WO2009063495A2

WO2009063495A2 - Substituted indole and its derivatives as cannabinoid modulators

Info

Publication number: WO2009063495A2
Application number: PCT/IN2008/000582
Authority: WO
Inventors: Brijesh Kumar Srivastava; Pankaj Ramanbhai Patel
Original assignee: Cadila Healthcare Limited
Priority date: 2007-09-20
Filing date: 2008-09-11
Publication date: 2009-05-22
Also published as: WO2009063495A3

Abstract

The present invention relates to novel substituted indole and indole derivatives to pharmaceutical compositions comprising the same, and to uses thereof. Compounds of the invention share pharmacological properties with cannabinoids and have a common wide range of beneficial therapeutic indications, hi particular, compounds of the invention are useful analgesic and anti-inflammatory agents by modulating the CB2 receptor.

Description

SUBSTITUTED INDOLE AND ITS DERIVATIVES AS CANNABINOID MODULATORS

FIELD OF INVENTION The present invention relates to novel substituted indole and indole derivatives to pharmaceutical compositions comprising the same, and to uses thereof. Compounds of the invention share pharmacological properties with cannabinoids and have a common wide range of beneficial therapeutic indications. In particular, compounds of the invention are useful analgesic and anti-inflammatory agents by modulating the CB2 receptor.

Compounds of general formula (I) their stereoisomers, regioisomers, tautomeric forms and novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. The present invention also relates to a process of preparing compounds of general formula (I), their stereoisomers, regioisomers, their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis. These compounds have beneficial effect in the treatment of pain and inflammation particularly chronic pain.

Formula (I)

BACKGROUND AND PRIOR ART

Marijuana has been used for therapeutic purposes for hundreds of the years [Prog. Med. Chem. 1998, _. 35, 199-243, Addiction 1996, 91, 1585-1614]. Tetrahydrocannabinol Δ⁹-THC is the main constituent of marijuana. THC binds with the receptors in the brain and these receptors are known as cannabinoid receptor [Pharmacol. Rev. 1986, 38, 75-149]. In addition to exogenous cannabinoid compounds, there are endogenous compounds, which bind with the human cannabinoid receptors [J. Med. Chem. 1996, 39, 471-479]. The structure of substance was determined to be arachidonylethanolamine [Science, 1992, 258, 1946-1949]. At this time the endocannabinoid. system [Science, 2002, 296, 678-682, Br. J. Pharmacol. 2004, 141, 765-774] is known to contain to receptors (CBl and CB2) [Nature, 1990, 346, 561-564, Nature, 1993, 365, 61-62] and several endogenous ligands which are distributed through out the body. After the cloning of the CBl and CB2 receptors [Nature, 1993, 365, 61-62] and to understand the physiological role many of the studies eventually revealed that these ligands are involved in the coordination of movement, memory, mood, emotions and etc [Biochem. Pharmacol. 1994, 48, 1537-1544]. Both CBl and CB2 receptors are G-protein coupled receptors [Neuropharmacol. 2004, 47, 345-358]. The human CBl was cloned in 1991 and, is a protein with 472 amino acids [Biochem. J. 1991, 279, 129-314]. The second cannabinoid receptor CB2 was cloned from human promyelocytic cell line (HL60), is a protein with 360 aminoacids [Nature, 1993, 365, 61-65]. CBl is predominantly expressed in the brain and as well as in few tissues in the periphery [Pharmacol. Ther. 1997, 74, 129-180] however, CB2 is predominantly expressed in periphery [Immunol. Today 1998, 19, 373-381]. Both CBl and CB2 are an attractive target for current drug development. Since cannabinoid receptors are transmembrane receptors, their three dimensional structures have been highly demanding, yet the knowledge of crystal structures are not known. After a brief development of potential therapeutic application for cannabinoid receptor modulators such as non-selected cannabinoid receptor agonist as CP-55940, WIN-55212-2 and THC have utility as appetite stimulants, analgesics and anti- glaucoma agents [CNS Drugs 2003, 17, Ϊ79-202, Curr. Med. Chem. 2003, 10, 2719- 2732] and there are report for use of these agonists as tumor growth inhibitors [Gastroenterology 2003, 125, 677-687]. Therapeutic applications of CB2 receptors are not very much explored but there is increasing evidence that CB2 receptors are involved in neuropathic pain [Eur. J. Neurosci. 2003, 17, 2750-2754]

There has also been an increased interest among the different pharmaceutical companies in developing drugs for the treatment of diseases connected with disorders of the cannabinoid systems [Greenberg D. A., Drugs News & Perspectives 1999, 12, 458; Kulkarni S. K. & Ninan, Indian Journal of Pharmacology 2001, 33, 170-184; Piomelli D et. al., Trends Pharmacol ScL 2000, 21, 218-24]. Several compounds which are either CB₁ &/or CB₂ antagonists have been reported [Bioorg. Med. Chem. Lett. 2008, 18, 3882-3886; Bioorg. Med. Chem. Lett. 2008, 18, 963-968; J. Med. Chem. 2007, 50, 5951-5966; J. Med. Chem. 2008, 51, 3526-3539 & etc] and are in the market or under various stages of development for e.g. SR-141716 A (Rimonabant, Sanofi), CP-272871 (Pfizer), LY-320135 (Eli Lily), AM-630 (Alexis), SR-144528(Sanofi) and Taranabant MK-0364 (Merck) etc. Synthesis and activity of tricyclic pyrazole ligands for CBl & CB2 receptors have been disclosed in Bioorg. Med. Chem., 2003, 11, 251-263.

Discovery of 2-[(2,4-Dichlorophenyl)amino]-A/^"-[(tetrahydro-2H-pyran-4- yl)methyl]-4-(trifluoromethyl)-5-pyrimidinecarboxamide, a selective CB2 Receptor Agonist for the treatment of inflammatory pain has been disclosed by GlaxoSmithKHne [J. Med. Chem. 2007, 50, 2597-2600]

WO 200720631 discloses novel tetracyclic benzofuran derivatives as useful analgesic and anti-inflammatory agents.

WO 2007057571 describes acylindole derivatives of the following general formula (A) having CB2 receptor selectivity.

(A)

WO 2007063418 describes indole compounds of the following general formula (I) having NOS inhibitory activity.

WO 2002060447 describes aminoalkylindole compounds of the following general formula having cannabimimetic activity

(0 WO 200128557 describes indole derivatives of the following general formula (I) having cannabimimetic activity

(I)

Joong-Youn Shim and Allyn C. Howlett [J. Chem. Inf. Model. 2005] have extensively explored the aminoalkyl indole of following general formula to study the differences in the nature of the ligand binding and ligand-specific conformational changes in the receptor.

Bristol-Myers Squibb reported several C-3 amido-indole derivatives of the following scaffolds as cannabinoid receptor modulators with excellent in vivo potency against LPS induced TNF-α release in murine models of cytokine production [Bioorg. Med. Chem. Lett. 2002, 12, 2399-2402]

Similarly, Raitio and et al. have reviewed the recent advances in the field of CB2 selective ligands. [Curr. Med. Chem. 2005, 12, 1217-1237] and more recently Whiteside et al. have elaborated the role of CB2 receptor in the pain modulation. [Curr. Med. Chem. 2007, 14, 917-936]

Naguib et al. have described design and synthesis of a novel N-alkylated Isatin acylhydrazone derivatives as selective CB2 receptor agonists for the treatment of neuropathic pain. [J. Med. Chem. 2008, doi 10.1021jm8002203]

Though research in the area of cannabinoids have been going on for more than a decade there are only few medicines available which modulate the cannabinoid receptors and fewer with minor side effects. Looking at the beneficial effects of cannabinoids, it would be highly desired to develop further compounds, which modulate the cannabinoid receptors, having better or comparable absorption, metabolic stability, and exhibiting lesser toxicity.

OBJECTS OF THE INVENTION It is an important object of the present invention to provide compounds of general formula (I), their stereoisomers, tautomeric forms, their regioisomers, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures and their use in medicine.

Formula (I)

In an embodiment of the present invention is provided a process for the preparation of novel compounds of general formula (I), their stereoisomers, regioisomers and their tautomeric forms, novel intermediates involved in their synthesis, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.

In a further embodiment is provided a method of treatment of diseases which can be treated or whose symptoms can be reversed with cannabis or their derivatives both natural and synthetic, by administering a therapeutically effective and non-toxic amount of the compound of formula (I) or their pharmaceutically acceptable compositions to the mammals. In a still further embodiment is provided compounds suitable for treating/ameliorating conditions associated with inflammation and pain to a mammal in need thereof. In a preferred embodiment, the compounds are useful in the treatment/amelioration of pain & inflammatory conditions in mammals. SUMMARY OF INVENTION

The present invention describes compounds useful as modulators of cannabinoid receptors. The general formulae (I) below define the compounds:

Formula (I) The compounds of the present invention mimic the actions of the cannabinoids making them useful for preventing or reversing the symptoms that can be treated with cannabis, some of its derivatives, and synthetic cannabinoids in a human or other mammalian subject. Preferably, the compounds of the present invention are selective agonists of the cannabis CB₂-receptor. These compounds therefore have beneficial effect in the treatment of pain and inflammation particularly in the treatment of neuropathic pain.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAINGS

Figure 1 Effect of compound 22 on CFA induced hyperalgesia (Weight Bearing

Protocol)

Figure 2 Effect of compound 22 on CCI induced neuropathic pain Figure 3 Effect of compound 22 on Formalin induced nociception DETAILED DESCRIPTION

The compounds of the present invention are defined by the general formula (I) below:

Formula (I) wherein R¹ is independently selected from H, optionally substituted groups selected from alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, cycloalkyl, sulphonyl alkyl, sulphonyl aryl, heterocycloalkyl and acyl groups; R² is independently selected from H, optionally substituted alkyl, sulphonyl alkyl groups;

R₃-R₆ at each occurrence is independently selected from H, halogen, cyano, nitro, hydroxy, optionally substituted groups selected from amino (preferably of the form -NR⁷R⁸, -NR⁷COR⁸ or -NR⁷SO₂R⁸), optionally substituted carbonyl (of the form - COR⁷), heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, cycloalkyl, sulphonylalkyl, sulphonylaryl, heterocyclo alkyl, alkyl, alkenyl, alkynyl groups, or groups selected from alkoxy (of the form -OR⁹), aryloxy, heteroaryloxy, cycloalkyloxy, hetero-cycloalkyloxy group, carboxylic acid or its derivatives such as esters, optionally substituted carboxamide (preferably of the form -CONR¹⁰R¹¹);

R and R at each occurrence, when present, are independently selected from H, optionally substituted groups selected from alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroaryalkyl, cycloalkyl, sulphonylalkyl, sulphonylaryl, heterocycloalkyl group; R⁹ is independently selected from optionally substituted groups selected from alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl heteroaryalkyl or cycloalkyl groups; R¹⁰ is H, or (Cj-C₃) alkyl group or may be part of ring formation with R¹ '. R¹ ' is independently selected from optionally substituted groups selected from alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroaryalkyl, cycloalkyl, heterocycloalkyl, or non-aromatic (C₃-C ^carbocyclic radicals which is unsubstituted or monosubstituted or poly substituted by a substituent selected from a halogen, a (C₁- C₄)alkyl, and a (C₁-C₄)alkoxy: Further, the non-aromatic (C₃-Q₅) carbocyclic radicals include saturated or unsaturated, fused, bridged or spiromonocyclic or polycyclic radicals, may be terpenic. These radicals are optionally monosubstituted or polysubstituted by a group selected from (Ci-C₄) alkyl, (C₁-C₄) alkoxy and halogen groups; the monocyclic radicals include cycloalkyls, the fused bridged or spiro dicyclic or tricyclic radicals which may be terpenic, include fro example bicyclo [2.2.1] heptyl or norbornyl radicals, bornyl, isobornayl, nonadamantyl, adamantly, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, spiro[5.5]undecyl, said radicals being unsubstituted or monosubstituted or polysubstituted by a (Cj-C₄) alkyl, halogen or a (C₁-C₄) alkoxy groups. The "aryl" or "aromatic" group is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl groups; The "heteroaryl" or "heteroaromatic" group is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl groups; The substituents on R¹ may be independently selected from hydrogen, alkyl, haloalkyl, thioalkyl groups; the substituents on R³, R⁴, R⁵ and R⁶ may be independently selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, cyano, alkylthio, thioalkyl groups.

In formula (I) rings A and B may be selected from any of the following system comprising

(i) both the rings A and B are unsaturated; (ii) ring A unsaturated and ring B are saturated; (iii) ring is A saturated and ring B is unsaturated; (iv) both the rings A and B are saturated; In a preferred embodiment R¹ is selected from H, alkyl, aryl alkyl, heterocycloalkyl, sulfonyl alkyl groups;

R² is selected from H, alkyl, sulphonylalkyl groups; R³ is selected from H or aryloxy groups; R⁴ is selected from H, halogen, hydroxy, alkyl, alkoxy, carboxylic acid or its derivatives like esters and heterocycloalkyloxy groups; R⁵ is selected from H, alkoxy and halogen groups; R⁶ is selected from H and halogen groups;

In a further preferred embodiment the groups, radicals described above may be selected from:

- the "alkyl" group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, π-propyl, wo-propyl, «-butyl, sec-butyl, tert-butyl, amyl, t-amyl, -rø-pentyl, n- hexyl, and the like;

- the "alkoxy" group used either alone or in combination with other radicals, is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n- propoxy, zsø-propoxy, n-butoxy, t-butoxy, wø-butoxy, pentyloxy, hexyloxy, and the like;

- the "haloalkyl" group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;

- the "haloalkoxy" group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fmoroethoxy, chloroethoxy and the like; - the "alkylthio" group used either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, ethylthio, propylthiό; - the heteroarylalkyl or arylalkyl group used alone or in combination represents an alkyl group as defined above, attached either to a heteroaryl group or an aryl group respectively.

Suitable groups and substituents on the groups may be selected from those described anywhere in the specification. Particularly useful compounds may be selected from

1 -(4-Trifluoromethyl-benzyl)- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

1 -(4-Trifluoromethyl-benzyl)-2,3 -dihydro- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3 ,3 - trimethyl-bicyclo[2.2.1]hept-2endo-yl)]-amide;

5-Chloro- 1 -(4-fluoro-benzyl)- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo [2.2.1 ]hept-2endo-yl] -amide;

5-Chloro-l -(4-methyl-benzyl)-l H-indole-2-carboxylic acid [(1R)-1 ,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; 5-Chloro-l-(4-methylbenzyl)-2,3-dihydro-lH-indole-2-carboxylic acid [(1R)-1,3,3- trimethyl-bicyclo [2.2.1 ]hept-2endo-yl]-amide;

5-Methoxy- 1 -(4-methylbenzyl)- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; l-Butyl-5-chloro-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

1 -Butyl-S-chloro-lH-indole^-carboxylic acid [(I S)-1 ,3,3-trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide;

5 -Methyl- 1 -pentyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2. l]hept-2endo-yl] -amide;

1 -Hexyl-5 -methyl- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1 ]hept-2endo.-yl]-amide;

5 -Methyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl-bicyclo [2.2.1 ]hept-

2endo-yl] -amide; l-Butyl-5-methyl-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

6-Methoxy- 1 H-indole-2-carboxylic acid [(1R)- 1 ,3 ,3-trimethyl-bicyclo [2.2.1 jhept-

2endo-yl] -amide;

6-Methoxy- 1 -pentyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethy 1- bicyclo[2.2. l]hept-2endo-yl] -amide; l-(2-Ethylbutyl)-5-methyl-lH-indole-2-carboxylic acid [( IR)- 1,3,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

1 -Hexyl-6-methoxy- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo [2.2.1 ]hept-2endo-yl] -amide; l-(2-[l,3]Dioxan-2-yl-ethyl)-5-methyl-lH-indole-2-carboxylic acid [(1R)-1,3,3- trimethyl-bicyclo[2.2. l]hept-2endo-yl]- amide;

6-Bromo- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3 ,3 -trimethyl-bicyclo [2.2.1 ]hept-2endo- yl] -amide;

5-Methoxy-2,3 -dihydro- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethy 1- bicyclo[2.2. l]hept-2endo-yl] -amide;

5-Chloro-l-(4-trifluoromethyl-benzyl)-lH-indole-2-carboxylic acid [(1R)-1,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide; l-(4-Fluoro-benzyl)-5-methoxy-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; 5 -Methoxy- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl-bicyclo [2.2.1 ]hept-

2endo-yl]-amide;

5-Chloro-l H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-2endo- yl]-amide; 5-Methoxy-lH-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-

2endo-yl]-amide; lH-Indole-2-carboxylic acid [(lS)-l,3,3-trimetliyl-bicyclo[2.2.1]hept-2endo-yl]- amide;

5-Chloro-l-(4-fluoro-benzyl)-lH-indole-2-carboxylic acid [(I S)- 1,3,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

1 -(4-Fluoro-benzyl)-5-methoxy- 1 H-indole-2-carboxylic acid [(I S)- 1 ,3,3-trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide;

1 -(4-Methyl-benzyl)- 1 H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide; l-Butyl-5-methoxy-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5 -Methoxy- 1 -pentyl- 1 H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5 -Methoxy- 1 -methyl- 1 H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide;

1 -Ethyl-5 -methoxy- 1 H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

1 -Ethyl-5-methoxy-7H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; l-(2-Ethyl-butyl)-5-methoxy-iH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide;

5-Methoxy-3-Methyl-7H-indole-2-carboxylic acid [(1R)-1 ,3,3 -trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide;.

5-Methoxy-3-Methyl-iH-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide;

5-Methoxy-3-Methyl-l-pentyl-lH-indole-2-carboxylic acid [(lR)-l,3₅3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Methoxy-3-Methyl-l -pentyl- 1 H-indole-2-carboxylic acid [(I S)-1 ,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-arnide; 5 -Chloro- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl-bicyclo [2.2.1 ]hept-2endo- yl] -amide;

5 -Methoxy- 1 -hexyl- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; 5 -Methoxy- 1 -hexyl- 1 H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5 ,7-Dichloro-3 -methyl- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

1 -Butyl-5-methoxy-3-methyl- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide;

1 -Butyl-5-methoxy-3 -methyl- 1 H-indole-2-carboxylic acid [(I S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Hydroxy- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl-bicyclo[2.2.1 ]hept-

2endo-yl]-amide; l-(2-Ethyl-butyl)-5-methoxy-iH-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide; ,

5 -Methoxy- 1 -methyl- 1 H-indole-2-carboxylic acid [(1R)-1,3,3 -trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide;

5 -Methoxy- 1 -(propane- 1 -sulfonyl)- 1 Η-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide;

3 -Methanesulfonyl-5 -methoxy- 1 Η-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide;

5-Chloro-l-methanesulfonyl-lΗ-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; 1 -Methanesulfonyl-5 -methoxy- 1 H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Methoxy-l-(isopropyl)-lH-indole-2-carboxylic acid [(lS)-l,3,3-tnmethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

2,2-Dimethyl-propionic acid 2-[(1R)-I₅ 3, 3-trimethyl-bicyclo[2.2.1]hept-2endo- yl carbamoyl]-lH-indol-5-yl ester;

5-Ethoxy- 1 H-indole-2-carboxylic acid [(I S)- 1 ,3 ,3 -trimethyl-bicyclo [2.2.1 ]hept-2endo- yl] -amide; -Pentyloxy-lH-indole-2-carboxylic acid [(lS)-l,3,3-trimetliyl-bicyclo[2.2.1]hept- endo-yl] -amide; 5-Butoxy-lH-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-2endo- yl]-amide;

Methanesulfonic acid 2-[(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-2endo-yl ]-lH-indol-

5-yl ester; 5-Ethoxy-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl-bicyclo[2.2.1]hept-

2endo-yl]-amide;

5-Ethoxy-l-ethyl-lH-indole-2-carboxylic acid [( IR)- 1,3,3 -trimethyl- bicyclo [2.2.1 ]hept-2endo-yl] -amide;

5-Chloro-l-(2-moφholine-4-yl-ethyl)-lH-Inole-2-carboxylic acid [(1S)-1,3,3- trimethyl-bicyclo[2.2.1 ]hept-2endo-yl]-amide;

5 -Methoxy- 1 -(4-methyl-benzyl)- 1 H-Indol-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethy 1- bicyclo[2.2.1 ]hept-2endo-yl]-amide;

5,6-Dimethoxy-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl-bicyclo[2.2.1]hept-

2endo-yl]-amide; 4-Benzyloxy-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl-bicyclo[2.2.1]hept-

2endo-yl]-amide;

5-(2-[l,3]Dioxan-2-yl-ethoxy)-lH-indole-2-carboxylic .acid [( IR)- 1,3,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Methoxy-l-(2-moφholin-4-yl-ethyl)-lH-indole-2-carboxylic acid [(1S)-1,3,3- trimethyl-bicyclo[2.2. l]hept-2endo-yl]-amide;

5 -Methoxy- 1 -(2-morpholin-4-yl-ethyl)- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 - trimethyl-bicyclo[2.2. l]hept-2endo-yl]-amide-p-toluene sulfonic acid;

Propane- 1 -sulfonic acid 2-[(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-2endo-yl carbamoyl)] -lH-indol-5-yl ester; S-Pentyloxy-lH-indole^-carboxylic acid [(lR)-l,3,3-trimethyl-bicyclo[2.2.1]hept-

2endo-yl] -amide;

5-Pentyloxy- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3-trimethyl-bicyclo [2.2.1 ]hept-

2endo-yl] -amide;

The compounds of the present invention may be prepared using the methods described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art. Referred methods include, but are not limited to those described below, where all symbols are as defined earlier. General process of preparation:

Compound of general formula (II) can be synthesized by coupling the compound of general formula (III) with fenchyl amine using coupling agents such as DMAP, DCC, HOBt.H₂O, and EDC. HCl₅ etc. in presence of organic bases such as TEA, pyridine, etc. in solvents such as tetrahydrofuran, dichloromethane, chloroform, etc. at ambient temperature.

Compound of general formula (I) can be synthesized by reacting compound of general formula (II) with substituted mesylate, halide, hyroxy compounds in presence of base such as NaH, NaOMe, NaOEt, etc. in solvents like THF, dichloromethane, chloroform etc.

Alternatively, compound of formula (I) may be prepared as follows: Compound of general formula (V) can be synthesized from compound of general formula (VI) by process similar to that described for compound (I) from compound (II) in Scheme I. Compound of general formula (IV) can be synthesized from the compound of general formula (V) via hydrolysis under basic condition or acidic conditions. Further Compound of general formula (I) can be synthesized by process similar to that described for compound of general formula (II) from compound of general formula (III) in Scheme I.

(Via) (VIb)

Compound (Ilia), (HIb), (Via) and (VIb) may be either procured or prepared by processes similar to those known in the literature, [e.g. J. Org. Chem. 1971, 36, 279- 284; J. Am. Chem. Soc. 1970, 92, 2476-2488; US 2006 7,060,842 etc.] Scheme Ϋ

"Reagents & conditions : (i) EDCHCl, HOBtH₂O, Et₃N, CH₂Cl₂, 25-27⁰C, 30 min; (iv) R¹Br, NaH, DMSO, 0-30⁰C₅ 2 h.

Scheme T

"Reagents & conditions : (i) R¹Br, NaH, DMSO, 0-30⁰C, 2 h; (ii) KOH, MeOH, H₂O, 60⁰C, 1 h; (iii) EDCHCl, HOBt-H₂O, Et₃N, CH₂CI₂, 25-27⁰C, 30 min. Scheme-3^a

(b)

^aReagents & conditions: (i) BBr₃, CH₂CI₂, -30-25 ⁰C, 5h, 58.%;(ii) R⁷X, K₂CO₃, C₃H₆O, 50-55⁰C, 12h or R⁷X, CH₂CI₂, Et₃N, 0-25⁰C, 1/2 h.

Example 1

Synthesis of 1 -(4-Trifluoromethyl-benzyl)-2,3 -dihydro- 1 H-indole-2-carboxylic acid (l,3₅3-trimethyl-bicyclo[2.21]hept-2-yl)-amide <

Step 1: Preparation of l-(4-Trifluoromethyl-benzyl)-l H-indole-2-carboxylic acid ethyl ester

To a solution of 1 H-indole-2-carboxylic acid ethyl ester (1 g, 5.71 mmol) in DMSO (15 niL) was added sodium hydride (0.205 g, 8.57 mmol). The reaction mixture was stirred at 50 ⁰C over a period of 30 min under nitrogen atmosphere. To the reaction mixture 4- (trifluoromethyl) benzyl bromide (1.63 g, 6.85 mmol) was added in three portions at same temperature. The reaction mixture was heated up to 80 ⁰C and stirred for 1 h. The progress of reaction was checked by TLC using mobile phase 20 % ethyl acetate in pet. ether. The reaction mixture was cooled to 25-27 ⁰C, poured into water (50 mL) and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na₂SO₄ and solvents were evaporated on a rotatory evaporator under reduced pressure to get oil. The oil was triturated in chilled methanol to afford l-(4- trifluoromethyl-benzyl)-l H-indole-2-carboxylic acid ethyl ester as white solid (1.2 g, 62.8%). Step 2: Preparation of l-(4-Trifluoromethyl-benzyl)-2,3-dihydro-lH-indole-2- carboxylic acid ethyl ester To a solution of l-(4-trifluoromethyl-benzyl)-lH-indole-2-carboxylic acid ethyl ester (0.5 g, 1.50 mmol) in trifluoroacetic acid (10 mL) was added sodium cyanoborohydride (94 mg, 1.50 mmol) in three portions at 0-5 ⁰C under nitrogen atmosphere. The color of reaction mixture changed to yellow with increase in temperature from 5 ⁰C to 27 ⁰C. The reaction mixture was stirred at 25-27 ⁰C for 4 h. The progress of reaction was checked by TLC using mobile phase 20 % ethyl acetate in pet. ether. The reaction mixture was poured into water and saturated solution of NaHCO₃ was added to make the pH = 9. Resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na₂SO₄ and solvents were evaporated on a rotatory evaporator under reduced pressure to afford 1- (4-trifluoromethyl-benzyl)-2,3-dihydro-lH-indole-2-carboxylic acid ethyl ester as white solid (0.225 g, 44.73%).

Step 3: Preparation of l-(4-Trifluoromethyl-benzyl)-2,3-dihydro-lH-indole-2- carboxylic acid To a solution of l-(4-trifluoromethyl-benzyl)-2,3-dihydro-lH-indole-2- carboxylic acid ethyl ester (0.22 g, 0.656 mmol) in methanol (4 mL) was added solution of KOH (0.147 g, 2.62 mmol) in water (4 mL). The reaction mixture was refluxed at 65-67 ⁰C for 4 h. The progress of reaction was checked by TLC using mobile phase 20 % ethyl acetate in pet. ether. The reaction mixture was cooled to 25-26 ⁰C, poured into water, to this 10% NaOH solution was added to make pH = 9 and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na₂SO₄ and solvents were evaporated on a rotatory evaporator under reduced pressure to afford l-(4-trifluoromethyl-benzyl)-2,3-dihydro-lH-indole-2- carboxylic acid as white solid (0.180 g, 85%) Step 4: l-(4-Trifluoromethyl-benzyl)-2,3-dihydro-lH-indole-2-carboxylic acid (1,3,3- trimethyl-bicyclo[2.21]hept-2-yl)-amide

To a solution of l-(4-trifluoromethyl-benzyl)-2,3-dihydro-lH-indole-2- carboxylic acid (0.150 g, 0.467 mmol) in dichloromethane (8 mL) was added HOBt. H₂O (0.126 g, .934 mmol) and EDCHCl (0.134 g, 0.700 mmol) at 25-26 ⁰C under atmosphere of nitrogen. To this fenchylamine hydrochloride (88 mg, 0.467 mmol) and trietylamine (94 mg, 0.934 mmol) were added. The reaction mixture was stirred at 25- 26 ⁰C for 25-30 min. The progress of reaction was checked by TLC by using mobile phase 20 % ethyl acetate in pet. ether. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na₂SO₄ and solvents were evaporated on a rotatory evaporator under reduced pressure to get oil. The oil was purified by the flash column .chromatography using eluent pet. ether : ethyl acetate (9.2 : 0.8) to afford l-(4-trifluoromethyl-benzyl)- 2,3 -dihydro- 1 H-indole-2-carboxylic acid (1 ,3 ,3 -trimethyl-bicyclo[2.21 ]hept-2-yl> amide as white solid (0.055 g, 25.82%).

¹H-NMR (400 MHz₅ DMSO-^) δ 7.67 (d, J = 8.0 Hz₅ 2H)₅ 7.55 (t, J = 8.4 Hz₅ 2H)₅ 7.31-7.38 (dd, J = 9.2 Hz & 2.8 Hz₅ IH)₅ 7.01(d, J = 8.0 Hz, IH), 6.93 (d, J= 8.0 Hz₃ IH)₅ 6.56-6.60 (dd, J= 12 Hz & 3.6 Hz₅ IH), 6.31(d, J= 8.0 Hz₅ IH)₅ 4.50 (d, J=15.6 Hz, IH), 4.30-4.37 (dd, J= 17.2 Hz & 8 Hz, IH), 4.22 (t₅ J= 15.6 Hz₅ IH) 3.47 (t, J = 5.4 Hz, IH), 2.92-2.98 (dd, J = 15.6 Hz & 8 Hz, IH)₅ 1.78-1.83 (m, IH) 1.63 (s₅ IH), 1.48 (d, J= 8.8 Hz, IH), 1.36-1.31 (m, IH), 1.11 (d₅ J= 10.0 Hz₅ IH), 0.98 (d, J= 8.4 Hz₅ 2H)₅ 0.94 (d, J= 8.0 Hz₅ 2H)₅ 0.89 (d, J= 13.6 Hz₅ 3H)₅ 0.82 (d, J= 6.0 Hz₅ 3H)

The following compounds were synthesized by procedure similar as described for Example 1 with appropriate modifications as are well within the scope of persons skilled in the art.

Example 2 ₄

1 -(4-Trifluorornethyl-benzyl)- 1 H-indole-2-carboxylic acid [(I R)- 1,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide 1H-NMR (400 MHz, OMSO-d₆) δ 7.69-7.63 (m, 2H), 7.58 (d, J= 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, IH)₅ 7.24-7.19 (m, 4H), 7.14-7.09 (m, IH)₅ 5.84 (S, IH)₅ 3.67 (d, J = 9.6 Hz₅ IH), 1.83-1.78 (m, IH)₅ 1.67 (d, J= 3.2 Hz₅ IH)₅ 1.58 (t, J= 9.6 Hz, 2H), 1.41 (d, J = 4.8 Hz, IH), 1.39-1.34 (m₅ IH)₅ 1.17 (t₅ J = 14.6 Hz₅ 3H)₅ 0.99 (t₅ J= 15.8 Hz, 3H), 0.71 (d, J= 14.4 Hz, 3H). Example 3 5-Chloro-l-(4-fluoro-benzyl)-lH-indole-2-carboxylic acid [(1R)-1, 3,3- trimethyl-bicyclo [2.2.1 ]hept-2endo-yl] -amide

¹H-NMR (400 MHz, DMSO-J₆) δ 7.80 (d, J = 9.6 Hz₅ IH), 7.73 (d, J = 1.0 Hz₅ IH)₅ 7.61 (d, J = 9.2 Hz, IH), 7.21-7.23 (dd, J = 8.8 Hz & 2 Hz, IH), 7.09 -7.14 (m, 3H), 7.03 -7.07 (m, 2H)₅ 5.72 (s, 2H), 3.72 (dd, J= 8.4 Hz & 1.6 Hz, IH)₅ 1.82 (s₅ IH), 1.69 (d, J= 3.2 Hz, IH), 1.56-1.62 (m, 2H)₅ 1.38 (t, J= 4.4 Hz, IH), 1.17 (d, J= 10 Hz, 4H)₅ 0.97 (d, J= 10.4 Hz₅ 3H)₅ 0.73 (d, J= 5.2 Hz₅ 3H). Example 4

5-Chloro-l-(4-methyl-benzyl)-lH-indole-2-carboxylic acid [(1R)-1 ,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide ¹H-NMR (400 MHz₅ DMSO-*/*) δ 7.8 (d, J = 9.6 Hz, IH)₅ 7.71 (d, J = 1.6 Hz, IH)₅ 7.58 (d, J = 8.8 Hz₅ IH)₅ 7.18-7.21 (dd J= 8.8 Hz & 2 Hz₅ IH)₅ 7.06 (s, IH), 5.68 (s, 2H), 3.73 (d, J= 8.4 Hz₅ IH), 2.19 (s, 3H), 1.84 (t, J= 5 Hz₅ IH), 1.69 (d, J= 3.2 Hz, IH)₅ 1.61(d, J= 12.2 Hz, 2H), 1.36-1.42 (m, IH) 1.18 (d, J= 9.6 Hz, IH), 1.04 (d, J = 9.2 Hz, 3H), 0.98 (s, 3H), 0.76 (s, 3H). Example 5

5-Chloro- 1 -(4-methylbenzyl)-2,3 -dihydro- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3,3-trimethyl-bicyclo[2.2. l]hept-2endo-yl]-amide 1H-NMR (400 MHz, DMSO-J₆) δ 7.35 (d, J= 9.2 Hz, IH), 7.09-7.18 (m, 4H)₅ 7.00 (s, IH), 6.95 (d, J= 9.6 Hz, IH)₅ 6.34 (t, J= 7.6 Hz, IH), 4.44 (d, J= 15.6 Hz, IH), 4.32 (t, J= 9.2 Hz, IH)₅ 3.22 (d, J= 9.2 Hz, IH), 3.22-3.28 (m, IH)₅ 2.84-2.90 (m, IH), 2.25 (s, IH), 1.64 (s, 1H),1.51 (t, J= 12.2 Hz, 3H),1.36 (d, J= 4.4 Hz, IH), 1.13 (d, J= 9.6 Hz, IH), 0.99 (d, J= 6 Hz, 1H),O.9O (d, J= 15.2 Hz, 3H)₅ 0.65 (s, 3H). Example 6 5-Methoxy-l-(4-methylbenzyl)-lH-indole-2-carboxylic acid [(1R)-1,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide

¹H-NMR (400 MHz, DMSO-^₆) δ 7.64 (d, J = 9.6 Hz, I¹H), 7.43 (d, J = 8.8 Hz, IH)₅ 7.09 (d, J= 2.4 Hz₅ IH), 7.0 (t, J= 6.2 Hz, 5H), 6.83-6.86 (dd, J= 9.6 Hz₅ 2.4 Hz₅ IH), 5.65 (s, 2 H)₅ 3.73 (d, J= 5.6 Hz, IH), 3.73 (t, J= 5.6 Hz, 3H), 2.18 (s, IH)₅ 1.82-1.87 (m, IH), 1.7 (d, J= 3.2 Hz, IH), 1.58-1.63 (m, 2H), 1.18 (d, J = 10 Hz, IH), 1.05 (s,

3H), 0.99 (s, 4H)), 0.77 (s, 3H) Example 7 l-Butyl-5-chloro-lH-indole-2-carboxylic acid [(lR)-l₅3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide 1H-NMR (400 MHz, DMSO-rf*) δ 7.79 (d, J= 9.6 Hz, IH)₅ 7.69 (d, J= 2 Hz, IH), 7.58 (d, J= 8.8 Hz₅ IH), 7.2-7.23(dd, J= 8.8 Hz & 2.4 Hz, IH)₅ 6.99 (s, IH), 4.44-4.51 (m, 2H), 3.75 (t, J= 4.8 Hz, IH), 1.85 (d, J= 6 Hz, IH ), 1.71 (d, J = 3.2 Hz, IH)₅ 1.55- 1.65 (m, 4H), 1.37-1.43 (m, IH), 1.08 (s, IH), 1.00 (d, J= 17.2 Hz, 4H), 0.84 (t, J= 7 Hz₅ 6H). Example 8

1 -Butyl-5-chloro- 1 H-indole-2-carboxylic acid [(I S)- 1 ,3,3-trimethyl-bicyclo[2.2. l]hept- 2endo-yl] -amide

¹H-NMR (400 MHz, OMSO-dd) δ 7.79 (d, J= 9.6 Hz₅ IH)₅ 7.69 (d, J= 2 Hz, IH), 7.58 (d, J= 8.8 Hz, IH), 7.2-7.23(dd, J= 8.8 Hz & 2.4 Hz, 1H),6.99 (s, IH), 4.47 (d, J= 4 Hz, 2H), 3.73-3.76 (dd, J= 9.6 Hz & 0.8 Hz, IH), 1.71 (d, J= 3.2 Hz, IH), 1.57-1.63

(m, 4H), 1.15-1.20 (m, 3H), 1.08 (s, IH), 1.03 (s, IH), 0.84 (d, J= 4.8 Hz, 3H), 0.8 (d,

J= 7.2 Hz, 3H).

Example 9 5-Methyl-l-pentyl-l H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide.

¹H-NMR (400 MHz, DMSO-^₅) δ 7.59 (d, J= 9.6 Hz, IH), 7.39 (d, J= 8 Hz, 2H), 7.05

(d, J= 8 Hz, IH), 6.94 (s, IH)₅ 4.45 (s, 2H)₅ 3.75 (d₅ J= 9.2 Hz₅ IH)₅ 2.37 (s, 3H)₅ 1.85

(s, IH)₅ 1.62 (t, J= 21 Hz₅ 5H)₅ 1.40 (s, IH), 1.03-1.20 (m, 13H)₅ 0.76-0.84 (m, 7H). Example 10 l-Hexyl-5-methyl-l H-indole-2-carboxylic acid [( IR)- 1,3,3 -trimethyl- bicyclo[2.2.1 ]hept-2endo-yl] -amide.

¹H-NMR (400 MHz₅ DMSO-^) δ 7.59 (d, J = 9.6 Hz, IH), 7.39 (d, J = 8.8 Hz₅ IH),

7.04-7.06 (dd, J= 8.4 Hz & 1.6 Hz₅ IH)₅ 6.94 (s, IH)₅ 4.45 (d, J = 5.2 Hz₅ IH)₅ 3.73- 3.76 (dd, J= 9.6 Hz & 1.2 Hz₅ IH)₅ 2.53 (s,lH), 2.37 (s, 3H ), 1.71 (d₅ J= 3.2 Hz, IH)₅

1.57-1.63 (m, 4H)₅ 1.19 (d, J = 10.8 Hz, 7H), 1.08 (s, 3H)₅ 1.03 (s₅ 3H)₅ 0.84 (s, 3H)₅

0.78 (t, J= 3.2 Hz₅ 3H).

Example 11

5-Methyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl-bicyclo [2.2.1 ]hept- 2endo-yl] -amide

¹H-NMR (400 MHz₅ DMSO-J₆) δ 11.45 (s, IH)₅ 7.36 (s, IH), 7.30 (d, J= 8.4 Hz, 2H)₅

7.22 d₅ J= 8.4 Hz₅ 2H), 6.98-7.01(dd, J= 8.4 Hz & 1.2 Hz, IH), 3.77-3.80 (dd, J= 9.2

Hz & 1.6 Hz, IH), 2.35 (s, 3H)₅ 1.83-1.90 (m₅ IH)₅ 1.64-1.72 (m, 3H), 1.39-1.47 (m,

IH), 1.19 (t, J= 8.2 Hz, IH), 1.08 (s, 3H), 0.8 (s, 3H). Example 12

1 -Butyl-5 -methyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide

¹H-NMR (400 MHz, OMSO-d₆) δ 7.6 (d, J= 9.6 Hz₅ IH)₅ 7.38-7.4 (q, 2H)₅ 7.04-7.06

(dd, J= 8.4 Hz & 1.6 Hz, IH), 6.93 (s, IH)₅ 4.43-4.47 (m, 2H), 3.73-3.76 (dd, J= 9.6 Hz & 1.6 Hz, IH), 2.37 (s, 3H ), 1.71 (d, J= 3.6 Hz, IH), 1.56-1.65 (m, 4H), 1.13-1.20

(m, 3H)₅ 1.08 (s₅ 3H)₅ 1.03 (s, 4H), 0.83 (d, J= 5.6 Hz, 4H)₅ 0.80 (d₅ J= 7.6 Hz₅ 2H).

Example 13

6-Methoxy-l H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo~yl]-arnide. ¹H-NMR (400 MHz, DMSO-J₆) δ 11.38 (s, IH)₅ 7.47 (d, J= 8.8 Hz, IH), 7.25 (d, J = 1.6 Hz, IH), 7.22 (d, J= 9.2 Hz, IH), 6.86 (d, J= 8.8 Hz, IH), 6.67-6.70 (dd, J= 8.8 Hz & 2.4 Hz, IH), 3.78(d, J= 1.6 Hz, IH)₃ 3.75 (s, 3H), 1.82-1.88 (m, IH), 1.71(d, J= 3.6 Hz, IH), 1.66 (t, J= 5 Hz, 2H), 1.40-1.46 (m, IH), 1.20 (d, J= IO Hz, IH), 1.08 (s, 4H).

Example 14

6-Methoxy- 1 -pentyl- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2. l]hept-2endo-yl] -amide 1H-NMR (400 MHz, DMSO-J_tf ) δ 7.47-7.51 (q, 2H), 6.98 (s, 2H), 6.70-6.73 (dd, J= 8 Hz & 1 Hz, IH), 4.44-4.48 (m, 2H), 3.80 (s, 3H), 3.72-3.74 (dd, J = 9.6 Hz & 1.6 Hz, IH), 1.71 (d, J= 3.6 Hz, IH), 1.59-1.65 (m, 4H ), 1.40 (s, IH)₅ 1.13-1.25 (m, IH), 1.07 (s, 3H), 1.02 (s, 4H), 0.89 (s, 3H), 0.84 (m, 3H). Example 15

1 -(2-Ethylbutyl)-5-methyl-l H-indole-2-carboxylic acid [(1R)-1 ,3,3-trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide

¹H-NMR (400 MHz₅ DMSO-J₆) δ 7.66 (d, J= 9.6 Hz, IH), 7.37 (d, J= 10.8 Hz, 2H)₅ 7.03-7.05(dd, J= 8.8 Hz & 1.6 Hz, IH), 6.91 (s, IH), 4.40 (d, J= 7.2 Hz, 2H)₅ 4.36 (d, J= 7.2 Hz, 2H), 3.74-3.77 (dd, J= 9.6 Hz & 1.6 Hz, IH)₅ 2.36 (s, 3H ), 1.71(d, J= 3.6 Hz₅ 2H), 1.57-1.70 (m, 4H)₅ 1.40 (s, 2H)₅ 1.15-1.22 (m, 3H), 1.09-1.13(m, 4H), 1.05 (t, J= 10 Hz, 3H), 0.76-0.87 (m, 7H). Example 16

1 -Hexyl-6-methoxy- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1 ]hept-2endo-yl] -amide 1H-NMR (400 MHz, DMSO-J₆ ) δ 7.47-77.51 (dd, J= 9.6 Hz & 3.6 Hz₅ 2H)₅ 6.98 (s₅ 2H), 6.70-6.73 (dd, J = 8.8 Hz & 2.4 Hz, IH), 4.44-4.48 (q, 2H)₅ 3.80 (s, 3H)₅ 3.71- 3.74 (dd, J= 9.6 Hz & 1.6 Hz₅ IH), 1.71 (d, J= 3.2 Hz₅ IH)₅ 1.62 (t, J= 9.6 Hz, 4H), 1.39 (s, IH)₅ 1.19-1.24 (m, HH), 1.07 (s, 3H)₅ 1.02 (s, 4H)₅ 0.77-0.83 (m, 7H); Example 17 l-(2-[l₅3]Dioxan-2-yl-ethyl)-5-methyl-lH-indole-2-carboxylic acid [(lR)-l,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]- amide

¹H-NMR (400 MHz, DMSO-J₆ ) δ 7.57. (d, J= 9.6 Hz, IH), 7.39 (s, 3H), 7.32(d, J = 8.4 Hz₅ IH), 7.00 (s, IH)₅ 4.46 (t, J= 7.2 Hz₅ 2H), 4.35 (s, IH), 3.94-3.98 (dd, J= 11.2 Hz & 4.4 Hz, 2H), 3.73 (d, J= 9.6 Hz₅ IH), 3.57 (t, J= 12 Hz, 2H), 2.37 (s, 3H ), 1.83- 1.87 (q, 4H), 1.71(d, J= 2.8 Hz, IH), 1.64 (d, J= 10 Hz, IH), 1.31 (s, IH), 1.19 (d, J= 9.6 Hz₅ IH), 1.08 (s, 3H), 1.03 (s, 4H), 0.83 (s, 3H); Example 18

6-Bromo-l H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl-bicyclo[2.2.1]hept- 2endo-yl] -amide

¹H-NMR (400 MHz, DMSO-J₆) δ 11.72 (s, IH), 7.58 (d, J= 8.8 Hz, 2H), 7.43 (d, J = 9.6 Hz, IH), 7.38 (d, J= 0.8 Hz, IH), 7.14-7.17 (dd, J= 8.4 Hz & 1.6 Hz, IH), 3.77- 3.80 (dd, J= 9.6 Hz & 1.6 Hz, IH), 1.85-1.88 (m, IH), 1.72 (d, J= 3.2 Hz, IH), 1.65 (t, J= 10 Hz, 2H), 1.42-1.46 (q, IH), 1.20 (d, J= 10 Hz, IH), 1.08 (s, 3H), 1.01 (s, 3H) , 0.81 (s, 3H); Example 19

5 -Methoxy-2,3 -dihydro- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide 1H-NMR (400 MHz, DMSO-J₆ ) δ 8.04-8.11 (q, IH), 7.20 (t, J = 8.0 Hz, IH), 6.97- 6.99 (dd, J= 5.6 Hz & 1.0 Hz, IH), 6.97-6.99 (m, IH), 4.87-4.94 (m, IH), 3.74 (s, 3H), 3.55-3.66 (m, IH), 3.49 (d, J = 9.2 Hz, 2H), 3.01-3.12 (m, IH), 1.69 (d, J = 3.6 Hz, 2H), 1.59-1.67 (m, 2H), 1.57-1.44 (m, IH), 1.17 (d, J= 9.6 Hz, IH);

Example 20 5-Chloro-l-(4-trifluoromethyl-benzyl)-lH-indole-2-carboxylic acid [(1R)-

1 ,3,3-trimethyl-bicyclo[2.2. l]hept-2endo-yl]-amide.

¹H-NMR (400 MHz, DMSO-J₆) δ 7.81 (d, J = 9.2 Hz, IH), 7.73 (s, IH), 7.61 (d, J =

8.4Hz, IH), 7.22 (d, J= 8.4Hz, IH), 7.12 -7.03 (m, 5H)₅ 5.71(s, 2H), 3.71(d, IH)₅ 1.82

(m, IH), 1.68-1.60 (m, 3H), 1.38 (m, IH)₅ 1.17 (d₅ IH), 1.04-0.96 (m, 7H)₅ 0.7 (s₅ 3H). Example 21

1 -(4-Fluoro-benzyl)-5-methoxy- 1 H-indole-2-carboxylic acid [( 1 R)- 1,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide.

¹H-NMR (400 MHz, DMSO-J₆) δ 7.63 (d, J= 9.6 Hz₅ IH), 7.45 (d, J = 9.2 Hz₅ IH)₅

7.139 - 7.103 (m₅ 3H)₅ 7.063 - 7.018 (m, 3H)₅ 6.87 (dd, J= 9.2 and 2.8 Hz₅ IH)₅ 5.68 (s, 2H ), 3.74 (s, 3H)₅ 3.71 (dd, J = 9.6 and 1.6 Hz₅ 3H)₅ 1.83 (m, IH)₅ 1.69 (d₅ IH)₅

1.62 ( d, 2H)₅ 1.38 (m, IH)₅ 1.17 (d₅ IH), 1.05 (s, 3H)₅ 0.989 (d₅ 4H)₅ 0.75 (s,3H).

Example 22

5-Methoxy-lH-indole-2-carboxylic acid [( IR)- 1,3,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide. ¹H-NMR (400 MHz, DMSO-J₆) δ 7.62 (d, J = 9.6 Hz, IH)₅ 7.42 (d, J = 9.2 Hz₅ IH), 7.1 (d, J= 2Hz₅ IH)₅ 7.09-6.97(m₅ 5H), 6.85 (dd₅ J= 8.8 and 2.4 Hz₅ IH)₅ 5.65 (s, 2H)₅ 3.73-3.72 (m, 4H), 2.18 (s, 3H)₅ 1.83 (m, IH)₅ 1.70 (s, IH)₅ 1.59 (d, 2H)₅ 1.42-1.36 (m, IH)₅ 1.18 (d, IH)₅ 1.19 (s, 3H), 1.05 (s, 4H)₅ 0.7 (s,3H). ^• Example 23

S-Chloro-lH-indole^-carboxylic acid [( IS)- 1,3,3 -trimethyl-bicyclo [2.2.1 jhept- 2endo-yl]-amide.

¹H-NMR (400 MHz, DMSO-J₆) δ 11.78 (s, IH), 7.67 (d, J= 2.0 Hz, IH), 7.46-7.40 (m, 2H), 7.33 (d, J = 1.6 Hz₅ IH)₅ 7.17 (dd, J = 8.8 and 4.0Hz₅ IH)₅ 3.78 (dd, IH)₅ 1.89- 1.84 (m, IH)₅ 1.71 (d, IH)₅ 1.64 (t, 2H), 1.47-1.38 (m, IH), 1.47 (d, IH), 1.08 (d, 4H), 1.01 (s, 3H), 0.8 (s₅ 3H). Example 24

5-Methoxy-lH-indole-2-carboxylic acid [(lS)-l,3₅3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide. 1H-NMR (400 MHz₅ DMSO- J₆) δ 11.4 (s, IH), 7.31=7.27 (m, 2H)₅ 7.21 (d, J = 1.6 Hz, IH), 7.05 (d, J= 2.4 Hz, IH)₅ 6.82 (dd₅ J= 8.8 and 2.4 Hz, IH), 3.79 (dd, IH), 3.74 (s, 3H)₅ 1.85-1.82 (m, IH), 1.71 (d, IH)₅ 1.66 (t, 2H), 1.47-1.39 (m, IH), 1.2 (d, IH), 1.07 (d, 4H), 1.01 (s, 3H), 0.8 (s, 3H).

Example 25 lH-Indole-2-carboxylic acid [(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-2endo- yl]- amide

¹H-NMR (400 MHz₅ DMSO-J₆) δ 11.58 (s, IH)₅ 7.6 (d, J= 8.0 Hz₅ IH)₅ 7.42 (dd, J =

8.4 and 0.8 Hz₅ IH), 7.33 (dd, J = 12.8. and 9.6 Hz₅ IH)₅ 7.18 (dd, J= 6.8 and 0.8 Hz, IH), 7.04 (dd, J= 8.0 and 0,8 Hz₅ IH ), 3.79 (dd, IH), 1.91-1.83 (m, IH), 1.72 (d, IH),

1.65 (d, 2H)₅ 1.48-1.39 (m, IH)₅ 1.21. (d, IH)₅ 1.20 (d, 4H), 1.01 (s, 3H), 0.8 (s, 3H).

Example 26

5-Chloro-l-(4-fluoro-benzyl)-lH-indole-2-carboxylic acid [(1S)-1,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide 1H-NMR (400 MHz, DMSO-J₆) δ 7.81 (d, J= 9.2 Hz₅ IH)₅ 7.73 (s, IH)₅ 7.61 (d, J =

8.4 Hz₅ IH)₅ 7.22(d, J = 8.4 Hz, IH)₅ 7.12-7.03 (m, 5H), 5.71 (s, 2H ), 3.71 (d, IH),

1.82 (m. IH)₅ 1.68-1.60 (m, 3H), 1.38 (m, IH)₅ 1.17 (d, IH)₅ 1.04-0.96 (m, 7H)₅ 0.7 (s,

3H).

Example 27 l-(4-Fluoro-benzyl)-5-methoxy-lH-indole-2-carboxylic acid [(1S)-1,3,3- trimethyl-bicy clo [2.2.1 ]hept-2endo-yl] -amide.

¹H-NMR (400 MHz, DMSO-J₆) δ 7.63 (d, J = 9.6 Hz, IH), 7.45 (d, J= 9.2 Hz₅ IH), 7.139-7.103 (m, 3H), 7.063-7.018 (m, 3H), 6.87 (dd, J= 9.2 and 2.8 Hz, IH), 5.68 (s, 2H ), 3.74 (s, 3H), 3.71 (dd, J= 9.6 and 1.6 Hz, 3H)₅ 1.83 (m, IH), 1.69 (d, IH)₅ 1.62 (d, 2H), 1.38 (m, IH)₅ 1.17 (d, IH)₅ 1.05 (s, 3H), 0.989 (d, 4H), 0.75 (s,3H). Example 28

1 -(4-Methyl-benzyl)- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide 1H-NMR (400 MHz₅ DMSO-J₆) δ 7.68 (d, J= 9.6 Hz, IH), 7.63 (d, J = 1.6 Hz₅ IH), 7.53 (d, J= 7.6 Hz, IH), 7.21-7.17 (m, IH), 7.10 (s, IH), 7.08 (m, IH), 7.013 (s, 4H)₅ 5.70 (s, 2H)₅ 3.74 (dd, J= 9.6 and 1.6 Hz, IH), 2.18 (s, 3H)₅ 1.86-1.83 (m, IH)₅ 1.70 (d₅ IH)₅ 1.64-1.58 (m, 2H), 1.40-1.39 (m, IH), 1.19 (d, IH)₅ 1.06 (s, 3H), 0.99 (s, 4H)₅ 0.77 (s, IH) Example 29 l-Butyl-5-methoxy-l H-indole-2-carboxylic acid [(lR)-l₅3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide.

¹H-NMR (400 MHz, DMSO-J₆) δ 7.58 (d, J= 9.6 Hz₅ IH), 7.42 (d, J = 8.8 Hz₅ IH)₅ 7.85 (d, J= 2.4 Hz, IH), 6.93 (s, IH), 6.87 (dd, J= 9.2 and 2.8 Hz₅ IH), 4.44 (t, 2H)₅ 3.73 (d, 4H), 1.88-1.81 (m, IH)₅ 1.71 (d, IH), 1.65-1.56 (m, 4H), 1.55 (m, IH), 1.41- 1.20 (m, 3H), 1.08 (s, 3H), 1.031 (s, 4H), 0.84-0.79 (m, 6H).

Example 30

S-Methoxy-l-pentyl-lH-indole^-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1 ]hept-2endo-yl] -amide.

¹H-NMR (400 MHz, DMSO-J_6.) δ 7.59 (d, J = 9.6 Hz, IH), 7.42 (d, J =9.2 Hz₅ IH), 7.08 (d, J= 2.8 Hz₅ IH)₅ 6.93 (s₅ IH)₅ 6.88 (dd, J = 9.2 and 2.8 Hz, IH), 4.46-4.20 (m, 2H ), 3.74 (d, 4H)₅ 1.85-1.75 (m, IH)₅ 1.71 (d₅ IH)₅ 1.62-1.58 (m, 4H)₅ 1.41-1.38 (m, IH), 1.24-1.16(m, 3H), 1.15-1.12 (m, 2H), 1.08 (s, 3H)₅ 1.03 (brs, 4H)₅ 0.84 (s, 3H)₅ 0.77 (t, 4H). Example 31

5 -Methoxy-1 -methyl- 1 H-indole-2-carboxylic acid [(I S)-l,3,3-trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide. ¹H-NMR (400 MHz, DMSCW₆): δ 7.53 (d, J= 9.6 Hz, IH), 7.41 (d, J= 8.8 Hz, IH), 7.08 (d, J= 2.4 Hz, IH), 7.01 (s, IH), 6.9 (dd, J = 9.2 and 2.4 Hz, IH), 3.87 (s, 3H), 3.73 (d, 4H), 1.86-1.80 (m, IH)₃ 1.71 (d, IH), 1.63 (dd, 2H), 1.43-1.37 (m, IH), 1.24- 1.18 (m, 2H), 1.09 (s, 3H), 1.34 (d, 4H), 0.82 (s, 4H). Example 32

1 -Ethyl-5 -methoxy- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide. 1H-NMR (400 MHz, DMSCW₆). δ 7.56 (d, J = 9.6 Hz, IH), 7.43 (d, J = 9.2 Hz, IH),

7.08 (d, J= 2.4 Hz, IH), 6.96 (s, IH), 6.89 (dd, J = 8.8 and 2.4 Hz, IH), 4.43(q, 2H), 3.74 (d, 4H), 1.87-1.82 (m, IH), 1.71 ( d, IH), 1.62 (d, 2H), 1.44-1.39 (m, IH), 1.23-

1.18 (m, 4H), 1.09 (s, 3H), 1.036 (brs, 4H), 0.84 (s, 3H). Example 33

1 -Ethyl-5 -methoxy-/H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide. 1H-NMR (400 MHz, DMSO-J₆). δ 7.56 (d, J = 9.2 Hz, IH), 7.43 (d, J = 9.2 Hz , IH),

7.09 (d, J= 2.4 Hz, IH), 6.92 (s, IH), 6.89 (dd, J = 9.2 and 2.4 Hz, IH), 4.43 (q, 2H), 3.73 (d, 4H), 1.87-1.80 (m, IH), 1.71 (d, IH), 1.63 (d, 2H), 1.43-1.39 (m, IH), 1.23- 1.18 (m, 4H), 1.09 (s, 3H), 1.037 (brs, 4H), 0.84 (s, 3H).

Example 34 l-(2-Ethyl-butyl)-5-methoxy-iH-indole-2-carboxylic acid [(I R)- 1,3,3 - trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide.

¹H-NMR (400 MHz, DMSO-J₆). δ 7.68 (d, J= 9.6 Hz, IH), 7.39 (d, J= 9.2 Hz , IH),

7.09 (d, J= 2.0 Hz, IH), 6.09 (s, IH), 6.87 (dd, J = 9.2 and 2.4 Hz, IH)₅ 4.44-4.32 (m,

2H ), 3.75 (d, 4H), 1.86 (m, IH), 1.71(d, IH), 1.65-1.56 (m, 3H), 1.41 (d, IH)₅ 1.20- 1.17 (m, 2H), 1.14-1.099(m, 2H), 1.071 (s, 4H), 1.04 (s, IH), 1.023 (s, 4H)₅ 0.84 (s,

3H)₅ 0.78 (t, 3H), 0.74 (t, 3H).

Example 35

5-Methoxy-3-Methyl-2H-indole-2-carboxylic acid [( IR)- 1,3,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide. 1H-NMR (400 MHz, DMSO-J₆) δ 11.25 (s, IH), 7.28 (d, J= 8.8 Hz, IH), 7.02 (d, J =

2.4 Hz₅ IH), 6.97 (d, J= 8.8 Hz₅IH)₅ 6.84 (dd, J = 8.8 and 2.4 Hz, IH), 3.75 (d, 4H ),

2.47 (s, 3H)₅ 1.72-1.62 (m, 4H)₅ 1.47-1.40 (m, IH), 1.20 (d, IH)₅ 1.11 (s, 4H)₅ 1.05 (s,

3H), 0.8 d (s, 3H). Example 36

S-Methoxy-S-Methyl-iH-indole^-carboxylic acid [(I S)-1 ,3,3-trimethyl- bicyclo [2.2.1 ]hept-2endo-yl] -amide.

¹H-NMR (400 MHz, DMSO-4) δ 11.25 (s, IH), 7.28 (d, J = 8.8 Hz, IH), 7.02 (d, J = 2.4 Hz, IH), 6.96 ( d, J= 8.8 Hz₅IH), 6.84 (dd, J = 8.8 and 2.4 Hz, IH), 3.77 (s, 3H ), 3.74 (dd, IH), 3.33 (t, 4H), 1.73 ( d, 2H), 1.66 (d, 2H), 1.48-1.41 (m, IH), 1.21 (d, IH), 1.11 (d, 4H), 1.05 (s, 3H), 0.8 (s, 3H). Example 37

5-Methoxy-3 -Methyl- 1 -pentyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 - triniethyl-bicyclo[2.2.1]hept-2endo-yl]-amide.

¹H-NMR (400 MHz, DMSO-^₆) δ 7.8 (d, J = 9.2 Hz, IH), 7.35 (d, J = 8.8 Hz, IH), 7.01 (d, J = 2.0 Hz, IH), 6.84 (dd, J = 9.2 and 2.4 Hz, IH), 4.24-4.15 (m, 2H), 3.76 (brs, 4H), 2.32 (s, 3H), 1.78 (m, IH), 1.71 (d, 2H), 1.58 (t, 3H), 1.33 (m, IH), 1.24-1.17 (m, 5H), 1.11 (s, 3H), 1.08 (s, 3H), 0.85 (s, 3H), 0.80 (t, 3H). Example 38

5 -Methoxy-3 -Methyl- 1 -pentyl- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 - trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide.

¹H-NMR (400 MHz, DMSOd₆). δ 7.8 (d, J = 9.6 Hz, IH), 7.35 (d, J = 8.8 Hz, IH), 7.01 (d, J= 2.0 Hz, IH), 6.83 (dd, J = 9.2 and 2.4 Hz, IH), 4.28-4.21 (m, IH ), 4.18- 4.11 (m, IH ), 3.77 (brs, 4H), 2.32 (s, 3H), 1.78-1.77 (m, IH), 1.70-1.65 (m, 2H), 1.58 (t, 3H), 1.41-1.34 (m, IH), 1.26-1.17 (m, 5H), 1.10 (d, 6H), 1.04 (t, IH), 0.85 (s, 3H), 0.78 (t, 3H). Example 39

5-Chloro- lH-indole-2-carboxylic acid [(1R)- 1 ,3 ,3-trimethyl-bicyclo[2.2. l]hept- 2endo-yl]-amide.

¹H-NMR (400 MHz, DMS(W₆) δ 11.78 (s,lH), 7.67 (d, J= 2.0 Hz, IH), 7.46-7.4 (m, 2H), 7.33 (d, J= 1.6 Hz, IH), 7.17 (dd, J= 8.8 and 4.0 Hz, IH), 3.78 (dd, IH), 1.89- 1.84 (m, IH), 1.71 (d, IH), 1.64 (t, 2H), 1.47-1.38 (m, IH), 1.47 (d, IH), 1.08 (d, 4H), 1.01 (s, 3H), 0.8 (s, 3H). Example 40

5-Methoxy- 1 -hexyl- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide. ¹H-NMR (400 MHz, DMSO-J₆) δ 7.58 (d, J = 9.6 Hz, IH), 7.42 (d, J = 9.2 Hz, IH),

7.08 (d, J= 2.4 Hz, IH), 6.93 (s,lH), 6.87 (dd, J = 8.8 and 2.4 Hz, IH), 4.46-4.42 (m,

2H), 3.73 (d, 4H)₅ 1.84 (m, IH), 1.70 (d, IH), 1.65-1.57 (m, 4H), 1.41 (m, IH), 1.17 (d,

7H), 1.08 (s, 3H), 1.05 (s, 4H), 0.84 (s, 3H), 0.78 (t, 3H). ^l Example 41

5-Methoxy-l -hexyl-lH-indole-2-carboxylic acid [(1R)-1 ,3,3-trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide

¹H-NMR (400 MHz, DMSO-J₆) δ 7.58 (d, J = 9.6 Hz, IH)₅ 7.42 (d, J = 8.8 Hz, IH),

7.08 (d, J= 2.4 Hz, IH)₅ 6.93 (s₅lH), 6.87 (dd, J = 9.2 and 2.4 Hz₅ IH), 4.46-4.41 (m, 2H ), 3.73 (d, 4H)₅ 1.86-1.83 (m, IH)₅ 1.71 (d, IH), 1.65-1.57 (m, 4H), 1.43-1.37 (m,

IH), 1.18 (d, 7H), 1.08 (s, 3H), 1.05 (d, 4H), 0.84 (s, 3H), 0.78 (t, 3H).

Example 42

5 ,7-Dichloro-3 -methyl- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide. 1H-NMR (400 MHz, DMSO-J₆) δ 11.75 (s, IH)₅ 7.68 (d, J= 1.6 Hz, IH), 7.47 (d, J=

8.8 Hz, IH), 7.38 (d, J= 2 Hz₅ IH), 3.77 (d, IH), 1.81-1.77 (m, IH)₅ 1.72 (d, IH), 1.67-

1.62 (m, 2H)₅ 1.49-1.40 (m, IH)₅ 1.22 (d, IH), 1.11 (brs, 4H)₅ 1.06 (d, 3H), 0.81 (s,

3H).

Example 43 l-Butyl-5-methoxy-3 -methyl- 1 H-indole-2-carboxylic acid [(I R)- 1,3, 3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide

¹H-NMR (400 MHz, DMSO-J₆). δ 7.79 (d, J = 9.6 Hz, IH), 7.35 (d, J = 8.8 Hz, IH),

7.01 (d, J= 2.4 Hz, IH), 6.83 (dd, J = 9.0 and 2.0 Hz, IH), 4.28-4.21 (m, IH), 4.19-

4.12 (m, IH), 3.78-3.75 (brs, 4H), 2.32 (s, 3H), 1.81-1.75 (m, IH), 1.71 (d, IH), 1.66 (d, IH), 1.59-1.55 (m, 3H), 1.43-1.37 (m, IH), 1.22-1.18 (m, 5H)₅ 1.11-1.08 (d, 6H),

0.9 (t, 3H), 0.85 (s, 3H) , 0.82 (t, 3H).

Example 44

1 -Butyl-5-methoxy-3 -methyl- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-arnide. 1H-NMR (400 MHz, DMSO-J₆) δ 7.79. (d, J = 9.6 Hz, IH), 7.35 (d, J = 8.8 Hz, IH),

7.01 (d, J = 2.4 Hz, IH), 6.83 (dd, J = 8.8 and 2.4 Hz, IH), 4.25-4.23 (m, IH), 4.17-

4.15 (m, IH), 3.77 (brs, 4H), 2.32 (s, 3H), 1.89-1.78 (m, IH), 1.71 (d, IH), 1.66 (d, IH), 1.59-1.55 (m, 3H), 1.47-1.32 (m, IH), 1.20 (m, 3H), 1.11-1.08 (d, 6H), 1.101 (m,

IH), 0.85 (s, 3H), 0.82 (t, 3H).

Example 45

5 -Hydroxy- lH-indole-2-carboxylic acid [( IR)- 1,3,3 -trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide

¹H-NMR (400 MHz, DMSO-J₆) δ 11.28 (s, IH)₅ 8.75 (s, IH)₅ 7.22 (dd, J= 9.6 and 4.8

Hz₅ 2H)₅ 7.108 (d, J = 1.2 Hz, IH)₅ 6.86 (d₅ J = 2 Hz₅ IH)₅ 6.71 (dd, J = 8.4 and 2Hz₅

IH), 3.77 (dd, IH)₅ 1.85 (d, IH), 1.71 (d₅ IH), 1.66 (d, 2H), 1.44-1.41 (m, IH)₅ 1.21-

1.14 (m, IH)₅ 1.07 (d₅ 4H)₅ 1.05 (s, 3H)₅ 0.8 (s, 3H). Example 46

1 -(2-Ethyl-butyl)-5-methoxy-iH-indole-2-carboxylic acid [(I S)-1 ,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide.

¹H-NMR (400 MHz₅ DMSCW₆) δ 7.68 (d₅ J= 9.6 Hz₅ IH)₅ 7.39 (d, J= 9.2 Hz₅ IH)₅

7.09 (d, J= 2.0 Hz, IH), 6.09 (s, IH), 6.87 (dd, J = 9.2 and 2.4 Hz₅ IH)₅ 4.43-4.30 (m, 2H)₅ 3.76 (d, 4H)₅ 1.86 (m, IH), 1.71(d, IH)₅ 1.65-1.56 (m, 3H), 1.43-1.36 (m, IH),

1.22-1.17 (m, 2H)₅ 1.14-1.10 (m, 2H), 1.072 (s, 4H)₅ 1.049, (s, IH)₅ 1.024 (s, 4H), 0.844

(m, 3H)₅ 0.78 (t, 3H)₅ 0.75 (t, 3H).

Example 47

5-Methoxy- 1 -methyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide.

¹H-NMR (400 MHz, DMSO-J₆) δ 7.52 (d, J= 9.6 Hz₅ IH), 7.41 (d₅ J= 2.0 Hz , IH),

7.08 (d, J= 2.4 Hz, IH)₅ 7.01 (d₅ J= 0.4 Hz₅ IH)₅ 6.9 (dd, J = 8.8 and 2.4 Hz₅ IH)₅

3.88 (s, 3H )₅ 3.75 (s, 3H), 3.71 (d, J= 2.0 Hz₅ IH), 1.86-1.80 (m, IH), 1.71 (d, 2H)₅

1.64 (d₅ 2H), 1.43-1.37 (m₅ IH)₅ 1.24-1.18 (m, 2H)₅ 1.09 (s, 3H), 1.035 (brs, 4H), 0.83 (s, 3H).

Example 48

5 -Methoxy- 1 -(propane- 1 -sulfonyl)- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 - trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide

¹H-NMR (400 MHz, CDCl₃) δ 7.90 (d, J= 10.4 Hz, IH)₅ 6.99 (dd, J= 8 and 2 Hz, 2H), 6.82 (s, IH), 6.13 (d, J= 9.6 Hz, IH), 3.84-3.81 (m, 4H), 3.80-3.78 (m, 3H), 1.96-1.86

(m, 2H), 1.81 (d, IH), 1.72-1.67 (m, 2H), 1.54-1.44 (m, IH)₅ 1.33-1.26 (m, 3H)₅ 1.22

(d, 6H)₅ 1.0 (t, 3H), 0.89 (s, 3H). Example 49

3 -Methanesulfonyl-5-methoxy- lH-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 - trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide

¹H-NMR (400 MHz, CDCl₃) δ 10.12 (s, IH), 9.23 (d, J= 9.2 Hz, IH), 7.55 (d, J= 2.4 Hz, IH), 7.40 (d, J= 8.8 Hz, IH), 7.05 (dd, J= 9.2 and 2.4 Hz, IH), 3.89 (brs, 4H)₅ 3.21 (s, 3H), 1.82-1.62 (m, 4H), 1.52-1.48 (m, IH), 1.30 (m, 2H), 1.2 (s, 3H), 1.19 (s, 3H), 0.9 (s, 3H). Example 50

5-Chloro- 1 -methanesulfonyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3-trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide

¹H-NMR (400 MHz, CDCl₃): δ 7.96 (d, J= 9.2 Hz, IH), 7.56 (d, J= 2 Hz, IH), 7.34 (dd, J= 8.8 and 2 Hz, IH), 6.78 (d, J = 0.8 Hz, IH), 6.10 (d, J = 10.0 Hz, IH), 3.80 (dd, J= 10.0 and 1.6 Hz , IH), 3.66 (s, 3H), 1.83 (d, IH), 1.72-1.67 (m, 2H), 1.53-1.47 (m, IH), 1.35-1.25 (m, 3H), 1.19 (d, 6H), 0.9 (s, 3H). Example 51 l-Methanesulfonyl-5-methoxy-lH-indole-2-carboxylic acid [(1S)-1,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide

¹H-NMR (400 MHz, DMSO-cfe) δ 8.16 (d, J= 9.6 Hz, IH), 7.79 (d, J= 9.2 Hz, IH), 7.21 (d, J= 2.4 Hz, IH), 7.0 (dd, J= 9.2 and 2.4 Hz, IH), 6.88 (s, IH)₅ 3.77 (s, 3H), 3.68 (d, 4H), 1.84-1.77 (m, IH), 1.7 (d, IH)₅ 1.63-1.57 (m, 2H), 1.43-1.35 (m, IH), 1.17 (d, IH), 1.05 (d, 6H), 0.86 (s, 3H). Example 52

5-Methoxy- 1 -(isopropyl)- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide. 1H-NMR (400 MHz, DMSO-J₆) δ 7.74 (s, IH)₅ 7.54 (s, IH), 6.95 (brs, IH)₅ 6.76 (d, 2H)₅ 5.13 (s, IH)₅ 3.74 (s, 4H), 1.81-1.40 (m, 12H), 1.18-1.04 (m, 8H)₅ 0.84 (s, 3H). Example 53

2,2-Dimethyl-propionic acid 2-[(1R)-I₅ 3, 3-trimethyl-bicyclo[2.2.1]hept- ^• 2endo- yl carbamoyl] -lH-indol-5-yl ester. 1H-NMR (400 MHz, DMSO-cfe) δ 11.69 (s, IH)₅ 7.40 (dd, J= 9.2 and 3.2 Hz, 2H)₅ 7.30 (dd, J= 10.8 and 1.2 Hz₅ 2H)₅ 6.87 (dd₅ J= 8.8 and 2.4 Hz₅ IH), 3.8 (d, J= 9.6 Hz, IH), 1.89-1.88 (m, IH)₅ 1.72 (d, IH)₅ 1.68-1.65 (m, 2H)₅ 1.46-1.42 (m, IH), 1.31 (s, 9H), 1.20 (d, IH), 1.08 (d, 4H), 1.02 (s, 3H), 0.81 (s, 3H). Example 54

5-Ethoxy- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3-trimethyl-bicyclo [2.2.1 ]hept- 2endo-yl]-amide.

¹H-NMR (400 MHz₅ CDCl₃) δ 9.09 (s, IH), 7.32 (d, J= 8.8 Hz, IH), 7.05 (d, J= 2 Hz₅ IH)₅ 6.96 (dd₅ J= 8.8 and 2.4 Hz₅ IH)₅ 6.75 (d, J= 2 Hz₅ IH)₅ 6.12 (d, J= 9.6 Hz₅ IH)₅ 4.06 (q, 2H)₅ 3.84 (dd, J= 9.6 and 1.6 Hz, IH)₅ 1.82 (d, IH)₅ 1.72 (d, 2H)₅ 1.56-1.51 (m, IH)₅ 1.44 (t, 3H)₅ 1.35-1.32 (m, IH)₅ 1.28 (d₅ 2H)₅ 1.58 (s, 3H)₅ 1.11 (s, 3H), 0.86 (s, 3H).

Example 55

S-Pentyloxy-lH-indole^-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide 1H-NMR (400 MHz₅ CDCl₃) δ 9.00 (s, IH)₅ 7.31 (d, J= 8.8 Hz, IH), 7.05 (d, J= 2 Hz₅ IH), 6.96 (dd, J = 8.8 and 2.4 Hz₅ IH)₅ 6.74 (d, J= 1.6 Hz₅ IH)₅ 6.11 (d, J= 10 Hz₅ IH)₅ 3.98 (t, 2H)₅ 3.82 (dd, J = 9.6 and 1.6 Hz, IH), 1.84-1.77 (m, 3H)₅ 1.72 (d, 2H), 1.54-1.32 (m, 6H), 1.28 (d, 2H)₅ 1.17 (s, 3H)₅ 1.11 (s, 3H)₅ 0.94 (t, 3H)₅ 0.8 (s, 3H). Example 56

5 -Butoxy- 1 H-indole-2-carboxylic acid [(1S)-1,3,3 -trimethyl-bicyclo [2.2.1 ]hept- 2endo-yl]-amide.

¹H-NMR (400 MHz₅ CDCl₃) δ 9.09 (s, IH)₅ 7.32 (d, J= 8.8 Hz₅ IH)₅ 7.05 (d, J= 2.4 Hz₅ IH)₅ 6.96 (dd, J= 8.8 and 2.4 Hz, IH)₅ 6.75 (d, J= 1.6 Hz₅ IH)₅ 6.12 (d, J= 9.6 Hz₅ IH)₅ 3.99 (t, 2H)₅ 3.83 (dd, J= 9.6 and 1.6 Hz₅ IH)₅ 1.82-1.71 (m, 5H)₅ 1.56-1.49 (m, 2H)₅ 1.35-1.33 (m, IH)₅ 1.29-1.25 (m, 2H)₅ 1.18 (s, 3H)₅ 1.11 (s, 3H)₅ 0.98 (t, 3H)₅ 0.86 (s₅ 3H). Example 57

Methanesulfonic acid 2-[(lS)-l,3₅3-triniethyl-bicyclo[2.2.1]hept-2endo-yl ]-lH- indol-5-yl ester. 1H-NMR (400 MHz₅ CDCl₃) δ 9.63 (s, IH)₅ 7.58 (d, J= 2.4 Hz₅ IH)₅ 7.47 (d, J= 8.8 Hz₅ IH), 7.20 (dd, J= 8.8 and 2 Hz, IH)₅ 6.87 (d, J= 1.6 Hz, IH), 6.18 (d, J= 8 Hz, IH), 3.86 (dd, J= 9.6 and 1.2 Hz₅ IH)₅ 3.13 (s, 3H)₅ 1.84 (t, IH), 1.74 (t, 2H)₅ 1.55- 1.50 (m, 2H), 1.39-1.31 (m, 3H)₅ 1.19 (s, 3H), 1.12 (s, 3H)₅ 0.8 (s, 3H). Example 58 S-Ethoxy-lH-indole^-carboxylic acid [(lR)-l,3₅3-trimethyl-bicyclo[2.2. ljhept- 2endo-yl] -amide.

¹H-NMR (400 MHz₅ CDCl₃) δ 9.06 (s, IH), 7.32 (d, J== 8.8 Hz₅ IH), 7.05 (d, J= 2 Hz, IH), 6.96 (dd, J= 8.8 and 2.4 Hz, IH), 6.75 (d, J= 1.2 Hz, IH), 6.12 (d, J= 9.2 Hz, IH), 4.05 (q, 2H), 3.83 (dd, J= 9.6 and 1.6 Hz, IH), 1.82 (d, IH), 1.73 (brd, 2H), 1.54- 1.49 (m, IH), 1.44 (t, 3H), 1.37-1.34 (m, IH), 1.28 (brd, 2H), 1.17 (s, 3H), 1.11 (s, 3H), 0.86 (s, 3H). Example 59

5 -Ethoxy- 1 -ethyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethy 1- bicyclo[2.2.1]hept-2endo-yl]-amide.

¹H-NMR (400 MHz, CDCl₃) δ 7.30 (d, J= 8.8 Hz, IH), 7.05 (d, J= 2.4 Hz, IH), 6.98 (dd, J= 9.2 and 2.4 Hz, IH), 6.72 (s, IH), 6.15 (d, J= 9.6 Hz, IH), 4.57-4.51 (m, 2H), 4.06 (q, 2H), 3.80 (dd, J= 9.6 and 1.6 Hz, IH), 1.81 (t, IH), 1.73-1.68 (m, 2H), 1.53. (m, IH), 1.44 (t, 3H), 1.39 (t, 3H), 1.32-1.24 (m, 3H), 1.19 (s, 3H), 1.12 (s, 3H), 0.88 (s, 3H).

Example 60

5 -Chloro- 1 -(2-morpholine-4-yl-ethyl)~ 1 H-Inole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 - trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide 1H-NMR (400 MHz, DMSOd₆) δ 7.74 (d, J= 9.6 Hz, IH), 7.69 (d, J= 1.2 Hz, IH), 7.57 (d, J= 8.8 Hz, IH), 7.24-7.21 (dd, J= 8.8 and 1.6 Hz, IH), 7.05 (br s, IH), 4.59 (t, J= 6.2 Hz, IH ), 3.73 (t, IH), 3.47 (t, 4H), 2.52 (d, IH), 2.34 (d, 4H), 1.86 (br s, IH), 1.71 (br s, IH), 1.63 (d, 2H), 1.40 (d, IH), 1.20 (t, 2H), 1.06 (t, 7H), 0.83 (d, 4H). Example 61

5-Methoxy-l-(4-methyl-benzyl)-lH-Indol-2-carboxylic acid [(I S)-l,3,3- trimethyl-bicyclo[2.2. l]hept-2endo-yl] -amide

¹H-NMR (400 MHz, DMSO-J₆) δ 7.62 (d, J= 9.6 Hz, IH), 7.41 (d, J= 9.2 Hz, IH), 7.09 (d, J= 2.4 Hz₅IH), 7.0 (d, J= 3.2 Hz, 5H), 6.86-6.83 (dd, J= 9.2 and 2.4 Hz, IH), 5.65 (br s, 2H), 3.72 (t, 4H)₅ 2.18 (br S₅ 3H), 1.70 (br s, IH), 1.63 (br s, IH), 1.61 (d, 2H), 1.39 (br s, IH), 1.16 (d, IH)₅ 1.05 (br s, 3H)₅ 0.99 (br s, 4H), 0.77 (br s, 3H). Example 62

5,6-Dimethoxy-l H-indole-2-carboxylic acid [(I R)- 1,3 ,3 -trimethy 1- bicyclo[2.2.1 ]hept-2endo-yl]-amide ¹H-NMR (400 MHz₃ DMSO-J₆) δ 9.18 (s, IH)₅ 7.02 (s, IH), 6.88 (s, IH), 6.75 (d, J =

1.6 Hz, IH)₅ 6.06 (d, J= 9.6 Hz₅ IH)₅ 3.94 (s, 3H)₅ 3.92 (s, 3H)₅ 3.82-3.84 (dd₅ J= 9.6 and 1.6 Hz, IH)₅ 1.82 (d, J- 3.2 Hz₅ IH), 1.70-1.76 (q, 2H)₅ 1.48-1.54 (m, IH)₅ 1.29 (t,

J= 5.2 Hz₅ 2H); Example 63

4-Benzyloxy-lH-indole-2-carboxylic acid [(lR)-l₅3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide

¹H-NMR (400 MHz₅ DMSO-J₆) δ 9.38 (s, IH)₅ 7.52 (d, J= 7.2 Hz₅ 2H)₅ 7.41-7.45 (q,

2H)₅ 7.35-7.38 (m, IH)₅ 7.18 (t, J= 8 Hz₅ IH)₅ 7.06 (d, J= 8.4 Hz₅ IH)₅ 6.99 (t, J= 1 Hz₅ IH)₅ 6.59 (d, J= 8 Hz₅ IH)₅ 6.16 (d, J= 9.6 Hz₅ IH)₅ 5.22 (s, 2H)₅ 3.83-3.86 (dd, J

= 9.6 and 1.6 Hz₅ IH)₅ 1.81 (d, J= 3.6 Hz₅ IH)₅ 1.73 (t, J= 4.8 Hz₅ IH)₅ 1.47-1.61 (m₅

IH), 1.33-1.40 (m, IH)₅ 1.26-1.29 (m, 2H);

Example 64

5-(2-[l₅3]Dioxan-2-yl-ethoxy)-lH-indole-2-carboxylic acid [(1R)-1,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide

¹H-NMR (400 MHz₅ DMSO-J₆) δ 11.54 (s, IH)₅ 7.28-7.31 (dd, J = 9.6 and 3.2 Hz₅

IH)₅ 7.20 (d, J= 1.6 Hz₅ IH)₅ 7.04 (d, J= 2 Hz, IH)₅ 6.81-6.83 (dd, J= 8.8 and 2.4 Hz,

IH), 4.74 (t, J= 5.2 Hz₅ IH)₅ 3.97-4.02 (m, 4H)₅ 3.74-3.79 (m, IH)₅ 3.68-3.71 (dd, J =

12 and 2Hz, 2H)₅ 1.90-1.95 (m, IH), 1.82-1.89 (m₅ IH)₅ 1.72 (d₅ J= 3.2 Hz₅ 2H)₅ 1.65 (d, J= 10 Hz₅ IH)₅ 1.43 (t, J= 4.8 Hz, IH)₅ 1.17 (d, J= 13.6 Hz₅ IH);

Example 65

5-Methoxy-l-(2-morpholin-4-yl-ethyl)-lH-indole-2-carboxylic acid [(lS)-l₅3₅3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide

¹H-NMR (400 MHz₅ DMSO-J₆) δ 7.34 (d, J = 9.2 Hz₅ IH)₅ 7.05 (d, J = 2.0 Hz, IH), 6.98 (dd, J= 9.2 and 2.0 Hz, IH), 6.75 (s, IH)₅ 6.17 (d, J= 9.6 Hz₅ IH)₅ 4.61-4.73 (s,

2H), 3.84 (s₅ 3H)₅ 3.81 (d, J= 10 Hz₅ IH)₅ 3.70 (t, J= 4.2 Hz₅ 4H)₅ 2.75 (t, J= 7.0 Hz, 2H), 2.56 (brs, 4H), 2.09 (s, IH)₅ 1.81 (s, IH), 1.72 (d, J= 8.4 Hz, 2H), 1.47-1.56 (m,

IH)₅ 1.25-1.36 (m, 3H), 1.12 (s, 3H), 0.89 (s, 3H);

Example 66 5-Methoxy-l-(2-moipliolin-4-yl-etliyl)-lH-indole-2-carboxylic acid [(1S)-1,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide-j3-toluene sulfonic acid.

¹H-NMR (400 MHz, DMSO-J₆) δ 11.70 (br s, IH), 7.87 (d, J= 8.0 Hz₅ 2H)₅ 7.58 (d, J

= 8.8 Hz₅ IH)₅ 7.23 (t, J= 9.2 Hz₅ 2H)₅ 7.0 (s, IH), 7.23 (t, J= 9.2 Hz₅ 2H)₅ 6.95 (t, J= 8.8 Hz₅ IH), 6.79 (s, 2H)₅ 6.21 (d, J= 92 Hz, IH)₅ 4.95 (t₅ J= 7.4 Hz, 2H)₅ 4.14 (t, J= 12.2 Hz, 2H), 4.0 (d, J= 12.4 Hz, 2H), 3.82 (s, 3H), 3.74 (d, J= 9.6 Hz, IH), 3.65 (d, J = 11.6 Hz, 2H)₅ 3.55 (d, J= 4.0 Hz₅ 2H), 3.07 (d, J= 9.2 Hz, 2H), 2.37 (s, 3H)₅ 1.83 (s, IH)₅ 1.71 (d, J= 8.8 Hz, 2H)₅ 1.53 (t, J= 8.2 Hz₅ IH), 1.28 (t, J= 8.6 Hz, 3H), 1.26 (s, 3H)₅ 1.17 (S₅ 3H), 0.87 (s, 3H) Example 67

Propane- 1 -sulfonic acid 2- [( 1 S)- 1 ,3 ,3 -trimethyl-bicyclo [2.2.1 ]hept-2endo-yl carbamoyl)]-lH-indol-5-yl ester. 1H-NMR (400 MHz₅ DMSOd₆) δ 9.45 (s, IH)₅ 7.57 (d₅ J= 2 Hz, IH)₅ 7.46 (d, J= 8.8 Hz₅ IH), 7.19 (dd, J= 8 and 2.4 Hz, IH), 6.86 (d, J= 1.6 Hz, IH), 6.17 (d, J- 9.6 Hz, IH), 3.87 (dd, J= 9.6 and 1.6 Hz, IH)₅ 3.23 (m, 3H), 1.99-2.06 (m, 2H), 1.83 (t, J = 1.8 Hz, IH), 1.73 (br d, 2H), 1.51-1.55 (m, IH), 1.25-1.35 (m, 3H)₅ 1.19 (s, 3H), 1.10- 1.14 (m, 6H), 0.87 (s, 3H). Example 68 5-Pentyloxy-lH-indole-2-carboxylic acid [( IR)- 1,3,3 -trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide. ^

¹H-NMR (400 MHz₅ DMSO-^₆) δ 9.08(s, IH)₅ 7.32 (d₅ J= 8.8 Hz₅ IH)₅ 7.04 (d₅ J= 2.4 Hz, IH), 6.96 (dd, J= 8.8 and 2.4 Hz, IH), 6.74 (t, J= 5.6 Hz, IH), 6.12 (d, J= 9.6 Hz, IH), 3.98 (t, J= 6.8 Hz, 2H), 3.87 (dd, J = 9.6 and 1.6 Hz, 3H), 1.73-1.83 (m, 3H), 1.70 (br d, 2H)₅ 1.51-1.55 (m, IH), 1.43-1.49 (m, 3H), 1.35-1.42 (m, 2H)₅ 1.32-1.35 (m, 2H)₅ 1.28 (br d, 2H), 1.17 (s, 3H)₅ 1.11 (s, 3H), 0.941 (t, 3H), 0.87 (s, 3H). Example 69

5-Pentyloxy-lH-indole-2-carboxylic acid [(lS)-l,3₅3-trimethyl- bicyclo[2.2.1 ]hept-2endo-yl] -amide. 1H-NMR (400 MHz, DMSO-^₆) δ 9.08 (s, IH), 7.31 (d, J= 8.8 Hz₅ IH)₅ 7.05 (d, J= 2 Hz, IH)₅ 6.96 (dd₅ J= 8.8 and 2.4 Hz, IH), 6.74 (d, J= 1.6 Hz, IH), 6.11 (d, J= 10 Hz, IH)₅ 3.98 (t, 2H)₅ 3.82 (dd, J= 9.6 and 1.6 Hz, IH), 1.84-1.77 (m, 3H)₅ 1.72 (d, 2H)₅ 1.54-1.32 (m, 6H)₅ 1.28 (d, 2H ), 1.17 (s, 3H)₅ 1.11 (s, 3H), 0.94 (t, 3H), 0.8 (s, 3H).

Biological activity: In vitro cAMP Assay for hCB2

Fatty acid-free BSA, IBMX, (Isobutyl methyl xanthine), RO20-1724 {4-[(3-butoxy-4- methoxyphenyl) methyl]-2-imidazololidinone}, forskolin and DMSO (liybrimax) were purchased from Sigma Chemical Co. cAMP detection ELISA kit was from Assay Designs, USA. Tissue culture reagents were procured from Sigma and Hi-media. Other reagents used were all of analytical grade.

The cAMP assay was carried out using Chinese Hamster Ovary (CHO) cells (CHOK 1) stably expressing human CB2 receptor. cAMP assay was performed following the method of Bouaboula et al [Eur. J. Biochem. 1996, 237, 704-711]. Cells grown to 80% confluence were maintained in HAM'S Fl 2 medium containing 10% fetal bovine serum at 1.0 mg/mL G-418 pressure and were seeded at a density of 50, 000 cells/well in 24 well plate. Cells were then incubated in plain HAM'S F12 containing 0.5% fatty acid free BSA at 37 °C/5% CO₂. Before addition of the compounds, cells were pre incubated with phosphodiesterase inhibitors - IBMX (0.1 mM) and RO20-1724 (0.1 niM). Compounds (at respective concentrations) and forskolin (at a final concentration of 4μM) were added simultaneously. The reaction was terminated by washing once with PBS and adding 200μL 0.1 N HCl and 0.1% Triton-X 100. Supernatant of the cell Iy sate was used for detection of c AMP. ELISA carried out using Assay Designs cAMP kit as per the manufacturer's instructions.

Table 1. In vitro hCB2 functional assay for assessing cAMP activity

Example No. % Forskolin Inhibition IC50

10O nM 10 μM

7 77.62 136.13

8 67.23 69.82

13 62.89 0

15 64.44 60.21

17 101.21 0

19 21.97 22.42 18O nM

22 61.42 29.74 0.027 nM

23 63.59 13,36 53.4 nM

24 91.49 29.31 17.2 nM

29 108.14 0

30 130.46 0

31 33.07 103.78

32 102.28 0

33 64.02 0

a Values indicate Mean ± SD performed in duplicate and the results being representative of at least three independent experiments.

In vivo pharmacological profile

The in vivo pharmacological profile has been shown in the accompanying drawings which are self-explanatory.

Table 2. Mean pharmacokinetic parameters of compound 22 in Wister rats.^a

a Values indicate mean ± SD for n=6 rats

It will be appreciated that in any of the above-mentioned reactions any reactive group in the substrate molecule may be protected, according to conventional chemical practice. Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art.

The compounds of formula (1) may be optionally converted ₍to their suitable pharmaceutically acceptable salts by processes as are known in the art. The novel compounds of the present invention can further be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.

The compounds of the present invention modulate the CB-2 receptor and are useful in the treatment of the pain.

Claims

We claim:

1. Compounds of general formula (I)₃ their stereoisomers, tautomeric forms, their regioisomers, pharmaceutically acceptable salts, their pharmaceutically acceptable solvates

Formula (I) wherein,

R¹ is independently selected from H, optionally substituted groups selected from alkyl, hetero-alkyl, halo-alkyl, aryl, hetero-aryl, aryl-alkyl, hetero-aryl-alkyl, cyclo- alkyl, sulphonyl-alkyl, sulphonyl-aryl, hetero cyclo alkyl and acyl groups; R² is independently selected from H, optionally substituted alkyl, sulphonyl-alkyl groups;

R₃-R₆ at each occurrence is independently selected from H, halogen, cyano, nitro, hydroxy, optionally substituted groups selected from amino (preferably of the form - NR⁷R⁸, -NR⁷COR⁸ or -NR⁷SO₂R⁸), optionally substituted carbonyl (of the form - COR⁷), heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, cycloalkyl, sulphonylalkyl, sulphonylaryl, heterocyclo alkyl, alkyl, alkenyl, alkynyl groups, or groups selected from alkoxy (of the form -OR⁹), aryloxy, heteroaryloxy, cycloalkyloxy, hetero-cycloalkyloxy group, carboxylic acid or its derivatives such as esters, optionally substituted carboxamide (preferably of the form -CONR¹⁰R¹¹); R⁷ and R⁸ at each occurrence, when present, are independently selected from H, optionally substituted groups selected from alkyl, hetero-alkyl, halo-alkyl, aryl, heteroaryl, arylalkyl or heteroaryalkyl., cyclo-alkyl, sulphonyl-alkyl, sulphonyl-aryl, hetero-cyclo-alkyl group; R⁹ is independently selected from optionally substituted groups selected from alkyl, hetero-alkyl, halo-alkyl, aryl, heteroaryl, arylalkyl heteroaryalkyl or cyclo-alkyl groups; R¹⁰ is H₅ or (C₁-C₃) alkyl group or is part of ring formation with R¹¹; R¹¹ is independently selected from optionally substituted groups selected from alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroaryalkyl, cycloalkyl, heterocycloalkyl, or non-aromatic (C₃-C₁₅) carbocyclic radicals.

2. A compound as claimed in claims 1 wherein the substitutions on R₂ are selected from H₃ alkyl, aryl alkyl, hetro-cyclo alkyl, sulfonyl-alkyl groups; substitutions on R₃ are selected from H and aryl-oxy groups; substitutions on R₄ are selected from H, halogen, hydroxy, alkyl, alkoxy, carboxylic acid or its derivatives like ester and hetero cyclo alkyl oxy groups; substitutions on R₅ are selected from H₅. alkoxy and halogen groups; substitutions on R₆ are selected from H and halogen groups.

3. A compound as claimed in claim 1 or 2, wherein the "aryl" group is selected from a suitable aromatic system containing one, two or three rings wherein such rings are attached together in a pendant manner or may be fused.

4. A compound as claimed in claim 3 wherein the aryl groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane or biphenyl groups.

5. A compound as claimed in claim 1 or 2, wherein the "heteroaryl" groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl and benzothiazolyl groups.

6. A compound as claimed in claim 1 or 2, wherein the "alkyl" groups are selected from methyl, ethyl, ra-propyl, wo-propyl, ra-butyl, sec-butyl, tert-butyl, amyl, t-amyl, «-pentyl and n-hexyl groups.

7. A compound as claimed in claim 1 or 2, wherein the "alkoxy" groups are selected from methoxy, ethoxy, «-propoxy, zsopropoxy, n-butoxy, t-butoxy, wø-butoxy, pentyloxy and hexyloxy groups.

8. A compound as claimed in claim 1 or 2, wherein the "haloalkyl" groups are selected from fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl and hexyl groups.

9. A compound as claimed in claim 1 or 2, wherein the "haloalkoxy" groups are selected from fluoromethoxy, chloromethoxy, fluoroethoxy and chloroethoxy groups.

10. A compound as claimed in claim 1 or 2, wherein "alkylthio" groups are selected from methylthio, ethylthio and propylthio groups.

11. A compound as claimed in any preceding claims selected from 1 -(4-Trifluoromethyl-benzyl)- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; l-(4-Trifluoromethyl-benzyl)-2,3-dihydro-l H-indole-2-carboxylic acid [(1R)-1,3,3~ trimethyl-bicyclo[2.2.1]hept-2endo-yl)]-amide; 5-Chloro-l-(4-fluoro-benzyl)-l H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Chloro-l-(4-methyl-benzyl)-l H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-CMoro- 1 -(4-methylbenzyl)-2,3-dihydro- 1 H-indole-2-carboxylic acid [(1R)- 1,3,3- trimethyl-bicyclo [2.2.1 ]hept-2endo-yl] -amide;

5-Methoxy-l-(4-methylbenzyl)-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide; l-Butyl-S-chloro-lH-indole^-carboxylic acid [( IR)- 1,3,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; l-Butyl-S-chloro-lH-indole^-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Methyl- 1 -pentyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

1 -Hexyl-5 -methyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide;

5-Methyl- 1 H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl-bicyclo[2.2.1]hept-

2endo-yl] -amide;

1 -Butyl-5-methyl- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; 6-Methoxy-l H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl-bicyclo[2.2.1]hept-

2endo-yl] -amide;

6-Methoxy- 1 -pentyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide;

1 -(2-Ethylbutyl)-5-methyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3-trimethyl- bicyclo[2.2.1 ]hept-2endo-yl] -amide;

1 -Hexyl-6-methoxy- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-ylj-amide;

1 -(2-[1 ,3]Dioxan-2-yl-ethyl)-5-methyl- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3 ,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]- amide; 6-Bromo- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3 ,3 -trimethyl-bicyclo [2.2. l]hept-2endo- yl]-amide;

5-Methoxy-2>dihydro-l H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; 5-Chloro-l-(4-trifluoromethyl-benzyl)-lH-indole-2-carboxylic acid [(1R)- 1,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide; l-(4-Fluoro-benzyl)-5-methoxy-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl3-anαide;

5-Methoxy-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl-bicyclo[2.2. l]hept- 2endo-yl]-amide;

5-Chloro- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl-bicyclo[2.2.1 ]hept-2endo- yl] -amide;

5-Methoxy-lH-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-

2endo-yl] -amide; lH-Indole-2-carboxylic acid [(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-2endo-yl]- amide;

5 -Chloro- 1 -(4-fluoro-benzyl)- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; l-(4-Fluoro-benzyl)-5-methoxy-l H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide;

1 -(4-Methyl-benzyl)- 1 H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

1 -Butyl-5-methoxy- 1 H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; 5 -Methoxy- 1 -pentyl- 1 H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5 -Methoxy- 1 -methyl- 1 H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo [2.2.1 ]hept-2endo-yl] -amide; l-Ethyl-5-methoxy-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide; l-Ethyl-5-methoxy-iH-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; l-(2-Ethyl-butyl)-5-methoxy-;H-indole-2-carboxylic acid [( IR)- 1,3,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-arnide; 5-Methoxy-3-Methyl-./H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Methoxy-3-Methyl-7H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo [2.2.1 ]hept-2endo-yl] -amide; 5-Methoxy-3-Methyl-l-pentyl-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5 -Methoxy-3 -Methyl- 1 -pentyl- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethy 1- bicyclo[2.2. l]hept-2endo-yl]-amide;

5-Chloro-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl-bicyclo[2.2. l]hept-2endo- yl]-amide;

5 -Methoxy- 1 -hexyl- 1 H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Methoxy- 1 -hexyl- 1 H-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; 5, 7-Dichloro-3 -methyl- 1 H-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

1 -Butyl-5 -methoxy-3 -methyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

1 -Butyl-5 -methoxy-3 -methyl- 1 H-indole-2-carboxylic acid [(1S)-1,3,3 -trimethy 1- bicyclo[2.2. l]hept-2endo-yl]-amide;

5-Hydroxy- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3-trimethyl-bicyclo [2.2.1 ]hept-

2endo-yl] -amide;

1 -(2-Ethyl-butyl)-5-methoxy-J^r H-indole-2-carboxylic acid [(I S)- 1 ,3 ,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; 5 -Methoxy- 1 -methyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3 -trimethy 1- bicyclo[2.2.1 ]hept-2endo-yl]-amide;

5 -Methoxy- 1 -(propane- 1 -sulfonyl)- 1 Η-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1 ]hept-2endo-yl]-amide;

3-Methanesulfonyl-5-methoxy-lΗ-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Chloro- 1 -methanesulfonyl- 1 H-indole-2-carboxylic acid [( 1 R)- 1 ,3 ,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

1 -Methanesulfonyl-5 -methoxy- 1 H-indole-2-carboxylic acid [( 1 S)- 1 ,3 ,3 -trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide; 5-Methoxy-l-(isopropyl)-lH-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

2,2-Dimethyl-propionic acid 2-[(1R)-I, 3, 3-trimethyl-bicyclo[2.2.1]hept-2endo- yl carbamoyl]-lH-indol-5-yl ester; 5-Ethoxy-lH-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-2endo- yl] -amide;

5-Pentyloxy-lH-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-

2endo-yl]-amide;

5-Butoxy-lH-indole-2-carboxylic acid [(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-2endo- yl]-amide;

5-yl ester;

5-Ethoxy-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl-bicyclo[2.2.1]hept-

2endo-yl] -amide; 5-Ethoxy-l -ethyl- lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Chloro-l-(2-moφholine-4-yl-ethyl)-lH-Inole-2-carboxylic acid [(1S)-1,3,3- trimethyl-bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Methoxy-l-(4-methyl-benzyl)-lH-Indol-2-carboxylic acid [( IS)- 1,3,3 -trimethyl- bicyclo[2.2. l]hept-2endo-yl]-amide;

5 ,6-Dimethoxy- 1 H-indole-2-carboxylic acid [(1R)-1,3,3 -trimethyl-bicyclo [2.2.1] hept-

2endo-yl] -amide;

4-Benzyloxy- 1 H-indole-2-carboxylic acid [(I R)- 1 ,3,3-trimethyl-bicyclo[2.2.1 ]hept-

2endo-yl]-amide; 5-(2-[l,3]Dioxan-2-yl-ethoxy)-lH-indole-2-carboxylic . acid [(lR)-l,3,3-trimethyl- bicyclo[2.2.1]hept-2endo-yl]-amide;

5-Methoxy-l-(2-morpholin-4-yl-ethyl)-lH-indole-2-carboxylic acid [(1S)-1,3,3- ^' trimethyl-bicyclo [2.2.1 ]hept-2endo-yl]-amide;

5-Methoxy-l-(2-morpholin-4-yl-ethyl)-lH-indole-2-carboxylic acid [(I S)-l,3,3- trimethyl-bicyclo[2.2. llhept^endo-yll-amide-^-toluene sulfonic acid;

Propane- 1 -sulfonic acid 2-[(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept-2endo-yl carbamoyl)] -lH-indol-5-yl ester;

5-Pentyloxy-lH-indole-2-carboxylic acid [(lR)-l,3,3-trimethyl-bicyclo[2.2.1]hept-

2endo-yl]-amide; S-Pentyloxy-lH-mdole^-carboxylic acid [(lS)-l,3,3-trimethyl-bicyclo[2.2.1]hept- 2endo-yl]-amide;

12. A pharmaceutical composition which comprises compounds of formula (I)₅ as claimed in any preceding claims and a pharmaceutically acceptable carrier, diluent or excipients.

13. A method of preventing or treating diseases caused by CB₂ cannabinoid receptors comprising administering an effective, non-toxic amount of compound of formula (I) or suitable pharmaceutical composition as defined in any preceding claims to a patient in need thereof.

14. Use of the compounds according to any preceding claims for preparing drugs for the treatment in mammalians and in men of diseases in which the CB₂ receptors are involved.

15. Use according to claim 14, wherein compounds according to any preceding claims have affinity for the CB₂ receptors.

16. Use of the compounds according to any preceding claims for preparing drugs for the treating/ameliorating conditions associated with inflammation and pain to a mammal.

17. A process for the preparing compound of formula (I) as claimed in claim 1, which comprises: converting carboxylic acid derivative of formula (III) into the amide derivative by reaction with salts of fenchylamine in presence of base to give compound of formula (II), which is further reacted with alkyl halide in presence of base to obtain compound of formula (I), wherein all symbols are as defined earlier, and optionally converting the compound of formula (I) to a compound of formula (VII), wherein all symbols are as defined earlier.

18. A process for the preparing compound of formula (I) as claimed in claim 1, which comprises: ethyl ester derivative of formula (VI) is reacting with alkyl halide in presence of base to obtain compound of formula (V) which is further reacting with salts of fenchylamine in presence of base to obtain compound of formula (I), wherein all symbols are as defined earlier.