists and antagonists have been shown to be effective in suppressing inflammation (Hanus et al., HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci U S A. (1999) 96:14228-14233, Ueda et al., Involvement of cannabinoid CB(2) receptor-mediated response and efficacy of cannabinoid CB(2) receptor inverse agonist, JTE-907, in cutaneous inflammation in mice. Eur J Pharmacol. (2005) 520:164-171 and Smith et al., The anti-inflammatory activities of cannabinoid receptor ligands in mouse peritonitis models Eur J Pharmacol. (2001) 432:107-119.). Furthermore, CB2 selective agonists inhibit disease severity and spasticity in animal models for multiple sclerosis (Baker et al., Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature (2000) 404:84-87.Arevalo-Martin et al., Therapeutic action of cannabinoids in a murine model of multiple sclerosis J Neurosci. (2003) 23:2511-2516.). Taken together, these results support the notion that CB2 receptor modulators can be employed for the treatment of medical conditions having an inflammatory component.

In addition to inflammation, CB2 agonists have been shown to inhibit pain and emesis. For instance, CB2 selective agonists blunt the pain response induced by thermal or other stimuli (Malan et al., CB2 cannabinoid receptor-mediated peripheral antinociception. Pain. (2001) 93:239-45 and Nackley et al., Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience (2003) 119:747-57.) CB2 activation has also been demonstrated to inhibit neuropathic pain response (Ibrahim et al., Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A. (2003) 100: 10529-33.) Finally, in contrast to the earlier data which did not find CB2 in the brain, a recent article demonstrated the expression of CB2 in the brain, at about 1.5 % of the level in the spleen. CB2 activation is shown by this article to be responsible for the anti-emetic effect of endocannabinoid (Van Sickle et al., Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005 310:329- 332. ) The foregoing results confirm that CB2 agonists can be used for the treatment of inflammatory and neuropathic pain as well as emesis.

BRIEF SUMMARY OF THE INVENTION The present invention provides novel compounds which bind to and are agonists, antagonists or inverse agonists of the CB2 receptor. The invention also provides a method and pharmaceutical compositions for treating inflammation by way of the administration of therapeutic amounts of these compounds. Lastly, the invention provides a method and pharmaceutical compositions for treating pain by way of the administration of therapeutic amounts of a subset of the new compounds which are CB2 agonists. DETAILED DESCRIPTION OF THE INVENTION

In its broadest generic aspect the invention provides compounds of the formula

(I) wherein,

R¹ and R² are each independently hydrogen, Ci-Cg alkyl, C₃-Cg cycloalkyl or methylcycloalkyl, each optionally independently substituted with 1 to 3 substituents; or

R¹ and R² together with the nitrogen atom to which they are attached form a C₃-Cg heterocyclic ring containing 1-3 heteroatoms optionally substituted with 1- 3 substituents;

R³ is hydrogen, Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen;

R⁴ is Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen;

R⁵ is hydrogen, Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen; R⁶ is hydrogen, Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen; and

R⁷ and R⁸ together with the nitrogen to which they are attached form a heterocyclic ring which may be mono- or bicyclic and which may be optionally substituted with 1-3 substitutents, wherein R⁷ and R⁸ together with the nitrogen to which they are attached do not form a pyrrolidinyl or piperidinyl ring

with the proviso that R⁴ and R⁶ cannot simultaneously equal methyl; and with the proviso that R¹ and R² cannot simultaneously equal hydrogen;

or the pharmaceutically acceptable salts thereof.

In a first subgeneric aspect, the invention provides compounds of the formula I wherein,

R¹ and R² are each independently hydrogen, Ci-Cg alkyl, C₃-Cg cycloalkyl, or methylcycloalkyl, each optionally independently substituted with 1 to 3 substituents; or

R⁴ is Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen R⁵ is hydrogen, Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen

R⁶ is hydrogen, Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen; and

R⁷ and R⁸ together with the nitrogen to which they are attached form a decahydroquinoline or a decahydroisoquinoline ring.

In a further subgeneric aspect, the invention provides compounds of the formula I wherein,

R¹ and R² are each independently hydrogen, Ci-Cs alkyl, C₃-C₆ cycloalkyl, or methylcycloalkyl, each optionally independently substituted with 1 to 3 substituents chosen from aryl, Ci-Cg alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocyclic ring, and halogen; or

R¹ and R² together with the nitrogen atom to which they are attached form a C₃-C₆ heterocyclic ring containing 1-3 heteroatoms optionally substituted with 1- 3 substituents chosen from Ci-C₆ alkyl, halogen, hydroxyl, Ci-C₆ alkoxy, Ci-C₆ alkoxymethyl and oxo;

R^Λ is hydrogen;

R⁴ is Ci-C₆ alkyl optionally substituted with 1-3 halogens, methoxy or halogen;

R⁵ is hydrogen, chloro or bromo;

R⁶ is hydrogen or methyl; and R⁷ and R⁸ together with the nitrogen to which they are attached form a decahydroquinoline or a decahydroisoquinoline ring.

In a still further subgeneric aspect, the invention provides compounds of the formula I wherein,

R¹ and R² are each independently hydrogen, Ci-Cs alkyl, or methylcycloalkyl, each optionally independently substituted with 1 to 3 substituents chosen from methyl or halogen; or

R¹ and R² together with the nitrogen atom to which they are attached form a C3-C6 heterocyclic ring containing 1-3 heteroatoms optionally substituted with 1- 3 substituents chosen from Ci-C₆ alkyl or halogen;

R³ is hydrogen;

R⁴ is methyl, ethyl, isopropyl, trifluoromethyl or chloro;

R⁵ is hydrogen or bromo;

R⁶ is hydrogen or methyl; and

In another generic aspect the invention provides compounds of formula IA

(^IA)

wherein,

R¹ and R² are each independently hydrogen, Ci-Cs alkyl, C₃-Cs cycloalkyl, methylcycloalkyl, or aryl, each optionally independently substituted with 1 to 3 substituents; or

R¹ and R² together with the nitrogen atom to which they are attached form a C₃-Cs heterocyclic ring containing 1-3 heteroatoms optionally substituted with 1-3 substituents;

R⁴ is hydrogen, Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen;

R⁵ is hydrogen, Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen;

R⁶ is hydrogen, Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen; R⁷ is Ci-C₆ alkyl, C3-C10 cycloalkyl, aryl or C5-C10 heteroaryl, each optionally independently substituted with 1 to3 substituents; and

X is a 5-membered heterocycle containing 1 to 3 heteroatoms

or the pharmaceutically acceptable salts thereof.

In a first subgeneric aspect, the invention provides compounds of the formula IA wherein,

R¹ and R² are each independently hydrogen, Ci-C₈ alkyl, C₃-C₈ cycloalkyl, methylcycloalkyl, or aryl, each optionally independently substituted with 1 to 3 substituents; or

R¹ and R² together with the nitrogen atom to which they are attached form a C₃-C₈ heterocyclic ring containing 1-3 heteroatoms optionally substituted with 1- 3 substituents;

R⁶ is hydrogen, Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen; R⁷ is Ci-C₆ alkyl, C3-C10 cycloalkyl, aryl, or C5-C10 heteroaryl, each optionally independently substituted with 1 to 3 substituents; and

X is a 5-membered heterocycle containing 1 to 3 heteroatoms chosen from nitrogen or oxygen.

In a further subgeneric aspect, the invention provides compounds of the formula IA wherein,

R¹ and R² are each independently hydrogen, Ci-Cg alkyl, C₃-Cg cycloalkyl, methylcycloalkyl, or aryl, each optionally independently substituted with 1 to 3 substituents chosen from aryl, Ci-Cg alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocyclic ring, and halogen; or

R¹ and R² together with the nitrogen atom to which they are attached form a C₃-C₆ heterocyclic ring containing 1-3 heteroatoms optionally substituted with 1-3 substituents chosen from Ci-C₆ alkyl, halogen, hydroxyl , Ci-C₆ alkoxy, Ci-C₆ alkoxymethyl and oxo;

R³ is hydrogen;

R⁴ is hydrogen, Ci-C₆ alkyl optionally substituted with 1-3 halogens, methoxy or halogen;

R⁵ is hydrogen, chloro or bromo;

R⁶ is hydrogen or methyl;

R⁷ is Ci-C₆ alkyl, C3-C10 cycloalkyl, aryl, or C5-C10 heteroaryl, each optionally independently substituted with 1 to 3 substituents; and

X is oxadiazole. In a still further subgeneric aspect, the invention provides compounds of the formula IA wherein,

R¹ and R² are each independently hydrogen, Ci-Cg alkyl, or methylcycloalkyl, each optionally independently substituted with 1 to 3 substituents chosen from methyl or halogen; or

R¹ and R² together with the nitrogen atom to which they are attached form a C₃-C₆ heterocyclic ring containing 1-3 heteroatoms optionally substituted with 1 to 3 substituents chosen from Ci-C₆ alkyl or halogen;

R^Λ is hydrogen;

R⁴ is hydrogen, methyl, ethyl, isopropyl, trifluoromethyl or chloro;

R⁵ is hydrogen or bromo;

R⁶ is hydrogen or methyl;

R⁷ is Ci-C₆ alkyl, C3-C10 cycloalkyl, or aryl, each optionally independently substituted with 1 to 3 substituents chosen from halogen or Ci-C₆ alkyl optionally substituted with halogen; and

X is oxadiazole. The invention also includes tautomers, prodrugs and pharmaceutically acceptable salts of the above-described compounds of the formula I and the formula IA.

Compounds of the formulae I and IA are agonists, antagonists or inverse agonists of the CB2 receptor and modulate the activity of this receptor. By virtue of this fact the compounds of the formulae I and IA can be used for treating inflammation, in a manner described more fully below.

Those compounds of the formulae I and IA which are agonists of the CB2 receptor can additionally be used for treating pain, in a manner described more fully below.

The compounds of formulae I and IA may be made using the general synthetic methods described below, which also constitute part of the invention.

GENERAL SYNTHETIC METHODS

The invention also provides processes for making compounds of formula (I) and (IA). In all methods, unless specified otherwise, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ , R⁸ and X in the formulas below shall have the meaning of R¹, R², R³, R⁴, R⁵, R⁶, R⁷ , R⁸ and X in formula (I) and (IA) of the invention described herein above. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC), if desired, and intermediates and products may be purified by chromatography on silica gel and/or by recrystallization.

The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds without undue experimentation. Starting materials and intermediates used, in the methods below, are either commercially available or easily prepared from commercially available materials by those skilled in the art.

Compounds of formula (I) may be synthesized by the method illustrated in Method A

IV

Method A

3-Chlorosulfonylbenzoic acids (formula II), have been reported in the literature or are generally prepared as described in adaptation of the following references: WO2001/000573 WO2005/115374 WO2004/018414 Wrobel, J. et al. Bioorg. Med. Chem. 10 (2002), 639-656

Me, Z. et al. J. Med. Chem. 48 (2005), 1596- 1609.

Reaction of a starting benzoic acid with chlorosulfonic acid provides 3-chlorosulfonylbenzoic acids of formula (II).

Reaction of the chlorosulfonylbenzoic acid of formula (II) with an amine of formula (III) in a suitable solvent affords a sulfonamide of formula (IV). Reaction of a sulfonamide of formula

(IV) with an appropriate amine of formula (V) can provide compounds of the general formula

(I) using methods such as those described in the following literature references:

WO2001/000573

WO2005/115374 Me, Z. et al. J. Med. Chem. 48 (2005), 1596-1609.

Alternatively the acid may be converted to the corresponding acid chloride under standard reaction conditions using thionyl chloride or oxalyl chloride and then reacted with an amine of formula (V) to give a compound of formula (I).

Compounds of formula (I) may also be synthesized by the method illustrated in Method B

VII

Method B

Benzamides of formula (VI) are generally prepared by adaptation of the methods described in the following literature reference

WO2001/000573

Reaction of the starting acid with an amine of formula (V) under standard coupling conditions, to provide a compound of formula (VI). Standard peptide coupling reactions known in the art

(see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer- Verlag) may be employed in these syntheses. An example of suitable coupling conditions is treatment of a solution of the carboxylic acid in a suitable solvent such as DMF with EDC, HOBT, and a base such as diisopropylethylamine, followed by the desired amine.

Alternatively the acid may be converted to the corresponding acid chloride under standard reaction conditions using thionyl chloride or oxalyl chloride and then reacted with an amine of formula (V) to give a compound of formula (VI). As in Method A, reaction of a the compound of formula (VI) with chloro sulfonic acid provides 3- chlorosulfonylbenzoic acids of formula (VII). Reaction of the chlorosulfonylbenzoic acid of formula (VII) with an amine of formula (III) in a suitable solvent affords a compound of formula (I).

Compounds of formula (I) may be synthesized by the method illustrated in Method C

Method C

As illustrated in Method C, reaction of the chlorosulfonylbenzoic acid of formula (VIII) with an amine of formula (III) in a suitable solvent, in the presence of a suitable base, affords a sulfonamide of formula (IX). Reaction of the sulfonamide of formula (IX) with carbondioxide, in a suitable solvent, in the presence of a suitable base at a suitable temperature provides a carboxylic acid of formula (X) which may also be converted to the corresponding methyl ester under standard reaction conditions. Hydrolysis of the ester of formula (X) followed by coupling with an amine of formula (V), under standard coupling conditions, provides a compound of formula (I). Alternatively the acid may be converted to the corresponding acid chloride under standard reaction conditions using thionyl chloride or oxalyl chloride and then reacted with an amine of formula (V) to give a compound of formula (I).

Compounds of formula (I) shown below, may also be synthesized as outlined in method D.

Method D

As shown in method D, reaction of sulfonamide benzoic acid of formula (IV) with an alcohol of formula (XII) using polymer supported DCC, in the presence of a suitable solvent and base, provides a compound of formula (I).

Compounds of formula (IA) may be prepared according to Method E

Method E

As illustrated in method E, reaction of the fluorosulfonylbenzoic acid of formula (XIII) with an amine of formula (III) in a suitable solvent affords a sulfonamide of formula (XIV). Reaction of the sulfonamide of formula (XIV) with hydroxyl amine hydrochloride in a suitable solvent, in the presence of a suitable base provides a benzamidine of formula (XV). Further reaction of the benzamidine of formula (XV) with an acid chloride of formula (XVI) in a suitable solvent, in the presence of a suitable base, provides a compound of formula (IA). Compounds of formula (IA) may also be prepared according to Method F.

Method F

Reaction of a benzoic acid of formula (IV), made according to Method A, with reagents such as thionyl chloride or oxalyl chloride under standard conditions provides an acid chloride of formula (XVII). Reaction of the acid chloride of formula (XVII) with a amidoxime of formula (XVIII) provides a compound of formula (IA). The amidoxime (XVIII) may be prepared using adaptation of procedures in the literature such as in US 3,897,447 and US 3,547,621.

Compounds of formula (IA) can also be prepared by Method G.

Method G

Reaction of a benzoic acid of formula (XI), made according to Method C, with reagents such as thionyl chloride or oxalyl chloride under standard conditions provides an acid chloride of formula (XIX). Reaction of the acid chloride of formula (XIX) with a amidoxime of formula (XVIII) provides a compound of formula (IA). The amidoxime (XVIII) may be prepared using adaptation of procedures in the literature such as in US 3,897,447 and US 3,547,621.

Specific Synthetic Examples The manner in which the compounds of the invention can be made will be further understood by way of the examples in the following Experimental Procedures.

Experimental Procedures

Method A

Synthesis of [4-Methyl-3-(piperidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)- methanone (Example 11 in Table 8)

Step 1: Synthesis of S-ChlorosulfonyM-methyl-benzoic acid 3-Chlorosulfonylbenzoic acids have been reported in the literature or were generally prepared as described in adaptation of the following references: WO2001/000573, WO2005/115374, WO2004/018414, Wrobel, J. et al. Bioorg. Med. Chem. 10 (2002), 639-656., Me, Z. et al. J. Med. Chem. 48 (2005), 1596-1609.

To 20 g (0.15 mol) of 4-toluic acid was added chlorosulfonic acid (100 mL) and the reaction was stirred at 60⁰C for 18 h until completion. The reaction was cooled to room temperature and carefully poured onto ice. The resulting precipitate was isolated by filtration, washed with water and dried under reduced pressure at 60⁰C to afford 30.3 g of 3-chlorosulfonyl-4-methyl-benzoic acid as an off-white solid.

Step 2: Synthesis of 4-Methyl-3-(piperidine-l-sulfonyl)-benzoic acid

To a suspension of 8 g (34.2 mmol) 3-chlorosulfonyl-4-methyl-benzoic acid in acetonitrile (160 mL) was added dropwise 10.1 mL (103 mmol, 3 equ.) of piperidine at 0 ⁰C. The reaction was stirred at 0 ⁰C for 0.5 h, then allowed to warm to room temperature and stirred until completion. The reaction was concentrated under reduced pressure to l/8th of the volume. The residue was dissolved in IM aqueous NaOH solution (50 mL) and washed with TBME (2 x 50 mL). The basic aqueous layer was cooled in an ice-bath and acidified with 2M aqueous HCl solution to pH 1-2. This acidic aqueous layer was then extracted with TBME (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford 5.0 g of 4-methyl-3 -(piperidine- 1 -sulfonyl)-benzoic acid.

According to this procedure the following sulfonamide benzoic acids were synthesised:

Table 1

Step 3: Synthesis of [4-Methyl-3-(piperidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2- yl)-methanone

Benzamides were generally prepared by adaptation of the methods described in the following literature references: WO2001/000573, WO2005/115374, Nie, Z. et al. J. Med. Chem. 48 (2005),1596-1609.

To a solution of 100 mg (0.35 mmol) 4-methyl-3-(piperidine-l-sulfonyl)-benzoic acid in DCM (1 mL) was added a catalytic amount of DMF, followed by 0.154 mL (2.12 mmol, 6 equ.) thionyl chloride. The reaction was stirred at room temperature for 4 h. The solution was concentrated under reduced pressure and the residue dissolved in DCM. To this solution, 60 μL (0.35 mmol, 1 equ.) of N,N-diisopropylethylamine were added, followed by 51 mg (0.35 mmol) of decahydroisoquinoline and a catalytic amount of DMAP. The reaction was stirred at room temperature for 18 h. The solution was then washed with sat. aqueous NaHCC>3 solution (5 mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica, eluent DCM, 0-20 % ethyl acetate) to afford 111 mg of [4-methyl-3-(piperidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)- methanone

Examples listed in Table 8, Method A were made according to this procedure.

Synthesis of [3-(l,l-Dioxo-lλ -thiomorpholine-4-sulfonyl)-4-methyl-phenyl]-(octahydro- isoquinolin-2-yl)-methanone (Example 19 in Table 8)

Step 1: Synthesis of [3-(l,l-Dioxo-lλ -thiomorpholine-4-sulfonyl)-4-methyl-phenyl]- (octahydro-isoquinolin-2-yl)-methanone

[3 -(l,l-Dioxo-lλ⁶-thiomorpholine-4-sulfonyl)-4-methyl -phenyl] -(octahydro-isoquinolin-2-yl)- methanone was synthesised either by general Method A (using 1 , 1 -dioxothiomorpholine) or by oxidation of the thiomorpholinesulfonamide (Example 10, Table 8) following a literature reference (Wroebel, J. et al. Bioorg. Med. Chem. 10, (2002), 639-656).

To a solution of 121 mg (0.29 mmol) of [4-methyl-3-(thiomorpholine-4-sulfonyl)-phenyl]- (octahydro-isoquinolin-2-yl)-methanone in glacial acetic acid (1.5 mL) were added 65 μL (1.14 mmol, 4 equ.) of 50 wt% aqueous hydrogen peroxide solution. The reaction was heated to 100 ⁰C for 18h. The reaction was concentrated under reduced pressure and the crude purified by column chromatography (silica, eluent DCM, 0-10 % ethyl acetate) to afford 22 mg of [3-(l,l-dioxo-lλ⁶- thiomorpholine-4-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone

Examples listed in Table 8, Method A were made according to this procedure.

Method B

Synthesis of [3-(4,4-Difluoro-piperidine-l-sulfonyl)-4-methyl-phenyl] -(octahydro- isoquinolin-2-yl)-methanone (Example 14 in Table 8)

Step 1: Synthesis of (Octahydro-isoquinolin-2-yl)-/>-tolyl-methanone

(Octahydro-isoquinolin-2-yl)-p-tolyl-methanone was generally prepared by adaptation of the methods described in the following literature reference: WO2001/000573

To a solution of 3.90 mL (26 mmol, 2 equ.) of decahydroisoquinoline in acetonitrile (25 mL) were added dropwise 1.74 mL (13 mmol) toluoyl chloride at room temperature. The reaction was shaken on an orbital shaker for 18 h. The solution was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (20 mL) and washed with IM aqueous HCl solution (20 mL). The acidic aqueous washes were back-extracted with ethyl acetate (20 ml). The combined organic extracts were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford 3.00 g (octahydro-isoquinolin-2-yl)-/>-tolyl-methanone.

According to this Method the following benzamides were synthesised.

Table 2

Step 2: Synthesis of 2-Methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonyl chloride

3.0 g (11.6 mmol) of (octahydro-isoquinolin-2-yl)-/?-tolyl-methanone were dissolved in 1, 2- dichloroethane (25 mL) and chlorosulfonic acid (25 mL). The reaction was heated to 80 ⁰C until completion. The reaction was poured carefully onto crushed ice and the resulting acidic aqueous solution extracted with ethyl acetate (3 x 200 mL). The organic extracts were combined, washed with brine (50 mL), dried over Na₂SO₄ and filtered. Concentrated under reduced pressure afforded 3.75 g of 2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonyl chloride.

According to this Method the following sulfonyl chlorides were synthesised:

Table 3

Step 3: Synthesis of [3-(4,4-Difluoro-piperidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro- isoquinolin-2-yl)-methanone 100 mg (0.28 mmol) of 2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonyl chloride and 108 mg (0.56 mmol, 2 equ.) of 4,4-difluoropiperidine hydrochloride salt were dissolved in acetonitrile (5 mL) and 97 μL (0.56 mmol, 2 equ.) of N, N-diisoproylethylamine were added. The reaction was shaken on an orbital shaker at room temperature for 2Oh. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in DCM (5 mL) and washed with IM aqueous HCl solution (1 mL), followed by sat. aqueous NaHCCh solution (1 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was further purified by flash column chromatography (silica, eluent DCM, 0- 10% ethyl acetate) to afford 89 mg of [3-(4,4-difluoro-piperidine-l-sulfonyl)-4-methyl-phenyl]- (octahydro-isoquinolin-2-yl)-methanone.

Examples listed in Table 8, Method B were made according to this procedure.

Method C

Synthesis of [3-(Morpholine-4-sulfonyl)-4-trifluoromethyl-phenyl]-(4a.S',8a/?)-octahydro- isoquinolin-2-yl-methanone (Example 25 in Table 8)

Step 1: Synthesis of 4-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-morpholine

To a suspension of 3.27 g (10.1 mmol) 4-bromo-2-trifluoromethyl-benzenesulfonyl chloride in acetonitrile (20 niL) at 0 ⁰C were added 1.76 mL (20.2 mmol, 2 equ.) of morpholine. The ice bath was then removed and the reaction stirred at room temperature until completion. The reaction was concentrated under reduced pressure. The residue was dissolved in DCM (30 mL) and washed with IM aqueous HCl (15mL) and brine (50 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give 3.11 g of 4-(4-bromo-2-trifluoromethyl- benzenesulfonyl)-morpholine.

According to this procedure the following sulfonamides were synthesised:

Table 4

Step 2: Synthesis of 2-Bromo-5-(morpholine-4-sulfonyl)-4-trifluoromethyl-benzoic acid

To a solution of 0.68 niL (4 mmol, 1 equ.) of 2,2',6,6'-tetramethylpiperidine in anhydrous THF (9 mL) were added 3.1 mL (4 mmol) of sec-butyllithium (1.4 M solution in cyclohexane) under inert atmosphere at -100 ⁰C. The solution was stirred for 20 min at -100 ⁰C. Then a solution of 1.5 g (4 mmol) of 4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-morpholine in anhydrous THF (4 mL) were added dropwise over 30 min and the resulting solution was stirred for 2.5 h at -100 ⁰C. The cooling bath was then removed. The reaction mixture was poured slowly under inert atmosphere onto solid CO₂ and warmed to room temperature with stirring. The reaction mixture was partitioned between TBME (20 mL) and water (20 mL). The aqueous layer was washed with

TBME (20 mL), then acidified to pH 1 with 2M aqueous HCl solution and extracted with DCM (2 x 20 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford 0.92 g of 2-bromo-5-(morpholine-4-sulfonyl)-4-trifluoromethyl-benzoic acid.

According to this procedure the following benzoic acids were synthesised:

Table 5

*To aid further purification at this stage and isolate the desired product from any unreacted starting material and/or undesired regioisomer, crude 2-bromo-5-(4,4-difluoro-piperidine-l- sulfonyl)-4-trifluoromethyl-benzoic acid (example in table 5) was converted into its methyl ester under standard methyl ester formation condition using TMS diazomethane:

To a suspension of 3.08 g (theor. 6.8 mmol) of crude 2-bromo-5-(4,4-difluoro-piperidine-l- sulfonyl)-4-trifluoromethyl-benzoic acid in toluene-MeOH (62 mL, 4: 1) were added 3.4 mL (6.8 mmol) TMS-diazomethane (2.0 M solution in diethyl ether) at 0 ⁰C under inert atmosphere; the bath was then removed and the reaction stirred at room temperature until completion. The reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, eluent toluene) to afford 0.78 g of the desired 2-bromo-5-(4,4-difluoro- piperidine-l-sulfonyl)-4-trifluoromethyl-benzoic acid. This material was used in the next step where hydrolysis of the methyl ester to the acid occurred in situ.

Step 2: Synthesis of 3-(Morpholine-4-sulfonyl)-4-trifluoromethyl-benzoic acid

To a suspension of 460 mg (1.1 mmol) of 2-bromo-5-(morpholine-4-sulfonyl)-4-trifluoromethyl- benzoic acid in 3M aqueous NaOH (3 mL) and ethanol (3 mL) were added at room temperature 1 g Ni-Raney slurry (50 wt% in water). The suspension was stirred at 30 ⁰C under inert atmosphere until completion. The mixture was then filtered through Celite^®, the cake washed thoroughly with water, and hot water-MeOH. The combined filtrates were acidified with concentrated HCl to pH 2-3 and extracted with DCM (2 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated to afford 0.21 g of 3-(morpholine-4- sulfonyl)-4-trifluoromethyl-benzoic acid.

According to this procedure the following benzoic acids were synthesised:

Table 6

Step 3: Synthesis of [3-(Morpholine-4-sulfonyl)-4-trifluoromethyl-phenyl]-(4a.S',8a/?)- octahydro-isoquinolin-2-yl-methanone

[3-(Morpholine-4-sulfonyl)-4-trifluoromethyl-phenyl]-(4a5',8a/?)-octahydro-isoquinolin-2-yl- methanone were generally prepared by adaptation of Method A:

197 mg (0.58 mmol) of 3-(morpholine-4-sulfonyl)-4-trifluoromethyl-benzoic acid were dissolved in DCM (10 mL), 0.25 mL (3.5 mmol, 6 equ.) thionyl chloride were added followed by a catalytic amount of DMF. The reaction was stirred at room temperature for 3.5 h. The reaction mixture was concentrated under reduced pressure. The crude acid chloride was redissolved in DCM (5 mL) and 0.17 mL (1.16 mmol, 2 equ.) of trans-decahydroisoquinoline were added. The reaction was shaken at room temperature for 20 h. The reaction was then washed with sat. aqueous NaHCC>₃ solution (3 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was further purified by preparative HPLC to afford 22 mg of [3-(morpholine-4-sulfonyl)-4- trifluoromethyl-phenyl]-(4a5',8ai?)-octahydro-isoquinolin-2-yl-methanone.

Examples listed in Table 8, Method C were made according to this procedure.

Method D

Synthesis of [4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4a/?,8a/?)-octahydro-isoquinolin- 2-yl-methanone (Example 18 in Table 8)

Step 1: Synthesis of cis-Decahydroisoquinoline Picrate Separation of decahydroisoquinoline into its diastereoisomers was achieved by following a literature reference (Baer, H. H.; Achmatowitz, B.; J. Org. Chem. 29 (1964), 3180-3185). 107 μL (0.72 mmol) decahydroisoquinoline (mixture of cis and trans diastereoisomers) was dissolved in methanol (1 mL) and a solution of 222 mg (0.72 mmol) picric acid in hot methanol (4 mL) was added. Dropwise addition of water until incipient turbidity and cooling produced yellow crystals. Isolation by filtration, washing with water and drying afforded 527 mg of cis- decahydroisoquinoline as its picrate salt; mp = 151-153 °C (lit. 154-156 °C)

Step 2: Synthesis of [4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4a/?,8a/?)-octahydro- isoquinolin-2-yl-methanone

To a solution of 110 mg (0.41 mmol) 4-methyl-3 -(pyrrolidine- 1 -sulfonyl)-benzoic acid in DCM (5 mL) was added a catalytic amount of DMF, followed by 0.178 mL (2.44 mmol, 6 equ.) thionyl chloride. The reaction was stirred at room temperature for 4 h. The solution was concentrated under reduced pressure and the residue dissolved in DCM. Then 0.211 mL (1.22 mmol, 3 equ.) of N,N-diisopropylethylamine were added, followed by 150 mg (0.41 mmol, 1 equ.) cis- decahydroisoquinoline picrate salt and a catalytic amount of DMAP. The reaction was stirred at room temperature for 18 h. The solution was then washed with sat. aqueous NaHCO₃ solution (5 mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified twice by column chromatography (silica, 1. eluent: DCM, 2. eluent: hexane: acetone, 3: 1) to afford 11 mg of [4-methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4ai?,8ai?)- octahydro-isoquinolin-2-yl-methanone.

Examples listed in Table 8, Method D were made according to this procedure.

Table 8:

[4-Methyl-3-(3-methyl-pyrrolidine-

1 -sulfonyl)-phenyl]-(octahydro- 405 B isoquinolin-2-yl)-methanone

[4-Methyl-3-(morpholine-4- sulfonyl)-phenyl]-(octahydro- 407 A isoquinolin-2-yl)-methanone

[3-(Azetidine-l-sulfonyl)-4-methyl- phenyl]-(octahydro-isoquinolin-2- 377 B yl)-methanone

[4-Methyl-3-(thiomorpholine-4- sulfonyl)-phenyl]-(octahydro- 423 B isoquinolin-2-yl)-methanone

[4-Methyl-3-(piperidine- 1 - sulfonyl)-phenyl]-(octahydro- 405 A isoquinolin-2-yl)-methanone

[3-(Azepane- 1 -sulfonyl)-4-methyl- phenyl]-(octahydro-isoquinolin-2- 419 B yl)-methanone

Method E:

Synthesis of 5-Cyclohexyl-3-[4-methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-[l,2,4]oxadiazole (Example 1 in Table 13)

Step 1: Synthesis of 4-Methyl-3-(pyrrolidine-l-sulfonyl)-benzonitrile

To a suspension of 0.5 g (2.51 mmol) of 5-cyano-2-methyl-benzenesulfonyl fluoride in acetonitrile (15 niL) at 0 ⁰C were added 0.6 mL (6.4 mmol, 2.55 equ.) of pyrrolidine. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction was concentrated under reduced pressure to approximately a third of the volume. The residual suspension was diluted with IM aqueous NaOH (45 mL) and extracted with TBME (3 x 25 mL). The combined organic extracts were washed with brine (2 x 25 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to afford 650 mg of 4-methyl-3-(pyrrolidine-l-sulfonyl)-benzonitrile.

According to this procedure the following sulfonamides were synthesised:

Table 9

Step 2: Synthesis of iV-Hydroxy-4-methyl-3-(pyrrolidine-l-sulfonyl)-benzamidine

A solution of 0.81 mg (3.2 mmol) of 4-methyl-3 -(pyrrolidine- 1 -sulfonyl)-benzonitrile, 0.23 g (3.2 mmol, 1 equ.) hydroxylamine hydrochloride salt and 0.45 mL (3.2 mmol, 1 equ.) of triethylamine in ethanol (5.2 mL) was heated to 80 ⁰C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (8 mL) and water (4 mL). The organic layer was separated and washed with additional water (2 x 5 mL) and saturated aqueous NaHCC>3 solution (2 x 5 mL). The organic layer was extracted with IM aqueous HCl (3 x 4 mL).The combined aqueous extracts were basified to pH 10 by addition of saturated aqueous Na₂COs solution and extracted with ethyl acetate (3 x 8 mL). The combined organic extracts were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford 0.49 g of N-hydroxy-4-methyl-3-(pyrrolidine-l-sulfonyl)-benzamidine.

According to this procedure the following N-hydroxy-3-sulfamoyl-benzamidines were synthesised:

Table 10

Step 3: Synthesis of 5-Cyclohexyl-3-[4-methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]- [1,2,4] oxadiazole

A solution of 130 mg (0.46 mmol) of N-hydroxy-4-methyl-3 -(pyrrolidine- 1 -sulfonyl)-benzami dine and 126 μL (0.92 mmol, 2 equ.) cyclohexanecarbonyl chloride in pyridine (2.6 mL) under nitrogen atmosphere was heated to 115 ⁰C for 18 h. The reaction mixture was concentrated under reduced pressure. The crude residue was suspended in ethyl acetate (30 mL), washed with 10 % aqueous CuSO₄ solution (2 x 10 mL) and brine (15 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by column chromatography (silica, eluent: cyclohexane, 0-20 % ethyl acetate) afforded 78 mg of 5-cyclohexyl-3-[4-methyl-3-(pyrrolidine-l- sulfonyl)-phenyl]-[l,2,4]oxadiazole.

Examples listed in Table 13, Method E were made according to this procedure.

Method F

Synthesis of l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-piperidine (Example 11 in Table 13)

Step 1: Synthesis of S-ChlorosulfonyM-methyl-benzoic acid

3-Chlorosulfonylbenzoic acids have been reported in the literature or were generally prepared as described in adaptation of the following references: WO2001/000573, WO2005/115374,

WO2004/018414, Wrobel, J. et al. Bioorg. Med. Chem. 10 (2002), 639-656., Me, Z. et al. J. Med. Chem. 48 (2005), 1596-1609.

To 20 g (0.15 mol) of 4-toluic acid was added chlorosulfonic acid (100 mL) and the reaction was stirred at 60 ⁰C for 18 h until completion. The reaction was cooled to room temperature and carefully poured onto ice. The resulting precipitate was isolated by filtration, washed with water and dried under reduced pressure at 60 ⁰C to afford 30.3 g of 3 -chlorosulfonyl-4-methyl -benzoic acid as an off-white solid.

Step 2: Synthesis of 4-Methyl-3-(piperidine-l-sulfonyl)-benzoic acid To a suspension of 8 g (34.2 mmol) 3-chlorosulfonyl-4-methyl-benzoic acid in acetonitrile (160 mL) was added dropwise 10.1 niL (103 mmol, 3 equ.) of piperidine at 0 °C. The reaction was stirred at 0 ⁰C for 0.5 h, then allowed to warm to room temperature and stirred until completion. The reaction was concentrated under reduced pressure to l/8th of the volume. The residue was dissolved in IM aqueous NaOH solution (50 mL) and washed with TBME (2 x 50 mL). The basic aqueous layer was cooled in an ice-bath and acidified with 2M aqueous HCl solution to pH 1-2. This acidic aqueous layer was then extracted with TBME (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford 5.0 g of 4-methyl-3 -(piperidine- 1 -sulfonyl)-benzoic acid.

Table 11

Step 3: Synthesis of iV-Hydroxy-2,2-diniethyl-propionaniidine

The synthesis of amidoximes has been reported in the literature or they have been prepared by adaptation of the procedures described in the following references: US 3,897,447, US 3,547,621

To a solution of 6.8 g (98 mmol) hydroxylamine hydrochloride salt in water (15 mL) was added a solution of 6.15 g (44.5 mmol, 0.5 equ.) potassium carbonate in water (10 mL), slowly followed by 6.25 g (98 mmol, 1 equ.) of trimethylacetonitrile and ethanol (50 mL). The reaction was heated to 80 ⁰C for 16 h. After cooling to room temperature, DCM (75 mL) and water (50 mL) were added to the suspension. The aqueous layer was extracted with DCM (3 x 50 mL) and the combined organic extracts were washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford 6.15 g N-hydroxy-2,2-dimethyl-propionamidine.

Step 4: Synthesis of l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]- piperidine

To a solution of 100 mg (0.35 mmol) of 4-methyl-3-(piperidine-l-sulfonyl)-benzoic acid in DCM (5 mL) were added dropwise 190 μL (3.98 mmol, 6 equ.) thionyl chloride at 0 ⁰C, followed by a few drops of DMF. The reaction was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was dissolved in pyridine (5 mL) and 41 mg (0.35 mmol, 1 equ.) of N-hydroxy-2,2-dimethyl-propionamidine were added. The reaction was heated at 80 ⁰C for 5.5 h. The mixture was then concentrated under reduced pressure and the residue purified by flash column chromatography (silica, eluent: DCM) to afford 44.1 mg of l-[5-(3-cyclohexyl- [1 ,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-piperidine.

Examples in Table 13, Method F were made according to this procedure.

Method G Synthesis of l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-trifluoromethyl-benzenesulfonyl]- 4,4-difluoro-piperidine (Example 9 in Table 13)

Step 1: Synthesis of l-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-4,4-difluoro-piperidine

To a suspension of 6.0 g (18.6 mmol) 4-bromo-2-trifluoromethyl-benzenesulfonyl chloride in acetonitrile (45 niL) at 0 ⁰C were added 3.05 g (19.5 mmol, 1.05 equ.) 4,4-difluoropiperidine hydrochloride salt, followed by 6.82 mL (39.0 mmol, 2.1 equ.) N, N-diisopropylethylamine. The ice bath was then removed and the reaction stirred at room temperature until completion. The reaction was concentrated under reduced pressure. The residue was dissolved in DCM (30 mL) and washed with IM aqueous HCl (15 mL) and brine (50 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography (silica, eluent: heptanes, 1-40 % ethyl acetate) gave 6.84 g of l-(4-bromo-2- trifluoromethyl-benzenesulfonyl)-4,4-difluoro-piperidine. According to this procedure the following sulfonamides were synthesised:

Table 12

Step 2: Synthesis of 2-Bromo-5-(4,4-difluoro-piperidine-l-sulfonyl)-4-trifluoromethyl- benzoic acid methyl ester

To a solution of 1.52 mL (8.98 mmol, 1.05 equ.) of 2,2',6,6'-tetramethylpiperidine in anhydrous THF (10.5 mL) were added 6.74 mL (8.76 mmol, 1.03 equ.) of sec-butyllithium (1.3 M solution in cyclohexane) under inert atmosphere at -100 ⁰C. The solution was stirred for 20 min at -100 ⁰C. Then a solution of 3.49 g (8.55 mmol, 1 equ.) of l-(4-bromo-2-trifluoromethyl-benzenesulfonyl)- 4,4-difluoro-piperidine in anhydrous THF (25 mL) was added dropwise over 30 min and the resulting solution was stirred for 2.5 h at -100 ⁰C. The cooling bath was then removed. The reaction mixture was poured slowly under inert atmosphere onto solid CO₂ and warmed to room temperature with stirring. The reaction mixture was concentrated to dryness under reduced pressure. The residue was then partitioned between water (40 mL) and TBME (3 x 40 mL). The combined organic extracts were washed with brine (70 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to afford 3.08 g of crude 2-bromo-5-(morpholine-4-sulfonyl)- 4-trifluoromethyl-benzoic acid. To aid further purification at this stage and isolate the desired product from any unreacted starting material and/or undesired regioisomer, crude 2-bromo-5-(4,4-difluoro-piperidine-l-sulfonyi)-4- trifluoromethyl-benzoic acid was converted into its methyl ester under standard methyl ester formation condition using TMS-diazomethane: To a suspension of 3.08 g (theor. 6.8 mmol) of crude 2-bromo-5-(4,4-difluoro-piperidine-l- sulfonyl)-4-trifluoromethyl-benzoic acid in toluene-MeOH (62 mL, 4: 1) were added 3.4 mL (6.8 mmol, 1 equ.) TMS-diazomethane (2.0 M solution in diethyl ether) at 0 ⁰C under inert atmosphere; the bath was then removed and the reaction stirred at room temperature until completion. The reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, eluent: toluene) to afford 0.78 g of the desired 2-bromo-5-(4,4-difluoro- piperidine- 1 -sulfonyl)-4-trifluoromethyl-benzoic acid methyl ester. Yield: 38%; ESI-MS: m/z 466/468 [M+H⁺]

Step 3: Synthesis of 3-(4,4-Difluoro-piperidine-l-sulfonyl)-4-trifluoromethyl-benzoic acid

To a suspension of 0.7 g (1.5 mmol) 2-bromo-5-(4,4-difluoro-piperidine-l-sulfonyl)-4- trifluoromethyl-benzoic acid methyl ester in 3M aqueous NaOH (13.3 mL) at room temperature were added 0.5 mL of THF and 1.6 g of Ni-Raney slurry (50 wt% in water). The suspension was stirred at 30 ⁰C under inert atmosphere for 24 h. The mixture was then filtered through Celite^® and the cake was washed thoroughly with water, and hot water-MeOH. The combined filtrates were concentrated under reduced pressure to approximately a third of the volume and washed with

DCM (25 mL). The basic aqueous layer was then acidified with concentrated HCl to pH 2- 3 and extracted with DCM (3 x 25 mL). The combined DCM extracts were washed with brine (20 mL), dried over MgSO₄, filtered and concentrated to afford 117 mg of 3-(4,4-difluoro-piperidine-l- sulfonyl)-4-trifluoromethyl-benzoic acid. Yield: 21%; ESI-MS: m/z 374 [M+H⁺] Step 4: Synthesis of l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-trifluoromethyl- benzenesulfonyl]-4,4-difluoro-piperidine

To a solution of 213 mg (0.44 mmol) of 3-(4,4-difluoro-piperidine-l-sulfonyl)-4-trifluoromethyl- benzoic acid in DCM (4 niL) were added dropwise 192 μL (2.64 mmol, 6 equ.) thionyl chloride at 0 ⁰C, followed by 100 μL of DMF. The reaction was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was dissolved in pyridine (5 mL) and a solution of 62 mg (0.44 mmol, 1 equ.) of N-hydroxy-cyclohexanecarboxamidine in pyridine (2 mL) was added. The reaction was heated at 110 ⁰C for 3 h. The mixture was then concentrated under reduced pressure and the residue dissolved in DCM (25 mL). The organic layer was washed with sat. aqueous NaHCO₃ solution (3 x 5 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent: DCM), followed by preparative HPLC afforded 12.3 mg of l-[5-(3-cyclohexyl-[l,2,4]oxadiazol-5-yl)-2- trifluoromethyl-benzenesulfonyl]-4,4-difluoro-piperidine.

Examples in Table 13, Method G were made according to this procedure.

Examples:

Table 13

Intermediates listed in tables 1 - 6 may be converted to compounds of formula (I) or (IA), respectively, using methods described herein above.

Assessment of Biological Properties

The biological properties of the compounds of the formula I were assessed using the assays described below.

A. Human CBl and CB2 Receptor Binding: Experimental Method: CB2 membranes were purchased and made from HEK293 EBNA cells stably transfected with human CB2 receptor cDNA (Perkin Elmer Life and Analytical Sciences). CBl membranes were isolated from HEK cells stably co-transfected with human CBl receptor and Ga 16 cDNA's. The membrane preparation was bound to scintillation beads (Ysi-Poly-L-lysine SPA beads, GE Healthcare) for 4 hours at room temperature in assay buffer containing 5OmM Tris, pH 7.5, 2.5mM EDTA, 5mM MgCl₂, 0.8% fatty acid free Bovine Serum Albumin. Unbound membrane was removed by washing in assay buffer. Membrane-bead mixture was added to 96-well assay plates in the amounts of 15ug membrane per well (CB2) or 2.5ug per well (CBl) and lmg SPA bead per well. Compounds were added to the membrane-bead mixture in dose-response concentrations ranging from Ix 10^"5 M to IxIO^"10 M with 0.25% DMSO, final. The competition reaction was initiated with the addition of ³H-CP55940 (Perkin Elmer Life and Analytical Sciences) at a final concentration of 1.5nM (CB2) or 2.5nM (CBl). The reaction was incubated at room temperature for 18hours and read on TopCount NXT plate reader. Total and non-specific binding was determined in the absence and presence of 1.25uM Win 55212 (Sigma). IC50 values for each compound were calculated as the concentration of compound that inhibits the specific binding of the radioactively labeled ligand to the receptor by 50% using the XLFit 4.1 four parameter logistic model. IC50 values were converted to inhibition constant (Ki) values using Cheng-Prusoff equation.

B. CB2R mediated modulation of cAMP synthesis: Compounds of the invention were evaluated for their CB2 agonist or inverse agonistic activity in accordance with the following experimental method. Compounds which were shown to bind to CB2 by the binding assay described above but which were not shown to exhibit CB2R-mediated modulation of cAMP synthesis by this assay were presumed to be CB2 antagonists.

Experimental Method: CHO cells expressing human CB2R (Euroscreen) were plated at a density of 5000 cells per well in 384 well plates and incubated overnight at 37°C. After removing the media, the cells were treated with test compounds diluted in stimulation buffer containing ImM IBMX, 0.25% BSA and lOuM Forskolin. The assay was incubated for 30 minutes at 37°C. Cells were lysed and the cAMP concentration was measured using DiscoverX -XS cAMP kit, following the manufacturer's protocol. In this setting, agonists will decrease forskolin induced production of cAMP while inverse agonists will further increase forskolin induced production of cAMP. EC50 of agonists were calculated as follows. The maximal amount of cAMP produced by forskolin compared to the level of cAMP inhibited by IuM CP55940 is defined as 100%. The EC50 value of each test compound was determined as the concentration at which 50% of the forskolin-stimulated cAMP synthesis was inhibited. Data was analyzed using a four-parameter logistic model. (Model 205 of XLfit 4.0).

C. CBlR mediated modulation of cAMP synthesis:

Compounds of the invention were evaluated for their CBl agonist or inverse agonistic activity in accordance with the following experimental method. Compounds which were shown to bind to CB 1 by the binding assay described above but which were not shown to exhibit CBIR-mediated modulation of cAMP synthesis by this assay were presumed to be CBl antagonists.

Experimental Method:

CHO cells expressing human CBlR (Euroscreen) were plated at a density of 5000 cells per well in 384 well plates and incubated overnight at 37°C. After removing the media, the cells were treated with test compounds diluted in stimulation buffer containing ImM IBMX, 0.25% BSA and lOuM Forskolin. The assay was incubated for 30 minutes at 37°C. Cells were lysed and the cAMP concentration was measured using DiscoverX -XS cAMP kit, following the manufacturer's protocol. In this setting, agonists will decrease forskolin induced production of cAMP while inverse agonists will further increase forskolin induced production of cAMP. EC50 of agonists were calculated as follows. The maximal amount of cAMP produced by forskolin compared to the level of cAMP inhibited by IuM CP55940 is defined as 100%. The EC50 value of each test compound was determined as the concentration at which 50% of the forskolin-stimulated cAMP synthesis was inhibited. Data was analyzed using a four-parameter logistic model. (Model 205 of XLfit 4.0).

Compounds Having Agonist Activity

Through the use of the above described assays the following compounds were found to exhibit agonistic activity and thus to be particularly well suited for the treatment of pain as well as for the treatment of inflammation:

N-Isopropyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide

[4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-pyrrolidin-l-yl-methanone

[3-(4-Hydroxy-piperidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3 -(pyrrolidine- 1 -sulfonyl)-phenyl]-(octahydro-quinolin- 1 -yl)-methanone N-sec-Butyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3-(piperidine- 1 -sulfonyl)-phenyl]-(octahydro-quinolin- 1 -yl)-methanone [3-(3,3-Difluoro-pyrrolidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)- methanone [4-Methyl-3-(3-methyl-pyrrolidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3-(morpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [3-(Azetidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3-(piperidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [3-(Azepane- 1 -sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone

N-Cyclopropylmethyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide

[3-(4,4-Difluoro-piperidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone

N-Bicyclo[2.2.1]hept-2-yl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3-(thiazolidine-3-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone N-Isobutyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4aR,8aR)-octahydro-isoquinolin-2-yl-methanone

[3 -( 1 , 1 -Dioxo- 1 λ thiomoφholine-4-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)- methanone [4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone

[4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl-methanone [4-Methyl-3-(piperidine-l-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl-methanone [3-(3-Fluoro-pyrrolidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Isopropyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [3-(Morpholine-4-sulfonyl)-4-trifluoromethyl-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl- methanone

(4aS,8aR)-Octahydro-isoquinolin-2-yl-[3-(pyrrolidine-l-sulfonyl)-4-trifluoromethyl-phenyl]- methanone [4-Chloro-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Chloro-3-(thiomorpholine-4-sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl- methanone

[4-Chloro-3-(piperidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Chloro-3-(piperidine-l-sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl-methanone [4-Chloro-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl-methanone [4-Chloro-3 -(pyrrolidine- 1 -sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone

[4-Chloro-3-(morpholine-4-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl-methanone 2-Chloro-N-isobutyl-5-((4aR,8aS)-octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3-(piperidine- 1 -sulfonyl)-phenyl]-piperidin- 1 -yl-methanone [4-Isopropyl-3-(morpholine-4-sulfonyl)-phenyl]-((4aR,8aS)-octahydro-isoquinolin-2-yl)- methanone

N-Isobutyl-2-isopropyl-5-((4aR,8aS)-octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide

[3-(Azepane-l-sulfonyl)-4-isopropyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone

[4-Isopropyl-3-(morpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone N-Cyclohexyl-N-isopropyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Isopropyl-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [3-(Azepane-l-sulfonyl)-4-isopropyl-phenyl]-((4aR,8aS)-octahydro-isoquinolin-2-yl)-methanone 3-Cyclopentanesulfonyl-4-methyl-phenyl)-(octahydro-isoquinolin-2-yl)-methanone

l-[5-(5-Cyclohexyl-[l,2,4]oxadiazol-3-yl)-2-methyl-benzenesulfonyl]-piperidine 5-Cyclohexyl-3-[4-methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-[l,2,4]oxadiazole l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-piperidine l-[5-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-2-isopropyl-benzenesulfonyl]-4,4-difluoro-piperidine 4,4-Difluoro- 1 - {2-trifluoromethyl-5-[3-(2-trifluoromethyl-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]- benzenesulfonyl} -piperidine l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-4,4-difluoro- piperidine

4-[5-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-thiomorpholine 1 -[5-(3-tert-Butyl-[ 1 ,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-piperidine 3-tert-Butyl-5-[4-methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-[l,2,4]oxadiazole

4,4-Difluoro- l-[2-isopropyl-5-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-benzenesulfonyl]-piperi dine 4-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-morpholine 4-[5-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-morpholine 4-[5-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-thiomorpholine

Of the above compounds, the following are preferred:

[3-(4-Hydroxy-piperidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3 -(pyrrolidine- 1 -sulfonyl)-phenyl]-(octahydro-quinolin- 1 -yl)-methanone N-sec-Butyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3 -(piperidine- 1 -sulfonyl)-phenyl]-(octahydro-quinolin- 1 -yl)-methanone [3-(3,3-Difluoro-pyrrolidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)- methanone [4-Methyl-3-(3-methyl-pyrrolidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3-(morpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [3-(Azetidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3-(piperidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [3-(Azepane-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone N-Cyclopropylmethyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide

[3-(4,4-Difluoro-piperidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone N-Bicyclo[2.2.1]hept-2-yl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3-(thiazolidine-3-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone N-Isobutyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4aR,8aR)-octahydro-isoquinolin-2-yl-methanone [3-(l , 1 -Dioxo- 1 lambda*6*-thiomorpholine-4-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin- 2-yl)-methanone

[4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl-methanone [4-Methyl-3-(piperidine-l-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl-methanone [3-(3-Fluoro-pyrrolidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Isopropyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [3-(Morpholine-4-sulfonyl)-4-trifluoromethyl-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl- methanone (4aS,8aR)-Octahydro-isoquinolin-2-yl-[3-(pyrrolidine- 1 -sulfonyl)-4-trifluoromethyl-phenyl]- methanone

[4-Chloro-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Chloro-3-(thiomorpholine-4-sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl- methanone [4-Chloro-3 -(piped dine- 1 -sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone

[4-Chloro-3-(piperidine-l-sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl-methanone [4-Chloro-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl-methanone [4-Chloro-3 -(pyrrolidine- l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Chloro-3-(morpholine-4-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl-methanone 2-Chloro-N-isobutyl-5-((4aR,8aS)-octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3-(piperidine- 1 -sulfonyl)-phenyl]-piperidin- 1 -yl-methanone [4-Isopropyl-3-(morpholine-4-sulfonyl)-phenyl]-((4aR,8aS)-octahydro-isoquinolin-2-yl)- methanone N-Isobutyl-2-isopropyl-5-((4aR,8aS)-octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [3-(Azepane-l-sulfonyl)-4-isopropyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Isopropyl-3-(morpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone N-Cyclohexyl-N-isopropyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Isopropyl-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [3-(Azepane-l-sulfonyl)-4-isopropyl-phenyl]-((4aR,8aS)-octahydro-isoquinolin-2-yl)-methanone 3-Cyclopentanesulfonyl-4-methyl-phenyl)-(octahydro-isoquinolin-2-yl)-methanone The following are preferred agonists of Formula IA: l-[5-(5-Cyclohexyl-[l,2,4]oxadiazol-3-yl)-2-methyl-benzenesulfonyl]-piperidine 5-Cyclohexyl-3-[4-methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-[l,2,4]oxadiazole l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-piperidine l-[5-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-2-isopropyl-benzenesulfonyl]-4,4-difluoro-piperidine 4,4-Difluoro- 1 - {2-trifluoromethyl-5-[3-(2-trifluoromethyl-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]- benzenesulfonyl} -piperidine l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-4,4-difluoro- piperidine 4-[5-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-thiomorpholine 1 -[5-(3-tert-Butyl-[ 1 ,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-piperidine 3 -tert-Butyl-5-[4-methyl-3 -(pyrrolidine- 1 -sulfonyl)-phenyl]-[ 1 ,2,4]oxadiazole 4,4-Difluoro- l-[2-isopropyl-5-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-benzenesulfonyl]-piperi dine 4-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-morpholine 4-[5-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-morpholine

4-[5-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-thiomorpholine Therapeutic Use

As can be demonstrated by the assays described above, the compounds of the invention are useful in modulating the CB2 receptor function. By virtue of this fact, these compounds have therapeutic use in treating disease-states and conditions mediated by the CB2 receptor function or that would benefit from modulation of the CB2 receptor function.

As the compounds of the invention modulate the CB2 receptor function, they have very useful anti-inflammatory and immune-suppressive activity and they can be used in patients as drugs, particularly in the form of pharmaceutical compositions as set forth below, for the treatment of disease-states and conditions.

The agonist, antagonist and inverse agonist compounds according to the invention can be used in patients as drugs for the treatment of the following disease-states or indications that are accompanied by inflammatory processes:

(i) Lung diseases: e.g. asthma, bronchitis, allergic rhinitis, emphysema, adult respiratory distress syndrome (ARDS), pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD), asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and " wheezy- infant syndrome", pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis; (ii) Rheumatic diseases or autoimmune diseases or musculoskeletal diseases: all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, and polymyalgia rheumatica; reactive arthritis; rheumatic soft tissue diseases; inflammatory soft tissue diseases of other genesis; arthritic symptoms in degenerative joint diseases (arthroses); tendinitis, bursitis, osteoarthritis, traumatic arthritis; collagenoses of any genesis, e.g., systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, Still disease, Felty syndrome; and osteoporosis and other bone resorption diseases;

(iii) Allergic diseases: all forms of allergic reactions, e.g., angioneurotic edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock (anaphylaxis), urticaria, angioneurotic edema, and contact dermatitis;

(iv) Vascular diseases: panarteritis nodosa, polyarteritis nodosa, periarteritis nodosa, arteritis temporalis, Wegner granulomatosis, giant cell arthritis, atherosclerosis, reperfusion injury and erythema nodosum;

(v) Dermatological diseases: e.g. dermatitis, psoriasis; sunburn, burns, eczema; (vi) Renal diseases: e.g. nephrotic syndrome; and all types of nephritis, e.g., glomerulonephritis; pancreatits;

(vii) Hepatic diseases: e.g. acute liver cell disintegration; acute hepatitis of various genesis, e.g., viral, toxic, drug-induced; and chronically aggressive and/or chronically intermittent hepatitis; (viii) Gastrointestinal diseases: e.g. inflammatory bowel diseases, irritable bowel syndrome, regional enteritis (Crohns disease), colitis ulcerosa; gastritis; aphthous ulcer, celiac disease, regional ileitis, gastroesophageal reflux disease;

(ix) Neuroprotection: e.g. in the treatment of neurodegeneration following stroke; cardiac arrest; pulmonary bypass; traumatic brain injury; spinal cord injury or the like; (x) Eye diseases: allergic keratitis, uveitis, or iritis; conjunctivitis; blepharitis; neuritis nervi optici; choroiditis; glaucoma and sympathetic ophthalmia;

(xi) Diseases of the ear, nose, and throat (ENT) area: e.g. tinnitus; allergic rhinitis or hay fever; otitis externa; caused by contact eczema, infection, etc.; and otitis media;

(xii) Neurological diseases: e.g. brain edema, particularly tumor-related brain edema; multiple sclerosis; acute encephalomyelitis; meningitis; acute spinal cord injury; trauma; dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease; Parkinson's disease and Creutzfeldt- Jacob disease; Huntington's chorea, Pick's disease; motor neuron disease), vascular dementia

(including multi-infarct dementia) as well as dementia associated with intracranial space occupying lesions; infections and related conditions (including HIV infection);

Guillain-Barre syndrome; myasthenia gravis, stroke; and various forms of seizures, e.g., nodding spasms; (^χiϋ) Blood diseases: acquired hemolytic anemia; aplastic anemia, and idiopathic thrombocytopenia;

(xiv) Tumor diseases: acute lymphatic leukemia; Hodgkin's disease, malignant lymphoma; lymphogranulomatoses; lymphosarcoma; solid malignant tumors; extensive metastases,; (xv) Endocrine diseases: endocrine ophthalmopathy; endocrine orbitopathia; thyrotoxic crisis; Thyroiditis de Quervain; Hashimoto thyroiditis; Morbus Basedow; granulomatous thyroiditis; struma lymphomatosa; and Graves disease; type I diabetes

(insulin-dependent diabetes);

(xvi) Organ and tissue transplantations and graft-versus-host diseases; (xvii) Severe states of shock, e.g., septic shock, anaphylactic shock, and systemic inflammatory response syndrome (SIRS);

(xviii) Acute pain such as dental pain, perioperative, post-operative pain, traumatic pain, muscle pain, pain in burned skin, sun burn, trigeminal neuralgia, sun burn; spasm of the gastrointestinal tract or uterus, colics; (^χi^χ) Visceral pain such as pain associated with chronic pelvic pain, pancreatitis, peptic ulcer, interstitial cystitis, renal colic, angina, dysmenorrhoea, menstruation, gynaecological pain, irritable bowel syndrome (IBS), non-ulcer dyspepsia, non-cardiac chest pain, myocardial ischemia;

(xx) Neuropathic pain such as low back pain, non-herpetic neuralgia, post herpetic neuralgia, diabetic neuropathy, nerve injury, acquired immune deficiency syndrome

(AIDS) related neuropathic pain, head trauma, painful traumatic mononeuropathy, toxin and chemotherapy induced pain, phantom limb pain, painful polyneuropathy, thalamic pain syndrome, post-stroke pain, central nervous system injury, post surgical pain, stump pain, repetitive motion pain, pain induced by post mastectomy syndrome, multiple sclerosis, root avulsions, postthoracotomy syndrome, neuropathic pain associated hyperalgesia and allodynia. (xxi) Inflammatory/nociceptive pain induced by or associated with disorders such as osteoarthritis, rheumatoid arthritis, rheumatic disease, teno-synovitis, gout, vulvodynia, myofascial pain (muscular injury, fibromyalgia), tendonitis, osteoarthritis, juvenile arthritis, spondylitis, gouty arthritis, psoriatic arthritis, muscoskeletal pain, fibromyalgia, sprains and strains, sympathetically maintained pain, myositis, pain associated with migraine, toothache, influenza and other viral infections such as the common cold, rheumatic fever, systemic lupus erythematosus;

(xxii) Cancer pain induced by or associated with tumors such as lymphatic leukemia; Hodgkin's disease, malignant lymphoma; lymphogranulomatoses; lymphosarcoma; solid malignant tumors; extensive metastases; (xxiii) Headache such as cluster headache, migraine with and without aura, tension type headache, headache with different origins, headache disorders including prophylactic and acute use;

(xxiv) various other disease-states or conditions including, restenosis following percutaneous transluminal coronary angioplasty, acute and chronic pain, atherosclerosis, reperfusion injury, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, necrotizing enterocolitis and syndromes associated with hemodialysis, leukopheresis, and granulocyte transfusion, sarcoidosis, gingivitis, pyrexia, edema resulting from trauma associated with bums, sprains or fracture, cerebral oedema and angioedema, Diabetes such as diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion). Other indications include: epilepsy, septic shock e.g. as antihypovolemic and/or antihypotensive agents, cancer, sepsis, osteoporosis, benign prostatic hyperplasia and hyperactive bladder, pruritis, vitiligo, general gastrointestinal disorders, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, tissue damage and postoperative fever, syndromes associated with Itching.

Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.

As noted before, those compounds which are CB2 agonists can also be employed for the treatment of pain.

For treatment of the above-described diseases and conditions, a therapeutically effective dose will generally be in the range from about 0.01 mg to about 100 mg/kg of body weight per dosage of a compound of the invention; preferably, from about 0.1 mg to about 20 mg/kg of body weight per dosage. For example, for administration to a 70 kg person, the dosage range would be from about 0.7 mg to about 7000 mg per dosage of a compound of the invention, preferably from about 7.0 mg to about 1400 mg per dosage. Some degree of routine dose optimization may be required to determine an optimal dosing level and pattern. The active ingredient may be administered from 1 to 6 times a day.

Combination Therapy

These compounds may also be employed in combination therapies with the following compounds: non-steroidal antiinflammatory drugs (NSAIDs) including COX-2 inhibitors such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenhufen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (meclofenamic acid, mefe- namic acid, and tolfenamic acid), biphenyl- carboxylic acid derivatives, oxicams (isoxicam, meloxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone), and the coxibs (celecoxib, valecoXID, rofecoxib and etoricoxib); opiate receptor agonists such as morphine, propoxyphene (Darvon), tramadol, buprenorphin; sodium channel blockers such as carbamazepine, mexiletine, lamotrigine, pregabaline, tectin, NW- 1029, CGX- 1002;

N-type calcium channel blockers such as Ziconotide, NMED- 160, SPI-860; serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram; corticosteroids such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone; histamine Hl receptor antagonists such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdiazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine; histamine H2 receptor antagonists such as cimetidine, famotidine and ranitidine; proton pump inhibitors such as omeprazole, pantoprazole and esomeprazole; leukotriene antagonists and 5 -lipoxygenase inhibitors such as zafhiukast, montelukast, pranlukast and zileuton; local anesthetics such as ambroxol, lidocaine;

VRl agonists and antagonists such as NGX-4010, WL- 1002, ALGRX-4975, WL-10001, AMG-517; nicotinic acetylcholine receptor agonists such as ABT-202, A-366833, ABT-594; BTG-102, A-85380, CGX1204; P2X3 receptor antagonists such as A-317491, ISIS-13920, AZD-9056;

NGF agonists and antagonists such as RI-724, RI- 1024, AMG-819, AMG-403, PPH 207;

NKl and NK2 antagonists such as DA-5018, R-116301; CP-728663, ZD-2249;

NMDA antagonist such as NER-MD-11, CNS-5161, EAA-090, AZ-756, CNP-3381; potassium channel modulators such as CL-888, ICA-69673, retigabine; GABA modulators such as lacosamide; serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram, flibanserin; and combination with anti-migraine drugs like sumatriptan, zolmitriptan, naratriptan, eletriptan.

General Administration and Pharmaceutical Compositions

When used as pharmaceuticals, the compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The compounds of the invention may also be administered alone or in combination with adjuvants that enhance stability of the compounds of the invention, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increased inhibitory activity, provide adjunct therapy, and the like. The compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances. In general, the compounds of this invention are administered in a therapeutically or pharmaceutically effective amount, but may be administered in lower amounts for diagnostic or other purposes.

Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted modes of administration of pharmaceutical compositions. Thus, administration can be, for example, orally, buccally (e.g., sublingually), nasally, parenterally, topically, transdermally, vaginally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The pharmaceutical compositions will generally include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles, or combinations thereof. Such pharmaceutically acceptable excipients, carriers, or additives as well as methods of making pharmaceutical compositions for various modes or administration are well-known to those of skill in the art. The state of the art is evidenced, e.g., by Remington: The Science and Practice of Pharmacy, 20th Edition, A. Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook of Pharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995; Handbook of Pharmaceutical Excipients, A.H. Kibbe (ed.), American Pharmaceutical Ass'n, 2000; H. C. Ansel and N. G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger, 1990; each of which is incorporated herein by reference in their entireties to better describe the state of the art.

As one of skill in the art would expect, the forms of the compounds of the invention utilized in a particular pharmaceutical formulation will be selected (e.g., salts) that possess suitable physical characteristics (e.g., water solubility) that is required for the formulation to be efficacious. Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Injectable pharmaceutical formulations are commonly based upon injectable sterile saline, phosphate -buffered saline, oleaginous suspensions, or other injectable carriers known in the art and are generally rendered sterile and isotonic with the blood. The injectable pharmaceutical formulations may therefore be provided as a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, including 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, fixed oils such as synthetic mono- or diglycerides, fatty acids such as oleic acid, and the like. Such injectable pharmaceutical formulations are formulated according to the known art using suitable dispersing or setting agents and suspending agents. Injectable compositions will generally contain from 0.1 to 5% w/w of a compound of the invention.

Solid dosage forms for oral administration of the compounds include capsules, tablets, pills, powders, and granules. For such oral administration, a pharmaceutically acceptable composition containing a compound(s) of the invention is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharine, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Such solid pharmaceutical formulations may include formulations, as are well-known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms, which include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form.

Liquid dosage forms for oral administration of the compounds include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs, optionally containing pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like. These compositions can also contain additional adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.

Topical dosage forms of the compounds include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, eye ointments, eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. Topical application may be once or more than once per day depending upon the usual medical considerations. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation, more usually they will form up to about 80% of the formulation.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Such patches suitably contain a compound of the invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%.

For administration by inhalation, the compounds of the invention are conveniently delivered in the form of an aerosol spray from a pump spray device not requiring a propellant gas or from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide, or other suitable gas. In any case, the aerosol spray dosage unit may be determined by providing a valve to deliver a metered amount so that the resulting metered dose inhaler (MDI) is used to administer the compounds of the invention in a reproducible and controlled way. Such inhaler, nebulizer, or atomizer devices are known in the prior art, for example, in PCT International Publication Nos. WO 97/12687 (particularly Figure 6 thereof, which is the basis for the commercial RESPIMAT® nebulizer); WO 94/07607; WO 97/12683; and WO 97/20590, to which reference is hereby made and each of which is incorporated herein by reference in their entireties.

Rectal administration can be effected utilizing unit dose suppositories in which the compound is admixed with low-melting water-soluble or insoluble solids such as fats, cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, or fatty acid esters of polyethylene glycols, or the like. The active compound is usually a minor component, often from about 0.05 to 10% by weight, with the remainder being the base component.

In all of the above pharmaceutical compositions, the compounds of the invention are formulated with an acceptable carrier or excipient. The carriers or excipients used must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the patient. The carrier or excipient can be a solid or a liquid, or both, and is preferably formulated with the compound of the invention as a unit- dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound. Such carriers or excipients include inert fillers or diluents, binders, lubricants, disintegrating agents, solution retardants, resorption accelerators, absorption agents, and coloring agents. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

Pharmaceutically acceptable carriers and excipients encompass all the foregoing additives and the like.

Examples of Pharmaceutical Formulations

The finely ground active substance, lactose, and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodium-carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

The active substance,corn starch, lactose, and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45°C and the granules are then passed through the same screen. After the magnesium stearate has been mixed in, convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine. The tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc. The finished coated tablets are polished with wax.

The substance and corn starch are mixed and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The finished mixture is packed into size 1 hard gelatine capsules.

The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg, and 50 mg of active substance.

The hard fat is melted. At 40⁰C, the ground active substance is homogeneously dispersed therein. The mixture is cooled to 38°C and poured into slightly chilled suppository molds.

The suspension is transferred into a conventional aerosol container with a metering valve. Preferably, 50 μL of suspension are delivered per spray. The active substance may also be metered in higher doses if desired (e.g., 0.02% by weight).

In Examples H, I, J, and K, the powder for inhalation is produced in the usual way by mixing the individual ingredients together.

Claims

What is claimed is:

1. A compound of the formula (I)

wherein,

or the pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 wherein,

R⁴ is Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen R »5 is hydrogen, Ci-C₆ alkyl optionally substituted with 1-3 halogens, C₃-C₆ cycloalkyl, Ci-C₆ alkoxy or halogen

3. The compound according to claim 2 wherein,

R³ is hydrogen;

R⁵ is hydrogen, chloro or bromo;

4. The compound according to claim 3 wherein,

R³ is hydrogen;

R⁴ is methyl, ethyl, isopropyl, trifluoromethyl or chloro;

R⁵ is hydrogen or bromo;

R" is hydrogen or methyl; and

5. A compound of the formula (IA)

(IA)

wherein,

X is a 5-membered heterocycle containing 1 to 3 heteroatoms

or the pharmaceutically acceptable salts thereof.

6. The compound according to claim 5 wherein,

R¹ and R² together with the nitrogen atom to which they are attached form a C₃-Cs heterocyclic ring containing 1-3 heteroatoms optionally substituted with 1- 3 substituents;

7. The compound according to claim 6 wherein,

R¹ and R² are each independently hydrogen, Ci-C₈ alkyl, C₃-C₈ cycloalkyl, methylcycloalkyl, or aryl, each optionally independently substituted with 1 to 3 substituents chosen from aryl, Ci-C₈ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocyclic ring, and halogen; or

R³ is hydrogen;

R⁵ is hydrogen, chloro or bromo;

R⁶ is hydrogen or methyl;

R⁷ is Ci-C₆ alkyl, C3-C10 cycloalkyl, aryl, or C5-C10 heteroaryl, each optionally independently substituted with 1 to 3 substituents; and X is oxadiazole.

8. The compound according to claim 7 wherein,

R^Λ is hydrogen;

R⁴ is hydrogen, methyl, ethyl, isopropyl, trifluoromethyl or chloro;

R⁵ is hydrogen or bromo;

R⁶ is hydrogen or methyl;

X is oxadiazole.

9. A compound chosen from

N-Isopropyl^-methyl-S^octahydro-isoquinoline^-carbony^-benzenesulfonamide [4-Methyl-3 -(pyrrolidine- 1 -sulfonyl)-phenyl]-pyrrolidin- 1 -yl-methanone [3-(4-Hydroxy-piperidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)- methanone

[4-Methyl-3 -(pyrrolidine- 1 -sulfonyl)-phenyl]-(octahydro-quinolin- 1 -yl)-methanone N-sec-Butyl^-methyl-S^octahydro-isoquinoline^-carbony^-benzenesulfonamide [4-Methyl-3 -(piperidine- 1 -sulfonyl)-phenyl] -(octahydro-quinolin- 1 -yl)-methanone [3 -(3 ,3 -Difluoro-pyrrolidine- 1 -sulfonyl)-4-methyl-phenyl] -(octahydro-isoquinolin-2-yl)- methanone

[4-Methyl-3-(3-methyl-pyrrolidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)- methanone

[4-Methyl-3-(morpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [3 -(Azetidine- 1 -sulfonyl)-4-methyl-phenyl] -(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3 -(piperidine- 1 -sulfonyl)-phenyl] -(octahydro-isoquinolin-2-yl)-methanone [3-(Azepane-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone N-Cyclopropylmethyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [3-(4,4-Difluoro-piperidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)- methanone

N-Bicyclo[2.2.1]hept-2-yl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)- benzenesulfonamide

[4-Methyl-3 -(thiazolidine-3 -sulfonyl)-phenyl] -(octahydro-isoquinolin-2-yl)-methanone

N-Isobutyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3 -(pyrrolidine- 1 -sulfonyl)-phenyl]-(4aR,8aR)-octahydro-isoquinolin-2-yl- methanone

[3 -( 1 , 1 -Dioxo- 1 λ thiomorpholine-4-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)- methanone [4-Methyl-3 -(pyrrolidine- 1 -sulfonyl)-phenyl] -(octahy dro-isoquinolin-2-yl)-methanone [4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl- methanone

[4-Methyl-3-(piperidine-l-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl-methanone [3-(3-Fluoro-pyrrolidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)- methanone

[4-Isopropyl-3 -(pyrrolidine- 1 -sulfonyl)-phenyl] -(octahy dro-isoquinolin-2-yl)-methanone [3-(Morpholine-4-sulfonyl)-4-trifluoromethyl-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl- methanone (4aS,8aR)-Octahydro-isoquinolin-2-yl-[3-(pyrrolidine-l-sulfonyl)-4-trifluoromethyl-phenyl]- methanone

[4-Chloro-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone

[4-Chloro-3-(thiomorpholine-4-sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl- methanone

[4-Chloro-3-(piperidine-l-sulfonyl)-phenyl] -(octahy dro-isoquinolin-2-yl)-methanone [4-Chloro-3-(piperidine- 1 -sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl-methanone [4-Chloro-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl- methanone

[4-Chloro-3 -(pyrrolidine- 1 -sulfonyl)-phenyl] -(octahy dro-isoquinolin-2-yl)-methanone [4-Chloro-3-(morpholine-4-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl- methanone

2-Chloro-N-isobutyl-5-((4aR,8aS)-octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3 -(piperidine- 1 -sulfonyl)-phenyl] -piperidin- 1 -yl-methanone [4-Isopropyl-3-(morpholine-4-sulfonyl)-phenyl]-((4aR,8aS)-octahydro-isoquinolin-2-yl)- methanone N-Isobutyl-2-isopropyl-5-((4aR,8aS)-octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [3-(Azepane-l-sulfonyl)-4-isopropyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Isopropyl-3-(morpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone N-Cyclohexyl-N-isopropyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)- benzenesulfonamide

[4-Isopropyl-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone

[3-(Azepane-l-sulfonyl)-4-isopropyl-phenyl]-((4aR,8aS)-octahydro-isoquinolin-2-yl)- methanone 3 -Cyclopentanesulfonyl-4-methyl-phenyl)-(octahydro-isoquinolin-2-yl)-methanone l-[5-(5-Cyclohexyl-[l,2,4]oxadiazol-3-yl)-2-methyl-benzenesulfonyl]-piperidine

5 -Cyclohexyl-3-[4-methyl-3 -(pyrrolidine- 1 -sulfonyl)-phenyl]-[ 1 ,2,4]oxadiazole l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-piperidine l-[5-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-2-isopropyl-benzenesulfonyl]-4,4-difluoro-piperidine 4,4-Difluoro- 1 - {2-trifluoromethyl-5-[3-(2-trifluoromethyl-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]- benzenesulfonyl} -piperidine l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-4,4-difluoro- piperidine

4-[5-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-thiomorpholine 1 -[5-(3-tert-Butyl-[ 1 ,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-piperidine

3-tert-Butyl-5-[4-methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-[l,2,4]oxadiazole

4,4-Difluoro- 1 - [2-isopropyl-5 -(3 -isopropyl- [ 1 ,2,4]oxadiazol-5 -yl)-benzenesulfonyl] - piperidine

4-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-morpholine 4-[5-(3-tert-Butyl-[ 1 ,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-morpholine and

4-[5-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-thiomorpholine or the pharmaceutically acceptable salts thereof.

10. A compound chosen from

[3-(4-Hydroxy-piperidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)- methanone [4-Methyl-3 -(pyrrolidine- 1 -sulfonyl)-phenyl]-(octahydro-quinolin- 1 -yl)-methanone N-sec-Butyl^-methyl-S^octahydro-isoquinoline^-carbony^-benzenesulfonamide [4-Methyl-3 -(piperidine- 1 -sulfonyl)-phenyl] -(octahydro-quinolin- 1 -yl)-methanone [3 -(3 ,3 -Difluoro-pyrrolidine- 1 -sulfonyl)-4-methyl-phenyl] -(octahydro-isoquinolin-2-yl)- methanone [4-Methyl-3-(3-methyl-pyrrolidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)- methanone

[4-Methyl-3-(morpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [3 -(Azetidine- 1 -sulfonyl)-4-methyl-phenyl] -(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3 -(piperidine- 1 -sulfonyl)-phenyl] -(octahydro-isoquinolin-2-yl)-methanone [3-(Azepane-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone N-Cyclopropylmethyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [3-(4,4-Difluoro-piperidine-l-sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)- methanone N-Bicyclo[2.2.1 ]hept-2-yl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)- benzenesulfonamide

[4-Methyl-3 -(thiazolidine-3 -sulfonyl)-phenyl] -(octahydro-isoquinolin-2-yl)-methanone N-Isobutyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4aR,8aR)-octahydro-isoquinolin-2-yl- methanone

[3 -(1 , 1 -Dioxo- 1 lambda* 6* -thiomorpholine-4-sulfonyl)-4-methyl-phenyl]-(octahydro- isoquinolin-2-yl)-methanone

[4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl- methanone

[4-Methyl-3-(piperidine-l-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl-methanone [3-(3-Fluoro-pyrrolidine- 1 -sulfonyl)-4-methyl-phenyl]-(octahydro-isoquinolin-2-yl)- methanone

[4-Isopropyl-3 -(pyrrolidine- 1 -sulfonyl)-phenyl] -(octahydro-isoquinolin-2-yl)-methanone [3-(Morpholine-4-sulfonyl)-4-trifluoromethyl-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl- methanone (4aS,8aR)-Octahydro-isoquinolin-2-yl-[3-(pyrrolidine-l-sulfonyl)-4-trifluoromethyl-phenyl]- methanone

[4-Chloro-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Chloro-3-(thiomorpholine-4-sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl- methanone [4-Chloro-3-(piperidine-l-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone

[4-Chloro-3-(piperidine-l-sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl-methanone

[4-Chloro-3-(pyrrolidine-l-sulfonyl)-phenyl]-(4aS,8aR)-octahydro-isoquinolin-2-yl- methanone

[4-Chloro-3 -(pyrrolidine- 1 -sulfonyl)-phenyl] -(octahydro-isoquinolin-2-yl)-methanone [4-Chloro-3-(morpholine-4-sulfonyl)-phenyl]-(4aR,8aS)-octahydro-isoquinolin-2-yl- methanone

2-Chloro-N-isobutyl-5-((4aR,8aS)-octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [4-Methyl-3 -(piperidine- 1 -sulfonyl)-phenyl] -piperidin- 1 -yl-methanone [4-Isopropyl-3-(morpholine-4-sulfonyl)-phenyl]-((4aR,8aS)-octahydro-isoquinolin-2-yl)- methanone

N-Isobutyl-2-isopropyl-5-((4aR,8aS)-octahydro-isoquinoline-2-carbonyl)-benzenesulfonamide [3-(Azepane-l-sulfonyl)-4-isopropyl-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [4-Isopropyl-3-(morpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone N-Cyclohexyl-N-isopropyl-2-methyl-5-(octahydro-isoquinoline-2-carbonyl)- benzenesulfonamide

[4-Isopropyl-3-(thiomorpholine-4-sulfonyl)-phenyl]-(octahydro-isoquinolin-2-yl)-methanone [3-(Azepane- 1 -sulfonyl)-4-isopropyl-phenyl]-((4aR,8aS)-octahydro-isoquinolin-2-yl)- methanone

3-Cyclopentanesulfonyl-4-methyl-phenyl)-(octahydro-isoquinolin-2-yl)-methanone The following are preferred agonists of Formula IA: l-[5-(5-Cyclohexyl-[l,2,4]oxadiazol-3-yl)-2-methyl-benzenesulfonyl]-piperidine 5-Cyclohexyl-3-[4-methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-[l,2,4]oxadiazole l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-piperidine l-[5-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-2-isopropyl-benzenesulfonyl]-4,4-difluoro-piperidine 4,4-Difluoro- 1 - {2-trifluoromethyl-5-[3-(2-trifluoromethyl-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]- benzenesulfonyl} -piperidine l-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-trifluoromethyl-benzenesulfonyl]-4,4-difluoro- piperidine

4-[5-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-thiomorpholine 1 -[5-(3-tert-Butyl-[ 1 ,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-piperidine 3-tert-Butyl-5-[4-methyl-3-(pyrrolidine-l-sulfonyl)-phenyl]-[l,2,4]oxadiazole 4,4-Difluoro- 1 - [2-isopropyl-5 -(3 -isopropyl- [ 1 ,2,4]oxadiazol-5 -yl)-benzenesulfonyl] - piperidine

4-[5-(3-Cyclohexyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-morpholine 4-[5-(3-tert-Butyl-[ 1 ,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-morpholine and 4-[5-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-2-methyl-benzenesulfonyl]-thiomorpholine or the pharmaceutically acceptable salts thereof.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 1 or 5.

12. A method of treating a disease or condition chosen from a lung disease, a rheumatic disease, an autoimmune disease, a musculoskeletal disease, an allergic disease, an allergic reaction, a vascular disease, a dermatological disease, a renal disease, a hepatic disease, a gastrointestinal disease, neurodegeneration eye disease, diseases of the ear, nose, and throat, neurological disease blood disease, tumors, endocrine diseases, organ and tissue transplantations and graft- versus-host diseases, severe states of shock, acute pain, visceral pain, spasm of the gastrointestinal tract or uterus, colics, neuropathic pain, inflammatory and nociceptive pain, cancer pain, headache, restenosis, atherosclerosis, reperfusion injury, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, necrotizing enterocolitis and syndromes associated with hemodialysis, leukopheresis, and granulocyte transfusion, sarcoidosis, gingivitis, and pyrexia said method comprising administering a therapeutically effective amount of a compound according to claims 1 or 5.