MXPA06007199A

MXPA06007199A - Cb1 modulator compounds

Info

Publication number: MXPA06007199A
Application number: MXPA/A/2006/007199A
Authority: MX
Inventors: Lynn Smith Daryl; Rebecca Allen Jennifer; Kudzovi Amegadzie Albert; Matthew Gardinier Kevin; Stuart Gregory George; Andrew Hitchcock Steven; J Hoogestraat Paul; Dennis Jones Junior Winton
Original assignee: Rebecca Allen Jennifer; Kudzovi Amegadzie Albert; Eli Lilly And Company; Matthew Gardinier Kevin; Stuart Gregory George; Andrew Hitchcock Steven; J Hoogestraat Paul; Dennis Jones Junior Winton; Lynn Smith Daryl
Priority date: 2003-12-23
Filing date: 2006-06-22
Publication date: 2006-12-13

Abstract

Novel compounds of structural formula (I) are disclosed. As modulators of the Cannabinoid-1 (CB1) receptor, these compounds are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. As such, compounds of the present invention are useful as in the treatment, prevention and suppression of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders (e.g., multiple sclerosis, Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis), cerebral vascular accidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, and nicotine. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith.

Description

CBL MODULATING COMPOUNDS Background of the Invention Marijuana. { Cannabis sativa L) and its derivatives have been used for centuries for medicinal and recreational purposes. A major active ingredient in marijuana and hashish has been determined to be? 9-tetrahydrocannabinol (? 9-THC). The detailed search has revealed that the biological action of? 9-THC and other members of the cannabinoid family originates through two G proteins coupled to receptors called CBi and CB2. The CBi receptor is mainly found in the central and peripheral nervous system and less widespread in several peripheral organs. The CB2 receptor is mainly found in lymphoid tissues and cells. Three endogenous ligands for cannabinoid receptors derived from arachidonic acid have been identified (anandamide, 2-arachidonyl glycerol and 2-arachidonyl glycerol ether). Each is an antagonist with activities similar to? 9-THC, which includes sedation, hypothermia, intestinal immobility, antinociception, analgesia, catalepsy, anti-emesis and appetite stimulation. Excessive exposure to? 9-THC can lead to overeating, psychosis, hypothermia, memory loss and sedation. Synthetic ligands specific for cannabinoid receptors have been developed and have helped in the characterization of cannabinoid receptors: CP55, 940 (J. Pharmacol, Exp. Ther, 1988, 247, 1046-1051); WIN55212-2 (J. Pharmacol, Exp. Ther, 1993, 264, 1352-1363); SR141716A (FEBS Lett 1994, 350, 240-244; Life Sci. 1995, 56, 1941-1947); and SR144528 (J. Pharmacol. Exp. Ther. 1999, 288, 582-589). The pharmacology and therapeutic potential for cannabinoid receptor ligands has been reviewed (Exp. Opin. Ther.Patents 1998, 8, 301-313; Ann. Rep. Med. Chem., A. Doherty, Ed .; Academic Press, NY 1999 , Vol. 34, 199-208; Exp. Opin. Ther.Patents 2000, 10, 1529-1538; Trends in Pharma, Csi. 2000, 21, 218-224). There is at least one CBi modulator characterized as a reverse agonist or an antagonist, N- (1-piperidinyl) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide (SR141716A ), in clinical trials for the treatment of eating disorders. Up to now, several classes of CBi modulators are known. U.S. Patent Nos. 5,624,941 and 6,028,084, PCT Publication Nos. W098 / 43636 and W098 / 43635, and European Patent Application No. EP-658546, describe substituted pyrazoles having activity against cannabinoid receptors. PCT Publications Nos. W098 / 31227 and W098 / 41519 also describe substituted pyrazoles having activity against cannabinoid receptors. PCT publications Nos. WO98 / 37061, WO00 / 10967 and WO00 / 10968 describe diaryl ether sulfonamides having activity against cannabinoid receptors. PCT Publications Nos. WO97 / 29079 and WO99 / 02499 describe alkoxy isoindolones and alkoxy quinolones having activity against cannabinoid receptors. U.S. Patent No. 5,532,237 describes N-benzyl indole derivatives having activity against cannabinoid receptors. U.S. Patent No. 4,973,587, U.S. Patent No. 5,013,837, U.S. Patent No. 5,081,122, U.S. Patent No. 5,112,820 and U.S. Patent No. 5,292,736 disclose aminoalkylindole derivatives having activity against cannabinoid receptors. PCT Publication No. WO03 / 027076 describes IH-imidazole derivatives having CBi agonist activity, CBi partial agonist or CBi antagonist. PCT Publication No. WO03 / 026648 discloses 4,5-dihydro-1H-pyrazole derivatives having potent CBi antagonist activity. US Publication No. 2003/0114495 describes substituted imidazoles as modulators of the cannabinoid receptor. U.S. Publication No. 2003/0119810 discloses pharmaceutical compositions containing 3-aminoazetidine derivatives which possess a high affinity for CBi receptors. They were found in the CA database, [4- (2,3-dihydro-indol-1-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) -methanone RN 439128-75-3, [ 4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] -morpholin-4-yl-methanone RN394228-83-2, and [4- (2,3-dihydro-indol-1-sulfonyl) - phenyl] -piperidin-1-yl-methanone RN 394228-85-4. A need still remains for potent, low molecular weight CBl modulators that have pharmacokinetic and pharmacodynamic properties suitable for use as pharmaceuticals in humans.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention provides compounds of formula I ) - | - X Formula I wherein: is a 6,5-bicyclic ring selected from the group consisting of: Rsi is selected from the group consisting of: 5 (a) hydrogen (b) alkylcarbonyl optionally substituted with heterocyclyl, (c) heterocyclylcarbonyl optionally substituted with alkyl or acetyl (d) alkyl or haloalkyl, (e) cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, oxo, Hydroxy, alkoxy, amino, alkylamino and dialkylamino, (f) heterocyclyl selected from the group consisting of: (g) aryl optionally substituted with halo, alkyl, alkoxy, cyano, amino, alkylamino or dialkylamino, and (h) heteroaryl selected from the group consisting of: R > 2 is hydrogen, alkyl, heterocyclyl or together with R1 and the carbon to which they are attached, form a saturated ring substituent selected from the group consisting of: (a) cycloalkyl, and (b) heterocyclyl selected from the group consisting of: tetrahydrofuranyl , tetrahydropyranyl and piperidinyl optionally N-substituted with alkyl, acetyl or aryl, X is -NR13R3 or R3 is selected from the group consisting of: (a) hydrogen, (b) alkyl optionally substituted with one or two substituents independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, alkylamino and dialkylamino, ( c) cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of hydroxy, alkoxy, halo, amino, alkylamino and dialkylamino, (d) heterocyclyl selected from the group consisting of: (e) cycloalkylalkyl selected from the group consisting of: c -yRd (f) heterocyclylalkyl selected from group 25 consisting of: (g) arylalkyl selected from the group consisting of: (h) heteroaryl selected from the group consisting of I am a heterocyclic ring selected from the R 4 is hydrogen, phenyl, halophenyl, acyl or alkoxycarbonyl; R5 is hydrogen, hydroxy or alkoxy; Each of R6 and R7 is independently selected from hydrogen, halo, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, dialkylaminocarbonyl, aryl, and aryloxy; R8 is hydrogen, hydroxyalkyl, acyl, oxo, aryl, pyridinyl, alkyl-S02-0-, Rb-NH-CH2-, arialkyl or Rc2N-CO-0; R9 is hydrogen, hydroxy, hydroxyalkyl, acyl, halo, dihalo, oxo, aryl, haloarylalkyl, pyridinyl, alkyl-S02-0-, Ra-NH-, Rb-NH-CH2-, arylalkyl, or Rc2N-CO-0-; R10 is hydrogen, alkyl, alkoxycarbonyl, aryl or haloaryl; R11 is hydrogen, alkyl or aryl; R12 is hydrogen or aryl; R13 is hydrogen or alkyl; R 14 is hydrogen, alkyl, aryl or acyl; Ra is hydrogen, alkoxycarbonyl or halophenyl; R b is hydrogen, alkoxy, phenyl, halophenyl, halophenyl, halopyridinyl, pyrimidinyl, alkoxycarbonyl, dialkylaminocarbonyl or dialkylaminothiocarbonyl; and Rc is hydrogen or alkyl; and all salts, solvates, optical and geometric isomers, and crystalline forms thereof with the proviso that the compound of formula (I) is different from [4- (2,3-dihydro-indol-1-sulfonyl) -phenyl) ] - (4-phenyl-piperazin-1-yl) -methanone, [4- (2,3-dihydro-indol-1-sulfonyl) -phenyl] -morpholin-4-yl-methanone and [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] -piperidin-1-yl-methanone.

In a preferred embodiment, ^ ~ - ^ Y is a ring 6, 5-bicyclic selected from the group consisting of: R1 is selected from the group consisting of: (a) hydrogen, (b) alkylcarbonyl optionally substituted with heterocyclyl, (c) heterocyclylcarbonyl optionally substituted with alkyl or acetyl, (d) methyl, propyl, t-butyl or trifluoromethyl, (e) cycloalkyl optionally substituted with oxo, hydroxy, methoxy, difluoro or methyl, (f) heterocyclyl selected from the group consisting of: (g) phenyl optionally substituted with halo, methyl, methoxy, cyano or dimethylamino, and (h) heteroaryl selected from the group consisting of: R2 is H, methyl, ethyl or together with R1 and the carbon to which they are attached, form a saturated ring substituent selected from the group consisting of: (a) cycloalkyl, and (b) heterocyclyl selected from the group consisting of: tetrahydropyranyl and N-methylpiperidin-4-yl; R3 is selected from the group consisting of: (a) hydrogen, (b) alkyl (C? -C2) optionally substituted with (C? -C2) alkoxy, (c) (C4-C6) cycloalkyl optionally substituted with one or two substituents independently selected from hydroxy, methoxy, amino, alkylamino and dialkylamino, (d) heterocyclyl selected from the group consisting of: (e) cycloalkylalkyl selected from the group consisting of: (f) heterocyclylalkyl selected from the group consisting of: (g) arylalkyl which is; and (h) heteroarylalkyl selected from the group consisting of: YO ^ - ^ is a heterocyclic ring selected from the group consisting of R 4 is hydrogen, phenyl, fluorophenyl, t-butyloxycarbonyl or methoxycarbonyl; R5 is hydrogen, hydroxy or methoxy; each of R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, fluoro, chloro, trifluoromethyl, cyano, methoxy, amino, monomethylamino, dimethylamino, methoxycarbonyl and dimethylaminocarbonyl; R8 is hydrogen, hydroxyalkyl, acyl, oxo, aryl, pyridinyl, alkyl-S02-0, R-NH-CH2-, arylalkyl or (CH3) 2N-CO-0-; R9 is hydrogen, hydroxy, hydroxymethyl, acetyl, fluoro, difluoro, oxo, phenyl, benzyl, pyridinyl, CH3-S02-0-, Ra-NH-, RD-NH-CH2-, or (CH3) 2N-CO-0; R10 is hydrogen or alkyl; R11 is hydrogen or alkyl; R 12 is hydrogen or phenyl; R13 is hydrogen or methyl; R14 is hydrogen, methyl, phenyl or acetyl; Ra is hydrogen, methoxycarbonyl, t-butyloxycarbonyl or fluorophenyl; and Rb is hydrogen, methoxy, phenyl, phenylalkyl, fluorophenylalkyl, fluorophenyl, pyridinyl, fluoropyridinyl, pyrimidinyl, methoxycarbonyl, t-butyloxycarbonyl, dimethylaminocarbonyl or dimethylaminothiocarbonyl.

In another preferred embodiment, GA is selected of the group consisting of: In another preferred embodiment, GA is In another preferred embodiment, GA is In another preferred embodiment, R ,? is aryl optionally substituted with halo, alkyl, alkoxy, cyano, amino, alkylamino or dialkylamino. More preferably, R1 is phenyl. In another preferred embodiment, R1 is cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, oxo, hydroxy alkoxy, amino, alkylamino and dialkylamino. More preferably, R1 is cyclopentyl. In another preferred embodiment, R1 is heterocyclyl selected from the group consisting of Xx K.}. * K > ^ -N S More preferably, R1 is tetrahydropyran-4-yl. In another preferred embodiment, R3 is heterocyclylalkyl selected from the group consisting of: More preferably, R is In another embodiment, R3 is heterocyclyl selected from the group consisting of: Y . More preferably, R3 is In another preferred embodiment, R3 is cycloalkylalkyl selected from the group consisting of: preferably, R 3 is ^ In another preferred embodiment, R3 is alkyl optionally substituted with one of two substituents independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, alkylamino and dialkylamino. More preferably, R3 is YA In another preferred embodiment, R3 is arylalkyl selected from the group consisting of: y In another preferred embodiment, R3 is heteroarylalkyl selected from the group consisting of: Y . More preferably In another embodiment, the present invention provides a compound of formula I O + C Formula I where: G YYA is a 6, 5-bicyclic ring selected from the group consisting of: R1 is selected from the group consisting of: (a) hydrogen, (b) alkylcarbonyl optionally substituted with heterocyclyl, (c) heterocyclylcarbonyl optionally substituted with alkyl or acetyl, (d) alkyl or haloalkyl, 5 (e) cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino and dialkylamino, (f) heterocyclyl selected from the group consisting of: (g) aryl optionally substituted with halo, alkyl, alkoxy, cyano, amino, alkylamino or dialkylamino, and (h) heteroaryl selected from the group consisting of: R 2 is hydrogen, alkyl, heterocyclyl or, together with R 1 and the carbon to which they are attached, form a substituted saturated ring selected from the group consisting of: (a) cycloalkyl, and (b) heterocyclyl selected from the group consisting of: tetrahydrofuranyl, tetrahydropyranyl and piperidinyl optionally N-substituted with alkyl, acetyl or aryl, X- is NR13R3 or R1) R3 is selected from the group consisting of: (a) hydrogen, (b) alkyl optionally substituted with one or two substituents independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, alkylamino and dialkylamino, (c) cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of hydroxy, alkoxy, halo, amino, alkylamino and dialkylamino, ( d) heterocyclyl selected from the group consisting of: j 5 10 ÍJ ° K_ > (e) cycloalkylalkyl selected from the group consisting of: (f) heterocyclylalkyl selected from the group consisting of: and (g) aralkyl selected from the group consisting of () heteroaryl selected from the group consisting of KJ is a heterocyclic ring selected from the group consisting of: R 4 is hydrogen, phenyl, halophenyl, acyl or alkoxycarbonyl; R5 is hydrogen, hydroxy or alkoxy; each of R6 and R7 is independently selected from hydrogen, halo, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, dialkylaminocarbonyl, aryl and aryloxy; R8 is hydrogen, hydroxyalkyl, acyl, oxo, aryl, pyridinyl, alkyl-S02-0-, Rb-NH-CH2-, arylalkyl or Rc2N-CO-0-; R9 is hydrogen, hydroxy, hydroxyalkyl, acyl, halo, dihalo, oxo, aryl, haloaryl-CH2-, pyridinyl, alkyl-S02-0-, Ra-NH-, Rb-NH-CH2-, arylalkyl, R10 is hydrogen, alkyl, alkoxycarbonyl, aryl or haloaryl; R11 is hydrogen, alkyl or aryl; R12 is hydrogen or aryl; R13 is hydrogen or alkyl; R 14 is hydrogen, alkyl, aryl or acyl; R is hydrogen, alkoxycarbonyl or halophenyl; Rb is hydrogen, alkoxy, phenyl, halophenyl, halophenylalkyl, halopyridinyl, pyrimidinyl, alkoxycarbonyl, dialkylaminocarbonyl or dialkylaminthiocarbonyl and Rc is hydrogen or alkyl; and all optical or geometric isomers, and crystalline forms thereof and with the proviso that the compound of formula (I) is different from [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] - ( 4-phenyl-piperazin-1-yl) methanone, [4- (2, 3-dihydro-indol-1-sulfonyl) -phenyl] -morpholin-4-yl-methanone and [4- (2,3-dihydro- indole-l-sulfonyl) -phenyl] -piperidin-1-yl-methanone. In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula I in an amount effective to antagonize the stimulation of the CB-1 receptor, and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula I, [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) -methanone. , [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] -morpholin-4-yl-methanone or [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] -piperidine -1-yl-methanone in an amount effective to antagonize the stimulation of the CB-1 receptor, and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula I, [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) -methanone. [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] -morpholin-4-yl-methanone, [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] -piperidine] -1-yl-methanone or [4- (3-fluoro-phenyl) -piperidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone in an amount effective to reduce the endocannabinoid neurotransmission through CB-1 receptors, and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula I, [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) -methanone. [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] -morpholin-4-yl-methanone, [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] -piperidine] -1-yl-methanone or [4- (3-fluoro-phenyl) -piperidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone and a carrier, diluent or pharmaceutically acceptable excipient. In another aspect, the present invention provides a method for treating a condition which is treatable by reducing stimulation of the CB-1 receptor, which comprises administering to a mammal in need therefor, a compound of Formula I or a pharmaceutical composition comprising a composition of Formula I in an amount effective to antagonize stimulation of the CB-1 receptor, or to reduce endocannabinoid neurotransmission and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, the present invention provides a method for treating a condition which is treatable by reducing the stimulation of the CB-1 receptor, which comprises administering to a mammal in need therefor, a compound selected from the group consisting of a compound of Formula I, [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) methanone, [4- (2,3-dihydro-indol-l-sulfonyl] ) -phenyl] -morpholin-4-yl-methanone, [4- (2, 3-dihydro-indol-1-sulfonyl) -phenyl] -piperidin-1-yl-methanone and [4- (3-fluoro-phenyl)] ) -piperidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone. In another aspect, the present invention provides a method for treating a condition which is treatable by reducing stimulation of the CB-1 receptor, which comprises administering to a mammal in need therefor, a pharmaceutical composition comprising a compound selected from the group consisting of of a compound of Formula I, [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) methanone, [4- (2,3-dihydro- indole-l-sulfonyl) -phenyl] -morpholin-4-yl-methanone, [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] -piperidin-1-yl-methanone and [4- ( 3-fluoro-phenyl) -piperidin-1-yl] - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone in an amount effective to antagonize the stimulation of the CB-1 receptor, or to reduce the endocannabinoid neurotransmission and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, the present invention provides a compound of Formula I, [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) -methanone, [4- (2,3-dihydro-indol-1-sulfonyl) -phenyl] -morpholin-4-yl-methanone, [4- (2,3-dihydro-indol-1-sulfonyl) -phenyl] -piperidin-1-yl -metanone or [4- (3-fluoro-phenyl) -piperidin-1-yl] - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone for use in therapy. In another aspect, the present invention provides the use of a compound of Formula I for the manufacture of a medicament for treating a condition which is treatable by reducing stimulation of the CB-1 receptor. In another aspect, the present invention provides the use of a compound of Formula I, [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) -methanone, [4- (2, 3-dihydro-indol-1-sulfonyl) -phenyl] -morpholin-4-yl-methanone, [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] -piperidine- 1-yl-methanone or [4- (3-fluoro-phenyl) -piperidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone for the manufacture of a medicament for treat a condition which is treatable by reducing the stimulation of the CB-1 receptor. In another aspect, the present invention provides a method for treating a condition selected from the group consisting of psychosis, memory deficit, cognitive disorder, migraine, neuropathy, neuroinflammatory disorder, stroke, head trauma, anxiety disorder, stress , depression, epilepsy, Parkinson's disease, schizophrenia, substance abuse disorder, obesity and an eating disorder associated with an excessive food intake comprising administering to the mammal in need thereof a compound of Formula I, [4- (2, 3- dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) methanone, [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] -morpholin-4-yl -metanone, [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] -piperidin-1-yl-methanone or [4- (3-fluoro-phenyl) -piperidin-1-yl] - [ 4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone. More preferably, the condition of obesity. In a preferred embodiment, the condition which is treatable by reducing stimulation of the CB-1 receptor is psychosis, memory deficit, cognitive disorder, migraine, neuropathy, neuroinflammatory disorder, stroke, head trauma, anxiety disorder, stress , depression, epilepsy, Parkinson's disease, schizophrenia, substance abuse disorder, obesity or eating disorder associated with excessive food intake. More preferably, the condition is obesity. In another preferred embodiment, the mammal to be treated is a human. In another aspect, the invention provides compounds of formula (lia) wherein: Y is halogen, cyclopent-1-enyl or cyclopentyl and R17 is alkyl. It will be appreciated that all combinations of the aspects and embodiments discussed above and the examples discussed below are contemplated to be encompassed by the present invention. In addition, all of the examples described in this document are for illustrative purposes, and are not intended to limit the scope of the invention in any way.

Detailed Description of the Invention As used above, and through the description of the invention, the following terms, unless otherwise indicated, will be understood to have the following meanings: "Acyl" means an alkylcarbonyl (i.e. alkyl-CO-, wherein the alkyl group is as described herein) or heterocyclylcarbonyl (ie, heterocyclyl-CO-, wherein heterocyclyl is as described herein). Preferred acyls contain a lower alkyl (eg, acetyl). "Alkoxy" means an alkyl-O- group, wherein the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, I-propoxy and n-butoxy. "Alkoxycarbonyl" means an alkyl-O-CO- group, wherein the alkyl group is as defined herein. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl or t-butyloxycarbonyl. "Alkyl" means a saturated aliphatic hydrocarbon group, which may be linear or branched, having 1 to 6 carbon atoms in the chain. Preferred alkyl groups have 1 to 4 carbon atoms in the chain. For example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. "Alkylamino" means an alkyl-NH group, wherein the alkyl group is as described herein. "Alkylcarbonyl" means an alkyl-CO- group, wherein the alkyl group is as described herein. "Alkylthio" means an alkyl-S- group, wherein the alkyl group is as described herein. Exemplary alkylthio groups include methylthio, ethylthio, I-propylthio and n-butylthio. "Aryl" means a mono- or bi-cyclic aromatic ring system of 6 to about 10 carbon atoms. Exemplary aryl groups include phenyl and 1- and 2-naphthyl. "Arylalkyl" means an aryl-alkyl group, wherein the aryl and alkyl groups are as defined herein. "Aryloxy" means an aryl-O- group, wherein the aryl group is as defined herein. Exemplary groups include phenoxy and naphthyloxy. "Aryloxycarbonyl" means an aryl-O-C (O) group, wherein the aryl group is as defined herein. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. "Arylthio" means an aryl-S- group, wherein the aryl group is as described herein. Exemplary arylthio groups include phenylthio or naphthylthio. "Carboxy" means a group HO (0) C- (ie, carboxylic acid). "Cycloalkyl" means a fully saturated mono-carbocyclic ring system of about 3 to about 6 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "Cycloalkylalkyl" means a cycloalkyl-alkyl group, wherein the cycloalkyl group and the alkyl group are as defined herein. "Dialkylamino" means a group (alkyl) 2-N-, wherein the alkyl group is as defined herein. It will be understood that the two alkyl groups may be the same or different.

"Dialkylaminocarbonyl" means a group (alkyl) 2-N-C (0) -, wherein the alkyl group is as defined herein. It will be understood that the two alkyl groups may be the same or different. "Dialkylaminothiocarbonyl" means a dialkylamino-C (S) - group, wherein the dialkylamino group is as defined herein. It will be understood that the two alkyl groups may be the same or different. "Effective amount" means an amount of a compound / composition in accordance with the present invention, effective in producing the desired therapeutic effect. "Halo" means, fluorine, chlorine, bromine or iodine, a preferred halo is fluoro. "Haloalkyl" refers to an alkyl group, as described herein, which is substituted with one to six halo groups, as described herein.

Preferred haloalkyls include fluoroalkyls, such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1, 2, 2, 2-pentafluoroethyl, 3-fluoropropyl, 3,3,3-trifluoropropyl and , 1,1,3,3,3-hexafluoroprop-2-yl. "Haloalkoxy" refers to an alkoxy group, as described herein, which is substituted with one to six halo groups, as described herein. Preferred haloalkoxy groups include fluoroalkyls, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy. "Haloaryl" refers to an aryl group, as described herein, which is substituted by halogen, as described herein. "Haloarylalkyl" refers to an alkyl group, as described herein, which is substituted by a haloaryl group, as described herein. "Halophenyl" refers to a phenyl group, which is substituted by halogen, as described herein. "Halophenylalkyl" refers to an alkyl group, as described herein, which is substituted by a halophenyl group, as described herein. "Halopyridinyl" refers to a pyridinyl group, which is substituted by a halogen group, as described herein. "Heteroaroyl" means a heteroaryl-CO- group, wherein the heteroaryl group is as described herein. Exemplary groups include thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, 1- and 2-naphthoyl and pyridinoyl. "Heteroaryl" means a fully saturated, monocyclic or bicyclic ring system of about 5 to 10 ring atoms, in which one or two ring atoms is a hetero element (s) other than carbon (eg, nitrogen, oxygen or sulfur) and the rest of the ring atoms are carbon. Preferred ring sizes include 5 to 6 ring atoms. Exemplary heteroaryl groups include pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl and isoquinolinyl. "Heteroarylalkyl" means heteroaryl-alkyl, wherein the heteroaryl group is as described herein. "Heterocyclyl" means a fully saturated, monocyclic ring system of about 3 to about 7 ring atoms, in which one or two of the ring atoms is a hetero element (s) other than carbon (e.g., nitrogen, oxygen) or sulfur) and the rest of the ring atoms are carbon. Heterocyclyl groups can optionally be substituted, for example with alkyl, hydroxy, alkoxy, aryl, acyl in particular methyl, phenyl, halophenyl, alkoxycarbonyl. Exemplary heterocyclic rings, for example, include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, and thiomorpholinyl. "Heterocyclylalkyl" means heterocyclyl-alkyl, wherein the heterocyclyl group is as described herein. "Hydrate" means a solvate, as defined herein, wherein the molecule (s) of the solvent is / are H20. "Hydroxyalkyl" means an HO-alkyl group, wherein the alkyl group is as described herein. "Obesity" refers to a condition wherein a mammal has a Body Mass Index (BMI), which is calculated as weight per height squared (Kg / m2), of at least 25.9. Conventionally, those with normal weight have a BMI of 19.9 or less than 25.9. "Phenylalkyl" refers to an alkyl group, as described herein, which is substituted by a phenyl group. The term "Salt (s)" refers to a pharmaceutically acceptable salt, as defined herein. "Pharmaceutically acceptable salts" refers to the relatively non-toxic organic and inorganic acid addition salt and base addition salts of the compound of the present invention. These salts can be prepared in situ during the isolation and final purification of the compounds. In particular, the acid addition salts can be prepared separately by reacting the purified compound in its free form with a suitable organic or inorganic acid and isolating the salt thus formed. Exemplary acid addition salts include the salts of hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulphamates, malonates, salicylates, propionates, methylene-bis-β-hydroxynaphthates, gentisatos, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and quinateslauryl sulphonates and the like. See, for example, S.M. Berger, et al., "Pharmaceuticals Salts," J. Pharm. Sci., 66, 1-19 (1977), which is incorporated herein by reference. It is also possible to prepare base addition salts separately, by reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed. The base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium and aluminum salts. Sodium and potassium salts are preferred. Suitable inorganic basic addition salts of metal bases were prepared which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide. Suitable amine base addition salts of amines were prepared which have sufficient basicity to form a suitable salt, and preferably include those amines which are frequently used in medicinal chemistry due to their low toxicity and acceptability for medical use, for example, ammonia, ethylenediamine, N-methyl-glycine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, efenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, for example, lysine and arginine and dicyclohexylamine and the like. "Prevention" (of obesity) refers to preventing obesity from occurring, if the treatment is administered before the attack of the obese condition. However, if the treatment is started in already obese subjects, such treatment is expected to prevent, or prevent the progress of, the medical sequel of obesity, such as, for example, arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases. , osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia and cholelithiasis. "Solvate" means a physical association of a compound of this invention with one or more molecules of the solvent. This physical association includes hydrogen bonds. In certain examples, the solvate will be capable of isolation, for example when one or more molecules of the solvent are incorporated into the crystal lattice structure of the crystalline solid. "Solvate" covers solvates of both solution phase and capable of being isolated. Exemplary solvates include hydrates, ethanolates, methanolates and the like. "Substance abuse disorders" includes dependence or substance abuse with or without physiological dependence. The substances associated with these disorders are: alcohol, amphetamines (or substances similar to amphetamines), caffeine, cannabis, ***e, hallucinogens, inhalants, nicotine, opioids, phencyclidine (or compounds similar to phencyclidine), sedative hypnotics or benzodiazepines and other substances ( unknown) and combinations of all the above. In particular, the term "substance abuse disorders" includes abstinence from drugs such as abstinence from alcohol with or without perceptual alterations; delirium of abstinence to alcohol; abstinence to amphetamine; abstinence from ***e; abstinence to nicotine; abstinence to opioids; abstinence to sedatives, hypnotics or anxiolytic with or without perceptual alterations; delirium of abstinence to sedatives, hypnotics or anxiolytics; and withdrawal symptoms due to other substances. It will be appreciated that the reference to nicotine withdrawal treatment includes the treatment of symptoms associated with quitting smoking. Other "substance abuse disorders" include anxiety disorders induced by substances with attack during abstinence; mood disorder induced by substances with attack during abstinence; and sleep disorder induced by substances with attack during abstinence. "Therapeutically effective amount" means the compound of structural formula I that will awaken the biological or medical response of a tissue, system, animal or human that is sought by the researcher, veterinarian, medical doctor and other physician. "Treatment" or "treating" (of obesity) refers to reducing the BMI of the mammal and in certain cases where it is desirable for weight loss. Treating or treating properly results in a reduction in food or calorie intake by the mammal.

The symbol "" or "~" in a molecular structure indicates the position of the junction for the particular substituent. When any variable (for example, R1, Rd, etc.) originates more than once in any constituent or in formula I, its definition in each event is independent of its definition to another event. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In the selection of compounds of the present invention, one of ordinary skill in the art will recognize that several substituents, ie R1, R2, etc., are selected in accordance with the well-known principles of chemical structure connectivity. Under the standard nomenclature used throughout this description, the terminal portion of the designated side chain is first described, followed by functionality adjacent to the point of attachment. For example, an arylcarbonylaminoalkyl substituent is equivalent to aryl-C (O) -NH-alkyl-. Compounds of Formula I may contain one or more centers and may thus originate as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention means that it comprises all isomeric forms of the compounds of Formula I. Some of the compounds described herein may exist with different points of hydrogen bonds, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. Individual tautomers as well as mixtures thereof are encompassed by the compounds of Formula I. Compounds of Formula I can be separated into diastereomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or acetate of ethyl or a mixture thereof. The pair of enantiomers thus obtained by being separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or a chiral CLAR column. Alternatively, any enantiomer of a compound of the general Formula I can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configurations. It is generally preferable to administer compounds of the present invention as enantiomerically pure formulations. The racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. This chiral chromatography includes derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization or diastereomeric salts. The present invention also provides novel crystalline forms of the compounds of formula (I). New crystalline forms can be prepared by crystallization under controlled conditions. The crystallization of a solution and suspension techniques are contemplated to be within the scope of the present process. In practice, a number of factors can influence the shape obtained which includes temperatures, solvent composition and also optional seeded. Seed crystals can be obtained from the previous synthesis of the compound in which the crystals were isolated. A variety of methods are available to characterize crystalline forms of organic compounds. For example, methods include differential scanning calorimetry, solid-state NMR spectrometry, infrared spectroscopy and X-ray powder diffraction. Among these, X-ray powder diffraction and solid-state NMR spectroscopy are very useful for identifying and distinguish between crystalline forms. It will be understood that, as used herein, references to compounds of Formula I also mean that they include pharmaceutically acceptable salts. The compounds of this invention are modulators of CBl receptors and as such are used for the prevention and treatment of disorders or diseases associated with the CBl receptor. Of course, another aspect of the present invention provides a method for the treatment (including prevention, alleviation, amelioration or suppression) of diseases or disorders or symptoms mediated by the binding CBl receptor and subsequently cellular activation, which comprises administering to a mammal an effective amount of a compound of Formula I. Such diseases, disorders, conditions or symptoms are, for example, but not limited to psychosis, memory deficits, cognitive disorders, migraine, neuropathy, anxiety disorders, depression, stress , epilepsy, Parkinson's disease, schizophrenia, substance use disorders, particularly opiates, alcohol and nicotine, obesity and eating disorders with excessive food intake. See DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders. Revised, 4th ed. Text Review (2000). See also DSM-IV, Diagnostic and Statistical Manual of Mental Disorders 4th Ed., (1994). The DSM-IV and DSM-IV-TR were prepared by the Command Force in the Nomenclature and Statistics of the American Psychiatric Association, and descriptions of diagnostic categories are provided. The expert technician will recognize that they are alternative nomenclatures, nosologies and classification systems for pathological psychological conditions and that these systems are involved with medical scientific processes. Obesity in this document may be due to any cause, genetic or environmental. Examples of disorders that can result in obesity or cause obesity include overfeeding and bulimia, polycystic ovary disorder, craniopharyngioma, Prader-Willi syndrome, Frohlinch syndrome, type II diabetes, deficient GH subjects, short stature normal variant, Turner syndrome and other pathological conditions that show reduced metabolic activity or a decrease in the remaining energy issued as a percentage of total fat-free mass, for example, in children with acute lymphoblastic leukemia. In addition, the compound of formula (I) can be used to improve weight gain, whether or not the associated weight gain is clinically classified as obese. The method of treatment of this invention comprises a method for modulating the CB1 receptor and treating the CB1 receptor mediated by the disease, by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the CB1 receptor. CB1 receptor in preference to other CB receptors or coupled to protein G. "Neutral antagonists" are ligands without intrinsic activity, that is, they do not influence the activity of the receptor itself (constitutive receptor activity) and completely prevent the binding of an agonist ( often endogenous) to the recipient. "Inverse antagonists" are ligands with intrinsic negative activity, inhibit the activity of the receptor itself (constitutive receptor activity) changes the balance of the conformation of the receptor to its inactive state. There is evidence to suggest that the CBl receptor ligands act as either neutral antagonists or inverse agonists; these ligands will reduce endocannabinoid neurotransmission through CB1 receptors by competitive receptor antagonism or receptor inactivation, respectively. Compounds of the formula la (ie, compounds of Formula I wherein they can be prepared in accordance with the process illustrated in Reaction Scheme I.

Reaction Scheme I In Reaction Scheme I, step a involves the introduction of the substitution R1 at position 3 in the indole portion of compound (I), (Ha) or (He) (where Y is I, Br, B ( OH) 2, or SnMe3) under standard conditions used for palladium-mediated cross coupling reactions. For example, a 3-haloindole of formula (I), (Ha) or (He) is reacted with a suitable aryl boronic acid (Suzuki type) or with a suitable aryl stannane (Stille type) generally described in Handbook of Palladium Catalyzed Organic Reactions, Malleron, JL .; Fiaud, J.-C-; Legros, J.-Y .; Academic Press, USA 1997, p.23-47. It will be understood by one skilled in the art that, in general, an aryl boronic ester can be used in place of an aryl boronic acid in the palladium cross-reactions described herein. By way of illustration, aryl boronic acids include, but are not limited to, the following: More specifically, compounds (I), (Ha) or (He) and the appropriate aryl boronic acid or the appropriate aryl boronic ester, together with a base (eg, aqueous sodium carbonate) and a catalyst (eg, complex [ 1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II)) were dissolved in a suitable solvent such as dichloromethane, and the mixture was heated. Aqueous recovery and chromatographic purification afforded the desired compound (2), (Hb) or (la). More specifically, in the Stille reaction, a compound of 3-iodoindole (I), (Ha), or (He) was combined with an aryl stannane (for example, 2-tributylstannyl pyrazine, 3-tributylstanilpyridine, 2-tributylstanilpyridine ) and a catalyst (e.g., tetrakis (triphenylphosphine) Pd (0)) in an appropriate solvent (e.g., DMF) and heated. After the aqueous was recovered, the compound (2), (la) or (Ib) was isolated by chromatographic purification. Alternatively, a 3-haloindole (I), (Ha) or (He) compound was subjected to a palladium-mediated coupling with an olefin (eg, cyclopentene) or an α, β-unsaturated ketone or ester (Heck type). ), then the resulting intermediate was hydrogenated to provide the desired compound (2), (Hb), or (la). (see generally Handbook of Palate Catalyzed Organic Reactions, Malleron, J, -L,; Fiaud, J.-C; Legros, J, -Y,; Academic Press, USA 1997 p.61-71). More specifically, a 3-iodoindole compound (I), (Ha) or (He) is combined with an olefin and a catalyst (e.g., palladium (II) acetate) together with tetrabutylamino chloride and a base (e.g., potassium acetate) and the resulting hot mixture. After the aqueous was recovered, the intermediate product was isolated by chromatographic purification, then subjected to hydrogenation to remove the resulting olefin, thereby providing the desired compound (2), (a) or (Hb). Alternatively, a 3-haloindole compound (I), (Ha) or (He) was subjected to a metal halogen exchange with a reagent such as cyclopentyl magnesium bromide and then treated with a ketone such as tetrahydro-4H-pyran-4-one. The resulting alcohol was isolated and treated with a reducing agent (e.g., triethylsilane and TFA) to provide the desired compound (2), (a), or (Hb). Alternatively, a compound (I), (Ha) or (He) when Y is B (OH) 2, or SnMe3 is reacted via palladium mediated coupling using a suitable aryl halide in a manner analogous to the procedure shown above. By way of illustration, suitable aryl halides include, but are not limited to, 5-bromo-2-methoxy pyridine, 5-bromo-2-fluoro-pyridine, 2-bromo-5-chloro-thiophene, 4-bromo- isoquinoline, 2-bromo-5-chloro-thiophene, 3-bromo-toluene, 4-bromo-toluene, l-bromo-3-methoxy-phenyl, 6-bromo-quinoline, l-bromo-4-dimethylamino-phenyl, l-bromo-3-fluoro-pyridine, 2-bromo-pyridine and 5-bromo-pyridine. In the reaction scheme 1, step b, a sulfonamide of formula (Ia), (Ha), (Hb) or (He) is prepared via the treatment of the appropriate indole of the formula (I) or (2) with the sulfonyl chloride requirement of formula ( 3) or (4) in the presence of a base under standard conditions. More specifically, the indole of formula (1) or (2) and the sulfonyl chloride of formula (3) or (4) are combined with a base (eg, diisopropylethylamine, potassium terbutoxide or sodium hydride) in a solvent suitable (for example, N, N-dimethylformamide, dioxane or tetrahydrofuran). Alternatively, the indole of formula (1) or (2) and sulfonyl chloride of the formula (3) or (4) were combined with a catalyst (for example DMAP or 4-pyrrolidinyl-1-yl-pyridine) with or without a base in an appropriate solvent (for example, N, N-dimethylformamide, dioxane or acetonitrile). Aqueous recovery and chromatographic purification afforded compound (la), (Ha), (Hb) or (He). In reaction scheme I, step c, the conversion of an ester of formula (Hb) to an amide of formula (la) was achieved under standard conditions via the carboxylic acid or acid chloride, referenced in Comprehensive Organic Transformations, RC, Larock VCH Publishers Inc., New York 1989. p. 972-976. More specifically, the ester of formula (Hb) is hydrolyzed to the acid in the presence of a base (e.g., sodium hydroxide), converted to the acid chloride with reactants such as oxalyl chloride, and then treated with the amine requirement in the presence of a base (e.g., triethylamine) to form the compound (la). Alternatively, the acid is coupled to the amine using a coupling reagent (e.g., EDC, BOP or PyBOP) with or without a catalyst (e.g., NHS). After an aqueous recovery, the products were isolated by chromatographic purification to provide the compound (the) . The compounds of formula (la) can also be prepared in accordance with the processes illustrated in Reaction Scheme 2.

Reaction Scheme 2 In Reaction Scheme 2, step a, direct alkylation of a compound (5), (lid) or (He) is achieved via heating with a ketone (eg, cyclohexanone or 2-methylcyclohexanone) and a base (e.g. , potassium hydroxide). The resulting olefin is hydrogenated to form a compound of formula (2), (Hb) or (la) (see for example, J. Med. Chem. (1997), 40, 250). Alternatively, the direct alkylation of a compound of formula (5), (Hd), (He) is achieved under conditions of protic acid or Lewis with an alcohol (for example, tert-butyl alcohol) or alkyl bromide (per example, as described in J. Org. Chem. (2002), 67, 2705). Alternatively, the addition of the conjugate to an OI, β-unsaturated ketone is achieved in the presence of indium tribromide and isopropylamine in solvents such as dichloromethane, as described in J. Org, Chem (2002), 67, 3700 for form a compound (2), (Hb) or (la). Steps b and c in Reaction Scheme 2 are accomplished as described in steps b and c of Reaction Scheme 1, respectively. It will be noted that when R1 is , stage a of the Scheme of Reaction 1 and 2 must be modified as shown in the Reaction scheme 3.

Reaction Scheme 3 In reaction scheme 3, step a, the indole compound (2a) was prepared by reacting with 3-amino via a palladium-mediated coupling of an amine with a 3-haloindole of formula (6) bearing a protecting group or nitrogen ( as described for example in Organic Lett. (2002), 4, 2885), followed by removal of the N-protected group. More specifically, N-protected from 3-bromoindole with a triisopropylsilanyl group was combined with an amine (for example, piperidine, morpholine or 1-methyl piperazine), a catalyst (for example, adduct of tris (dibenzylidene ketone) palladium (0) chloroform and 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl), and a base (e.g., lithium bis (trimethylsilyl) amine), and the mixture heated in an appropriate solvent (e.g., THF). The resulting intermediate was deprotected with terbutyl ammonium fluoride, after which an aqueous recovery and chromatographic purification afforded an isolated compound (2a). The compounds of formula Ib (for example, where O- is CA R1 C R'1 OAR-1 CAR1 '0- can be synthesized by methods known in the art, as illustrated in Reaction Scheme 4.

Reaction Scheme 4 In Reaction scheme 4, step a involves reducing the indole compound (2) to the corresponding indole compound (7) using standard conditions such as sodium borohydride or sodium cyanoborohydride, and as described in Yamamoto, Y et. a., Bull Chem. Soc. Jpn., 44, 1971, 541-545. Step b involves reacting the indole compound (7) with the appropriate sulfonyl chloride compound (4) or (3) under standard conditions described above in Reaction Scheme 1 or 2. Alternatively, the indole compound ( 2) was coupled to the sulfonyl chloride according to Reaction Scheme 1, 2 or 3, followed by the reduction in accordance with step a, to give (Ib). Alternatively, the compound (Ia) can be prepared by a general method found in Reaction Schemes 1, 2 or 3. In general, when R1 is aryl, step a is completed with the first step. When R1 is alkyl or cycloalkyl, step b is completed with the first step. The compounds, wherein R1 and R2 are taken together to form a ring, are synthesized by methods known in the art. The examples shown in this document represent typical syntheses of the compounds of the present invention. Reagents and starting materials are readily available to one of ordinary skill in the art.

Preparation 1 3- (6-Methoxy-cyclohex-l-enyl) -IH-indole ml of dry MeOH was added to a N2 flask containing indole (1 g, 8.5 mmol, 8.5 eq) and potassium hydroxide. (202 mg, 3.59 mmol, 1 eq). To this solution was added 2-methoxy-cyclohexane (834 mg, 6.5 mmol, 6.5 eq). The reaction was heated at 63 ° C for 18 hours. The reaction was cooled and the crude material was purified by silica gel chromatography to give 442 mg (30% yield) of 3- (6-Methoxy-cyclohex-1-enyl) -IH-indole as a yellow waxy solid. Mass Spectrum (m / e): 228.02 (MH +).

Preparation 3- (2-Methoxy-cyclohexyl) -lH-indole 3- (6-methoxy-cyclohex-l-enyl) -IH-indole (200 mg, .879 mmol) was treated with 10% Pd / C (400 mg) in EtOAc under atmospheric hydrogenation conditions for 1.5 hours. The resulting solution was filtered over Celite to remove the catalyst. The crude was concentrated on a rotoevaporator and purified on silica gel chromatography to give 3- (2-methoxy-cyclohexyl) -lH-indole (127 mg, 63% yield). Mass Spectrum (m / e); 230.03 (MH +), 228.14 (M-) Preparation 3 3- (lH-Indol-3-yl) -cyclopentanone The reaction was conducted according to the procedure according to the literature (JOC, vol 67, 2002, p 3700-3704) to give final 3- (lH-indol-3-yl) -cyclopentanone (1.38 g, 81% performance) as a light pink solid. Mass Spectrum (m / e): 199.99 (MH +).

Preparation 10 N- [2-Phenyl-et- (Z) -ylidene] -N '-pyridin-4-yl-hydrazine 4-Hydrazinopyridine HCl was reacted with phenylacetaldehyde under conditions in accordance with the literature (J Chem Soc, 1959, p 3830). Instead of NH3, it was neutralized with IN of NaOH and extracted with CHC13. The organics were dried over MgSO4 and concentrated in a rotoevaporator to give N- [2-Phenyl-et- (Z) -ylidene] -N'-pyridin-4-yl-hydrazine (7.3 g, approx. Crude thick oil that can be used is additional purification. Mass Spectrum (m / e); 212.02 (MH +).

Preparation 11 3-phenyl-lH-pyrrole [3, 2-cj pyridine N- [2-Phenyl-et- (Z) -ylidene] -N'-pyridin-4-yl-hydrazine (7.25 g, 34.22 mmol) was reacted under conditions in accordance with the literature (Can J Chem, vol 44 , 1966, p 2455) to give 3-Phenyl-lH-pyrrole [3,2-c] pyridine (2.28 g, 34% yield) after silica gel chromatography: Mass Spectrum (m / e): 194.96 (MH +).

Preparation 12 4- (4-Fluoro-benzylcarbamoyl) -benzenesulfonyl chloride 4-Chlorosulphonyl-benzoyl chloride (103 g (0.433 mol) and anhydrous THF (1.2 1) was added to a 5-necked 3-necked round-bottom flask equipped with overhead stirrer, brine funnel, N2 line, and temperature and cooled to -78 ° C. A solution of 4-fluorobenzylamine (52 g, 0.416 mol), triethylamine (42 g, 0.415 mol), and 4-DMAP (5.3) was added to the solution stirred for 4 hours. g, 0.043 mol) in dry THF (1.2 1) The resulting mixture was slowly brought to room temperature and stirred overnight.The solids were filtered, subsequently washed with THF and the filtrate was concentrated to a solid. it was partitioned between IN of HCl (11) and ethyl acetate (2 X 11) The organics were combined, dried over magnesium sulfate, filtered and concentrated to a solid The solid was suspended in methyl t-ether. butyl (11), stirred at room temperature for 2 hours, filtered and washed with ethyl ether (500 ml). The resulting white was dried (20 mm Hg, 40 ° C) to give 4- (4-fluoro-benzylcarbamoyl) -benzenesulfonyl chloride as a white solid. (108.5 g, 80%): 1HR N (DMSO- 6) d 9.07 (t, J = 5.9 Hz, 1H), 7. 82 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 7.8 Hz, 2H), 7.35 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 4.44 (d, J = 5.9 Hz, 2H); MS (ESI) m / z 326 (m-H); CLAR, 93.6%.

Preparation 4 3- (3, 3-Difluoro-cyclopentyl) -lH-indole Following a procedure according to the literature (Tec, Vol 46, No 13-14, p 4925, 1990) previously reported to convert 3- (lH-Indol-3-yl) -cyclopentanone to 3- (3,3-difluoro-cyclopentyl) -lH-indole (246 mg, 22% yield): Mass Spectrum (m / e): 220.11 (MH-).

Preparation 15 3-Morpholin-4-yl-l-triisopropylsilanyl-lH-lndol 3-Bromo-1-triisopropylsilanyl-1H-indole (0.33 g, 0.94 mmol), morpholine (0.10 ml, 1.15 mmol), 2-dicyclohexylphosphino-2 '- (N, -dimethylamino) biphenyl (0.012 g, 0.03 mmol) were combined. ), and adduct of tris (dibenzylidene ketone) dipalladium (0) chloroform (0.012 g, 0.01 mmol) in a pressurized tube. 1N of a solution of lithium bis (trimethylsilyl) amide in THF (2.00 ml, 2.00 mmol) was added, the tube was flushed with nitrogen gas, and the tube was closed. It was stirred at 65 ° C for 18 hours, cooled to room temperature, diluted with water, and extracted with EtOAc. The EtOAc layer was washed with water, brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified by flash chromatography using 0 to 50% EtOAc in hexanes to give the title compound (0.20 g 60%): MS (ES) 359.1 (M + 1) +.

Preparation 16 3- (4-Methyl-piperazin-1-yl) -1-triisopropylsilanyl-1H-indole Following a method similar to 3-morpholin-4-yl-l-triisopropylsilanyl-lH-indole using 3-bromo-l-triisopropylsilanyl-lH-indole (0.70 g, 1.99 mmol), 1-methyl-piperazine (0.30 g, 3.00 mmol), 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (0.02 g, 0.05 mmol), adduct of tris (dibenzylideneacetone) dipalladium (0) chloroform (0.05 g, 0. 05 mmol) and IN of a solution of lithium bis (trimethylsilyl) amide in THF (2.40 ml). Purified by flash chromatography using 0 to 12% MeOH in dichloromethane to give the title compound (0.23 g, 32%). MS (ES) 372.1 (M + 1) +.

Preparation 17 3-Piperidin-l-yl-l-triisopropylsilanyl-lH-indole Following a method similar to 3-morpholin-4-yl-1-triisopropylsilanyl-1H-indole using 3-bromo-1-triisopropylsilanyl-1H-indole (0.70 g, 1.99 mmol), piperidine (0.26 g, 3.04 mmol), 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (0.02 g, 0.05 mmol), adduct of tris (dibenzylideneacetone) dipalladium (0) chloroform (0.05 g, 0. 05 mmol) and 1N of a solution of lithium bis (trimethylsilyl) amide in THF (2.40 ml) to prepare the title compound.

Purified by flash chromatography using 0 to 40% EtOAc in hexanes to give the title compound (0.20 g, 29%): MS (ES) 357.1 (M + H) +.

Preparation 18 3-Morpholin-4-yl-lH-indole A 1N solution of tetrabutylammonium fluoride (0.70 ml, 0.70 mmol) was added to a solution of 3-Morpholin-4-yl-1-triisopropylsilanyl-1H-indole (0.20 g, 0.56 mmol) in THF (2.0 ml). It was stirred at room temperature for 2 hours, diluted with water, extracted with EtOAc. The EtOAc was washed with saturated NaHCO 3, dried (Na 2 SO 4), and concentrated under vacuum. The residue was purified by flash chromatography using 20 to 80% EtOAc in hexanes to give the title compound (0.10 g, 89%). MS (ES) 203.1 (M + 1) +.

Preparation 19 3- (4-Methyl-piperazin-1-yl) -lH-indole Following a method similar to 3-morpholin-4-yl-lH-indole using 3- (4-Methyl-piperazin-1-yl) -1-triisopropylsilanyl-1H-indole (0.35 g, 0.94 mmol) and an IN solution of tetrabutylammonium fluoride (1.40 ml) to prepare the title compound. Purified by flash chromatography using 2 to 12% methanol in dichloromethane to give the title compound (0.12 g, 60%). MS (ES) 216.1 (M + H) +.

Preparation 20 3-Piperidin-l-yl-lH-indole Following a method similar to 3-morpholin-4-yl-lH-indole using 3-Piperidin-l-yl-l-triisopropylsilanyl-lH-indole (0.30 g, 0.84 mmol) and an IN solution of tetrabutylammonium fluoride (1.30 ml) ). Purified by flash chromatography using 20 to 50% EtOAc in hexanes to give the title compound (0.12 g 71%). MS (ES) 201.1 (M + 1) +.

Preparation 21 1- (2-Fluoro-phenyl) -cyclobutanecarbonitrile C? CN NaOH (922 mg, 23.0 mmol) was slowly added to a solution of (2-fluorophenyl) -acetonitrile (1.27 mL, 9.95 mmol) in DMSO (40.0 mL). The mixture was stirred at room temperature for 30 minutes then a solution of 1,3-dichloropropane (0.95 ml, 10.0 mmol) in DMSO was added via cannula. (20 ml). After the addition was complete, it was stirred at 95 ° C for 5 hours. The mixture was poured into ice (60 g) and extracted with Et20 (3 X 50 ml). The organic solutions were combined and washed with brine (50 ml), dried, filtered and concentrated. The material was purified by flash chromatography (using a linear gradient of 100% hexanes to 35% EtOAc / hexanes) to give the title compound (1.4 g, 80%) as a yellow oil. 2H NMR (400MHz, CDC13): d 7.32 (m, 1H), 7.25 (dt, 1H, J = 1.9, 8.0), 7.16 (dt, 1H, J = 0.9, 7.5), 7.09 (ddd, 1H, J = 1.2, 8.1, 10.7), 2.86 (m, 2H), 2.69 (m, 2H), 2.50 (m, 1H), 2.05 (m, 1H).

Preparation 22 4- (2-Fluoro-phenyl) -tetrahydro-pyran-4-carbonitrile NaH (920 mg, 23.0 mmol) was slowly added to a solution of (2-fluorophenyl) -acetonitrile (1.27 mL, 9.95 mmol) in DMSO (40.0 mL). The mixture was stirred at room temperature for 30 minutes then a solution of 1,3-dichloropropane (1.0 ml, 8.53 mmol) in DMSO (20 ml) was added via cannula. After the addition was complete, it was stirred at 75 ° C for 5 hours. The mixture was poured onto ice (60 g) and extracted with Et20 (3 X 50 ml). The organic solutions were combined and washed with brine (50 ml), then dried, filtered and concentrated. The material was purified by flash chromatography (using a linear gradient of 100% hexanes to 35% EoOAc / hexanes) to give the title compound (1.4 g, 80%) as a yellow oil. 1 H NMR (400MHz, CDC13): d 7.43 (dt, 1H, J = 1.7, 7.9), 7.36 (m, 1H), 7.19 (dt, 1H, J = 1.4, 7.7), 7.13 (ddd, 1H, J = 1.4, 6.6, 14.5), 4.08 (m, 2H), 3.94 (dt, 2H, J = 1.7, 7.9), 2.26 (dt, 2H, J = 4 .4, 13. 7), 2 .19 (m, 2H) Preparation 23 Spiro [indolin-3, 4 - "-tetrahydro-pyrano] LiAlH4 (398 mg, 10.5 mmol) was added to a solution of 4- (2-fluoro-phenyl) -tetrahydro-pyran-4-carbonitrile (1.39 g, 6.77 mmol) in dimethoxyethane (25 mL). The solution was stirred under reflux overnight, then an aqueous saturated Rochelle's saline solution (30 ml) was added and stirred for an additional 1 hour at room temperature. The mixture was extracted with CH2C12 (3 X 30 ml). The organic extracts were combined and washed with saturated aqueous Rochelle's saline solution (30 ml) and brine (30 ml). The organic solution was dried, filtered and concentrated, then the crude material was purified by flash chromatography, using a linear gradient of 100% hexanes and 50% EtOAc / hexanes, to give the title compound (581 mg, 45% ) as a white solid. XH NMR (400MHz, CDC13): d 7.09 (d, 1H, J = 7.3), 7.06 (t, 1H, J = 7.6), 6.77 (m, 1H), 6.67 (m, 1H), 3.97 (m, 2H ), 3.94 (dt, 2H, J = 1.7, 7.9), 3.56 (dt, 2H, J = 2.1, 11.8), 3.55 (s, 2H), 1.99 (m, 2H), 1.67 (m, 2H).

Preparation 24 C- [1- (2-Fluoro-phenyl) -cyclobutyl] -methylamine LiAlH4 (416 mg, 12.1 mmol) was added to a solution of 1- (2-fluoro-phenyl) -cyclobutanecarbonitrile (1.38 g, 7.88 mmol) in dimethoxyethane (30 mL). The solution was stirred under reflux overnight, then saturated, aqueous Rochelle's saline (30 ml) was added and stirred for an additional 1 hour at room temperature. The mixture was extracted with CH2C12 (3 X 30 ml). The organic extracts were combined and washed with saturated, aqueous Rochelle's saline (30 ml) and brine (30 ml). The organic solution was dried, filtered and concentrated, then the crude material was purified by flash chromatography, using 20% MeOH / CH 2 Cl 2 to give the title compound (1 g, 71%) as a white solid. MS (ES) 180.1 (M + H) +.

Preparation 25 Spiro [cyclobutan-1,3 '-indoline] LiAlH (266 mg, 7.01 mmol) was added to a solution of 4- (2-fluoro-phenyl) -tetrahydro-pyran-4-carbonitrile (488 mg, 2.72 mmol) in dimethoxyethane (30 mL). The solution was stirred at reflux for 4 days, then an aqueous, saturated Rochelle's saline solution (30 ml) was added and stirred for an additional 1 hour at room temperature. The mixture was extracted with Et20 (3 X 30 ml). The organic extracts were combined and washed with brine (30 ml). The organic solution was dried, filtered and concentrated, then the crude material was purified by flash chromatography, using a linear gradient of 100% hexanes to 30% EtOAc / hexanes, to give the title compound (44 mg, 10%). as a white solid. 1H NMR (400MHz, CDC13): d 7.31 (m, 1H), 7.03 (dt, 1H, J = 1.4, 7.5), 6.79 (dt, 1H, J = 0.9, 7.5), 6.64 (d, 1H, J = 7.9), 2.36 (m, 2H), 2.21 (m, 2H), 2.02 (m, 2H).

Preparation 26 3-Cyclopropyl-1-triisopropylsilanyl-1H-indole 3-bromo-l-triisopropylsilanyl-lH-indole was dissolved (1.02 g, 2.89 mmol), cyclopropylboronic acid (259 mg, 3.01 mmol) and K3P04 (1.8 g, 8.5 mmol) in a mixture of toluene (20 mL) and water (0.8 mL). Tricyclohexyl phosphine (86 mg, 0.31 mmol) and palladium (II) acetate (50 mg, 0.22 mmol) were added and the mixture was stirred at 70 ° C for 3 hours. The mixture was filtered through celite and the solids were washed with EtOAc (30 ml). the filtrate was collected and concentrated and the residue was purified by flash chromatography, using a linear gradient of 100% hexanes to 10% EtOAc / hexanes, to give the title compound as a clear oil 765 mg (84%): MS (ES) 314.1 (M + H) +.

Preparation 27 3- ter-jutil-li? -indol Trifluoroacetic acid (TFA, 1.0 mL, 1.5 g, 13 mmol, 1.6 equiv) was added to a solution of indole (1.00 g, 8.54 mmol, 1 equiv) and tert-butyl alcohol (1.0 mL, 0.78 g, 10 mmol, 1.2 equiv) in anhydrous 1,2-dichloroethane (40 ml). The colorless solution slowly turned brown while heating to reflux. After 1 hour at reflux, more TFA (2 ml) and tert-butyl alcohol (2 ml) were added. After 16 hours at reflux, the reaction solution was rotary evaporated (80 ° C) to give a dark brown solid. This material was transferred to a column of silica gel (235 mm x 35 mm dia.) And the desired 3-tert-butyl-1H-indole was levigated (0-10% EtOAc / hex) which was co-levigated with a trifluoroacetate derivative of itself (3: 1) providing 284 mg of a brown oil. This material was levigated with (10% EtOAc / hex) again through a column of silica gel (125 mm x 25 mm dia.) Yielding 124 mg (8.4%) of pure 3-tert-butyl-IH-indole. as a light orange crystalline solid. MS (m / z): 173.

Preparation 28 I-Bromo-1-methyl-cyclopentane 1-Methylcyclopentanol (1.12 g, 11.2 mmol, 1 equiv) was stirred vigorously with aqueous HBr (48%, 5.0 mL, 7.4 g. [0.48] = 3.6 g HBr, 44 mmol, 4.0 equiv) for 30 minutes. The organic layer was separated and the aqueous layer was extracted with hexanes (5 ml). The organic layers were combined, dried (MgSO4 anhydride) and rotary evaporated (35 ° C, some of the product was distilled) providing 657 mg (36.0%) of 1-bromo-1-methyl-cyclopentane as a green liquid light.

Preparation 29 3- (1-Methyl-cyclopentyl) -lfl-indole N, N-diisopropylethylamine (890 μl, 660 mg, 5.1 mmol, 2.2 equiv) was added to a mixture of indole (410 mg, 3.5 mmol, 2.0 equiv), tetrabutylammonium iodide (860 mg, 2.3 mmol, 1.0 equiv), and zinc triflate (1000 mg, 2.8 mmol, 1.2 equiv) in anhydrous toluene (10 ml). After stirring for 15 minutes, 1-bromo-1-methyl-cyclopentane (380 mg, 2.3 mmol, 1 equiv) was added. After 15 hours, the reaction mixture was quenched with aqueous, saturated NH4C1 (10 mL). The organic layer was separated and the aqueous layer was extracted with Et20 (10 ml). The combined organic layers were dried (anhydrous MgSO 4) and rotary evaporated (40 ° C) to give 440 mg of the material as light yellow oil. This material was transferred to a column of silica gel (125 mm x 25 mm dia.) And levigated (CH2Cl2 / 5-20% hex). Much of the desired product was co-eluted with the indole starting material. This material was transferred to a column of silica gel (80 mm x 20 rare dia.) And was levigated (CH2Cl2 / 0-15% hex) to provide 99 mg (21%) of 3- (1-methyl-cyclopentyl) ) -IH-pure indole as a colorless oil. MS (m / z): 199.

Preparation 30 1- [(Toluen-4-sulfonyl) -lH-indol-3-yl] -ethanone 1.0 M t-BuOK (3.0 mL, .003 mol) was added to a stirred solution of 3-acetyl-indole (0.478 g, .0030 mol) in dry DMF (20 mL) under N2 at room temperature and stirred by 30 minutes. Toluenesulfonyl chloride was added to this solution and the resulting mixture was stirred overnight. The reaction was poured into EtOAc-H20, the organic layer was separated and extracted several times with H2O, washed with brine, dried (MgSO4), filtered and evaporated on a rotary evaporator. Chromatography on ISCO levigated with a hexane-EtOAc gradient (0-100%) for 30 minutes to give 0.73 g (78%) of the title compound as a solid: 1H (CDC13) d 7.8 (d, 1H), 8.2 (s, 1H), 7.9 (d, lH), 7.7 (d, 2H), 7.4 (m, 2H), 7.3 (d, 2H), 2.6 (s, 3H), 2.4 (s, 3H).

Preparation 31 2- [1- (Toluen-4-sulfonyl) -lH-indol-3-yl] -propan-2-ol Methyl magnesium bromide 3. OM (0.40 ml) was added to a stirred solution of 1- [(toluenesulfonyl) -lH-indol-3-yl] -ethanone 0.31g, .0010 mol) in dry THF under N2 at 30. A solid precipitated immediately. The reaction mixture was allowed to warm to 0-10 ° C and was stirred for 1 hour. The mixture was cooled in an ice bath and quenched with a saturated solution of NH 4 Cl. It was diluted with Et20, and the organic layer was separated, washed with brine, dried (MgSO4), filtered. It was concentrated to give an oil (0.36 g). Chromatographed using a hexane-EtOAc gradient (0-100 for 30 minutes) to give 0.20 (62%) of the desired as a white solid: 1H NMR CDC13) d 8.0 (d, 1H) 7.8 (m, 3H) , 7.45 (s, 1H), 7.4-7.2 (m, 4H), 2.4 (s, 3H), 1.7 (s, 6H).

Preparation 32 3-Isopropyl-1- (toluene-4-sulfonyl) -lH-indole TFA (1.35 mL, 0.0174 mol) was added to a stirred solution of 2- [1- (Toluene-4-sulfonylindol-3-yl] -propan-2-ol (0.358 g, .001 mol) in CH2C12 (20 mL) a 0 ° C. The resulting mixture was stirred at 0-5 ° C. for 1 hour and allowed to warm to room temperature and stirred for 1 1/2 hours.The solution was poured into a mixture of saturated NaHCO 3 -CH 2 Cl 2. The organic phase was separated, filtered and evaporated on a rotary evaporator to give 0.103 g of the desired compound: 1 H NMR (CDC13) d 8.0 (d, 2 H), 7.8 (d, 2 H), 7.55 (d, 1 H), 7.3-7.2 (m, 5H), 3.1 (m, 1H), 2.38 (3H), 1.28 (d, 6H).

Preparation 33 3-Isopropyl indole Five mole of NaOH (3.0 mL), 0.015 mol) was added to a suspension of 3-isopropyl-1- (toluene-4-sulfonyl) -1H-indole 0.100 g, 0.032 mmol) in EtOH (6.0 mL) at Room temperature and the resulting mixture was heated and stirred at 90 ° C overnight. The mixture was diluted with H20 (5.0 mL) and concentrated on the rotary evaporator. The resulting suspension was extracted with Et20. The organic layer was separated, dried (MgSO 4) and filtered. Evaporated to give the title compound 0.0387 (77%) as a yellow oil: 1 H NMR (CDC13) d 7.88-7.82 (bs, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 7.25 (t , 1H), 7.2 (t, 1H), 7.0 (d, lH), 3.3 (m, 1H), 1.43 (d, 6H).

Preparation 34 4- (3-Phenyl-indole-1-sulfonyl) -benzoic acid It was added to a 2-neck 3-necked flask equipped with a reflux condenser, thermometer and nitrogen inlet, 4- (3-iodo-indol-l-sulfonyl) -benzoic acid methyl ester (0.1 mole, 44.1 g) , phenylboronic acid (0.12 mol, 22.35 g), dichloropalladium of 1,1-bis (diphenylphosphino) ferrocene (0.0025 mol, 2.04 g), 2M sodium carbonate (140 ml) and 0.5 1 of THF. The mixture was refluxed under nitrogen for 2 hours. THF was removed under vacuum, and MTBE (500 mL) and DI water (200 mL) were added to the residue. The solution was filtered through a pad of Celite, and washed with MTBE (500 ml). The organic layer was separated and concentrated under vacuum to give a brown solid. The solid was dissolved in THF (250 ml) to this 5N NaOH solution (35 ml) by dropping over a period of 30 minutes. The reaction was stirred at room temperature for 3 hours, quenched with DI water (250 ml). The aqueous layers were combined and washed with MTBE (500 mL). The aqueous layer was stirred at room temperature for 2 hours, filtered and washed with DI water (500 ml). The gray, off-white solid was dried in a vacuum oven at 65 ° C for 16 hours to obtain 25.4 g. ""? NMR (DMSO) 8.2 (d, 2H), 8.1 (m, 3H), 7.9 (d, 1H), 7.7 (d, 2H), 7.4 (m, 5H). MS (ES-) = 376.2 (M-1). Anal. Cale, stop C2? H? 5N04S: C 66.8308; H 4.0060; N 3.7112; found C 66.54; H 4.07; N 3.20.

Preparation 35 4- (3-Isopropyl-indole-1-sulfonyl) -benzoic acid methyl ester 1.0 M tert-butoxide (1.6 ml, 0.0016 mol) was added dropwise to a stirred solution of 3-isopropyl indole (0.217 g, .00136 mol) in dry DMF (20 ml) under N2 at room temperature. The reaction mixture was stirred for 30 minutes and methyl ester of 4-chlorosulfonyl benzoic acid (0.328 g, 0.0014 mol) was added in portions. The clear brown reaction mixture immediately decolorized. The resulting yellow solution was stirred overnight. It was poured into a mixture EtOAc-H20 (100 to 300 mL). The EtOAc was separated and extracted sequentially with H20 (3x 250 ml), washed with brine, dried (MgSO 4), filtered and evaporated to yield 0.38 g. It was chromatographed on ISCO using a hexane-EtOAc gradient (0-50%, 30 minutes) to yield 0.249 g (51%) of the title compound as a waxy solid. Mass Spectrum (m / e) (M + H) 358.1113. found (M + H) 358.1129.

Preparation 36 4- (3-Isopropyl-indole-1-sulfonyl) -benzoic acid Five molar NaOH (1.5 mL, 0.0075 mol) was added to a stirred solution of 4- (3-isopropyl-indole-1-sulfonyl) -benzoic acid methyl ester (0.230 g, 0.00061 mol) in THF (10.0 mL) at room temperature under N2. The resulting mixture was stirred overnight. It was diluted with 5% NaHCO3 (75 mL) and extracted with Et20. The aqueous layer was separated and acidified with 37% HCl. The resulting precipitate was extracted into EtOAc, washed with brine, dried (MgSO 4), filtered and evaporated to yield 0.187 g of the title compound as an off-white solid: Mass spectrum (m / e) (M-H) 342.0800; Found (M-H) 342.0802.

Preparation 37 4- [3- (2-Fluoro-pyridin-3-yl) -indol-1-sulfonyl] -benzoic acid A mixture of 4- (3-iodo-indol-1-sulfonyl) -benzoic acid methyl ester (1.33 g, 3.01 mmol, 1 equiv.), 2-fluoropyridine-3-boronic acid (Frontier) is refluxed.

Scientific®; 0.47 g, 3.3 mmol, 1.1 equiv.), Sodium carbonate (2M in H2O, 3.0 ml, 6.0 mmol, 2.0 equiv.), And complex [1,1'-bis (diphenylphosphino) ferrocen] dichloropalladium (II) with dichloromethane (62 mg, 0.080 mmol, 0.025 equivalent), in THF ( 15 ml) under N2 for 2h (reaction mixture became very dark when heated). The reaction mixture was rotary evaporated. The resulting residue was dissolved in Et20 (15 ml) and washed with H20 (5 ml). The aqueous layer was extracted again with Et20 (5 ml). The combined organic layers were dried with anhydrous (Na 2 SO 4), and evaporated by rotation (40 ° C) yielding 4- [3- (2-fluoro-pyridin-3-yl) -indol-1-sulfonyl) methyl ester. ] -benzoic crude as a brown foam. This material was dissolved in THF (10 ml) and . added 5 M aqueous NaOH (2 mL). After 18 h, H20 (25 ml) and Et20 (25 ml) were added. The aqueous layer was separated and the organic layer was extracted with H20 (25 ml). The aqueous layers are combined and washed with Et20 (25 mL). This aqueous layer was acidified with aqueous 1M HCl (8 ml) to pH 5 causing a lot of precipitation. This mixture was extracted with CHC13 (Ix 50 ml, 2x 25 ml). The combined organic layers were dried (anhydrous Na 2 SO 4) and rotary evaporated (40 ° C) yielding 673 mg (56.3%) of 4- [3- (2-fluoro-pyridin-3-yl) -indol-1- sulfonyl] -benzoic acid as a brown powder. EM (m / e): 396.94 (M + l); 394.99 (M-l).

Preparation 38 4- [3- (6-Fluoro-pyridin-3-yl) -indol-1-sulfonyl] -benzoic acid The title compound was prepared by a similar method described for 4- [3- (2-fluoro-pyridin-3-yl) -indol-1-sulfonyl] -benzoic acid using methyl 4- (3-iodo) acid -indol-l-sulfonyl) -benzoic acid (1.33 g, 3.01 mmol, 1 equivalent), 2-fluoropyridine-5-boronic acid (Frontier Scientific®; 0.47 g, 3.3 mmol, 1.1 equivalent) to produce 965 mg (80.8%) of brown powder. MS (m / e): 396.94 (M + 1); 394.98 (M-l).

Preparation 39 4- (3-Cyclopropyl-indole-1-sulfonyl) benzoic acid methyl ester A solution of tetrabutylammonium fluoride (3.0 mL, 3.0 mmol; 1.0M in THF) was added to a solution of 3-cyclopropyl-1-triisopropylsilanyl-1H-indole (0.76 g, 2.4 mmol) in THF (15.0 mL). It was stirred at RT for 15 min, concentrated to a viscous oil, and redissolved in Et20 (50 mL). The organic solution was washed with water (30 ml) and saturated NaHCO 3 (30 ml). The organic solution was dried, filtered and concentrated and the residue was purified by flash chromatography, using a linear gradient of 100% hexanes at 30% EtOAc / hexanes, to yield the title compound as a light yellow oil which still contains triisopropyl fluoride as an impurity. The material was used directly in the next reaction without further purification. Potassium tert-butoxide (280 mg, 2.49 mmol) was added to a solution of above 3-cyclopropyl-1H-indole in DMF (10.0 mL). The solution was treated with 4-chlorosulfonyl-benzoic acid methyl ester (590 mg, 2.51 mmol) and stirred at RT for 2 h. The solution was diluted with EtOAc (30 ml) and washed with water (20 ml) and saturated NaHCO 3 (20 ml). The organic solution was dried, filtered and concentrated and the residue was purified by flash chromatography, using a linear gradient of 100% hexanes at 20% EtOAc / hexanes, to afford the title compound as light yellow oil (505 mg , 59%, 2 stages). EM 3.55.9 (M + l) +.

Preparation 40 4- (3-Cyclopropyl-indole-1-sulfonyl) -benzoic acid Lithium hydroxides monohydrate (181 mg, 4. 31 mmol) was added to a solution of 4- (3-cyclopropyl-indole-1-sulfonyl) -benzoic acid methyl ester (505 mg, 1.42 mmol) in 3: 1 dioxane: water (6.0 ml). The mixture was stirred at RT for 4 h, diluted with water (80 ml) and INN HCl was added until the mixture reached pH 2. The white solid was collected by filtration and dried overnight under vacuum to yield the title compound. title (450 mg, 93%). MS (ES) 341.9 (M + 1) +, 340.1 (M-1) -.

Preparation 41 4- [3- (4-Hydroxy-tetrahydro-pyran-4-yl) -dole-1-sulfonyl] -benzoic acid methyl ester [Note: All the glass was dried in a 120 ° C oven and heated up prior to the reaction].

A 3-neck, 3-necked round bottom flask was equipped with a head stirrer, temperature probe, N2 line, and septum and charged with 4- (3-iodo-indol-l-sulfonyl) methyl ester. -benzoic (159.0 g, 0.360 mol). THF (IL) was introduced via cannula and the solution was stirred and cooled to -75 ° C under N2. A dropping funnel was dried as above and mounted in the flask and 2 M cyclopentylmagnesium bromide in diethyl ether (200 ml, 0.400 mol) was added to the dropping funnel via cannula. The solution was added dropwise over 0.5 h and the resulting mixture was stirred for 0.5 h. The mixture was warmed to 0 ° C, stirred an additional 0.5 h, again cooled down to -10 ° C, and treated with a solution of tetrahydro-4H-pyran-4-one (43.0 g, 0.429 mol) in THF (100 ml) was added via cannula to a new dripper funnel previously dried. The ketone was added for 0.5 h to maintain the internal temperature below -10 ° C. The solution was heated to room temperature and stirred for 1.5 h in the process. The mixture was quenched under N2 by the addition of aqueous saturated ammonium chloride (1L), the layers were separated, and the organic layer was dried under sodium sulfate. Concentrated to provide the dark oil and dissolved in MTBE (1L). The addition of 0.5 L hexanes produced a solid and allows the solid to remain overnight at room temperature. The solid was filtered, washed again with 2: 1 MTBE / hexanes (150 ml) to yield a tan solid. The solid was re-formed into a slurry in ethyl acetate (1L), stirred at room temperature for 2 h, filtered, dried (20 mm Hg, 450 ° C) and found to be highly the title compound. (49.2 g, 33%); ^? NMR (DMSO-d6) d 8.15 4H), 7.94 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.60 (s, 1H), 7.36 (t, J = 7.7 Hz , 1H), 7.27 (t, J = 7.7 Hz, 1H), 5.27 (s, 1H), 3.85 (s, 3H), 3.81 (m, 2H), 3.69 (m, 2H), 2.06 (m, 2H) 1.78 (m, 2H); MS (ESI) M / Z 398 (M + h, M-H20). [Note: The filtrate of the ethyl acetate which is formed again in a slurry is concentrated and the resulting solid is filtered from the methylene chloride / hexanes / ethyl ether to produce a second crop of good quality alcohol, 32 g. Therefore, the total yield is 81.2 g, 54%. The initial filtrate of the crystallization of MTBE / hexanes was concentrated to an oil and the addition of methylene chloride / hexanes / ethyl ether to produce a solid consisting mainly of the corresponding 3-protioindole analog, 28 g.

Preparation 42 4- [3- (Tetrahydro-pyran-4-yl) -indol-1-sulfonyl] -benzoic acid methyl ester It was added to a solution of 4- [3- (4-hydroxy-tetrahydro-pyran-4-yl) -indol-1-sulfonyl] -benzoic acid methyl ester (20.0 g, 48.19 mmol) in anhydrous methylene chloride ( 500 ml) at room temperature, triethylsilane (20.0 ml, 125.19 mmol) and trifluoroacetic acid (61.5 mL, 798.2 mmol). The resulting solution was stirred for 1 h, concentrated, and the oil was obtained and partitioned between ethyl acetate (500 ml) and saturated sodium bicarbonate. (500 ml). The organic layer was dried over sodium sulfate, filtered through a pad of silica gel, and washed again with ethyl acetate (400 ml). The filtrate was concentrated at low volume, hexanes were added, and the solid separated. The solid was filtered and maintained, 14 g. The filtrate was concentrated to low volume and MTBE was added to provide a second crop of crystals, filtered and found identical by HPLC (3: 2 hexanes / ethyl acetate) to the original batch, 2.8 g. The two batches were combined and dried (20 mm Hg, 40 ° C) to yield a batch of highly pure title compound for subsequent hydrolysis (16.8 g, 87%); X H NMR (DMSO-d 6) d 8.10 (m, 4 H), 7.93 (d, J = 8.2 Hz, 1 H), 7.68 (d, J = 7.7 Hz, 1 H), 7.57 (s, 1 H), 7.37 (t, J = 7.7 Hz, 1H), 7.28 (t, J = 7.1 Hz, 1H), 3.94 (m, 2H), 3.85 (s, 3H), 3.50 (t, J = 11.5 Hz, 2H), 3.03 (m, 1H), 1.86 (m, 2H), 1.70 (m, 2H); MS (ESI) m / z 400 (m + H).

Preparation 43 4- [3- (Tetrahydro-pyran-4-yl) -indol-1-sulfonyl] -benzoic acid It was added to a suspension of 4- [3- (tetrahydro-pyran-4-yl) -indol-1-sulfonyl] -benzoic acid methyl ester (16.7 g, 41.83 mmol) in methanol (200 mL) with THF stirring (600 ml). The solution was treated with 5N NaOH (23.5 ml, 2.8 eq.) And stirred for 2 h at room temperature. The solution was concentrated to near dryness and treated with IN HCl (125 mL), a solid was separated. It was diluted to a total volume of 500 ml with water, filtered, washed again with water, and dried (20 mm Hg, 60 ° C) to yield a resulting solid found to be the pure title compound (15.8 g. , 98%); 1H NMR (DMSO-d6) 13.57 (s, 1H), 8.08 (m, 4H), 7.93 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.57 (s, 1H), 7.37 (t, J = 8.2 Hz, 1H), 7.57 (s, 1H), 7.37 (t, J = 8.2 Hz, 1H), 7.27 (t, J = 7.1 Hz, 1H), 3.95 (m, 2H), 3.47 (t, J = 12.0 Hz, 2H), 3.03 (, 1H), 1.85 (m, 2H), 1.70 (m, 2H); MS (ESI) m / z 384 (m-H).

Preparation 44 4- (3-Cyclopent-l-enyl-indol-l-sulfonyl) -benzoic acid methyl ester It was added to a 2-L 3-necked round-bottom flask equipped with an overhead stirrer, N2 line, and temperature probe, 4- (3-iodo-indol-1-sulfonyl) -benzoic acid methyl ester ( 69.0 g, 0.156 mol) and anhydrous DMF (700 ml). The stirred solution was added at room temperature to cyclopentene (138.0 ml, 1.57 mol), palladium II acetate (1.8 g, 8.0 mmol), tetrabutylammonium chloride (43.5 g, 0.156 mol), and potassium acetate (46.0 g, 0.469 mol). ). The resulting dark mixture was heated at 60-65 ° C for 16 h. The reaction mixture was cooled, filtered through celite, and washed again with ethyl acetate. (1L) The solution was partitioned with 2X 1L of brine, the organic layer was dried over sodium sulfate, and chromatographed on flash silica gel (10% ethyl acetate in hexanes gradually increased to 20% ethyl acetate. in hexanes) to yield the pure title compound (48.3 g, 81%); MS (ESI) m / z 382 (m + H); XH NMR (DMSO-dg) reveals the material which is in fact a mixture of 3-substituted olefinic cyclopentenes (approximately 1: 1, with olefinic H 's at 5.8, 5.9 and 6.0 ppm which make up 1H each), suitable as such for the subsequent hydrogenation.

Preparation 45 4- (3-Cyclopentyl-indol-1-sulfonyl) -benzoic acid methyl ester 4- (3-Cyclopent-1-enyl-indole-1-sulfonyl) -benzoic acid (2.2 g, 5.77 mmol) was dissolved in ethanol (25 mL) and ethyl acetate (25 mL) and hydrogenated with 10% of the mixture. % palladium on carbon (300 mg) at 33 psi for 16 h. The catalyst was filtered over celite and washed again with 1: 1 ethane / ethyl acetate (50 ml). It was concentrated to produce a dark solid and dissolved in 1: 1 ethyl acetate / hexanes (50 ml) and passed through a plug of silica gel. The plug was washed again with 1: 1 ethyl acetate / hexanes (100 ml) and the filtrate was concentrated to an oil, which solidified at rest and was found to be the pure title compound (2.0 g, 90 %); 1 H NMR DMSO-de) d 8.10 (m, 4H), 7.93 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.53 (s, 1H), 7.36 (t, J = 7.1 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 3.84 (s, 3H), 3.16 (m, 1H), 2.08 (m, 2H), 1.62 (m, 6H); MS (ESI) m / z 384 (m + H).

Preparation 46 C- (5-Fluoro-pyridin-3-yl) -methylamine Xj NXm * To a Bottle of Parr 2, 6-dichloro-3-cyano-5-fluoropyridine (5g, 26.18 mmol), ethanol (50 ml), concentrated hydrochloric acid (4.3 ml) and 10% Pd-C ( 0.5 g). It was placed in a Parr Agitator Apparatus under 36 psig of hydrogen for 6 hours at room temperature. Potassium acetate (10.28 g, 104.72 mmol) was added and 48 psig of hydrogen was continued overnight at room temperature. The reaction was filtered over Celite and the filtrate was concentrated in vacuo to a residue. The THF residue (100 ml) was added. The solid was filtered, and the filtrate was concentrated under vacuum to yield (5-fluoro-pyridin-3-yl) -methylamine as a clear oil (6 g). X H NMR (DMSO): 8.6 (d, 2 H), 8.0 (d, 1 H), 4.2 (s, 2 H). MS (ES +) = 127.5.

Preparation 47 C- (2-Fluoro-pyridin-3-yl) -methylamine hydrochloride Concentrated HCl (0.46 ml) was added to a suspension of 2-fluoro-nicotinonitrile (0.34 g, 2.8 mmol) and 5% Pd / C (0.5 g) in methanol (10 ml) at RT. The suspension was stirred under an atmosphere of hydrogen at 1 atm. For 6 hours. The reaction mixture was filtered and the filtrate was concentrated. Ether was added to the residue, bubbled with HCl gas through the suspension, the precipitate filtered, and dried to yield the title compound (0.37 g, 82%). MS (ES) 127.1 (M + H) A 2 H NMR (400 MHz, DMSO) d: 8.65 (brs, 3 H), 8.24 (m, 1 H), 8.16 (m, 1 H), 7.41 (m, 1 H), 4.06 (m, 2H).

Preparation 48 C- (2-Fluoro-pyridin-4-yl) -methylamine hydrochloride Following a method similar to C- (2-Fluoro-pyridin-3-yl) -methylamine hydrochloride, using 2-fluoro-isonicotinonitrile (0.65 g, 5.3 mmol), concentrated HCl (1.2 ml), and 5% Pd / C (1.2 g) to yield the title compound (0.43 g, 50%). MS (ES) 127.1 (M + 1) A Preparation 49 C- (4-Trifluoromethyl-pyridin-3-yl) -methylamine Raney nickel (0.5 g) was added to a solution of 4-trifluoromethyl-nicotinonitrile (1.0 g, 5.8 mmol) in ethanol saturated with ammonia (20.0 ml) and shaken under hydrogen at 500 psi for 1 hour. The reaction was filtered, the filtrate was concentrated, and the obtained solid was dried to yield the title compound (1.0 g, 98%). MS (ES) 177.0 (M + 1) +.

Preparation 50 2-Fluoro-isonicotinonitrile A solution of 2-chloro-4-cyanopyridine was treated (6.0 g, 43.5 mmol) and potassium fluoride (7.56 g, 130.3 mmol) in l-methyl-2-pyrrolidinone (20 ml) with tetrabutylphosphonium bromide (14.8 g, 43.7 mmol) and heated at 100 ° C for 18 minutes. hours. It was diluted with water and extracted with EtOAc. EtOAc was washed with water, brine, dried with Na 2 SO 4, and concentrated to yield the title compound (2.3 g, 43%). ? M (ES) 123.1 (M + l) +. XH NMR (400 MHz, CHC13) d 8.43 (d, 1H, J = 5.2 Hz), 7.45 (m, 1H), 7.22 (m, 1H).

Preparation 51 2-Fluoro-nicotinonitrile g, 12.0 mmol) was added to a solution of 2-fluoro-nicotinamide (0.6 g, 4.3 mmol) in dichloroethane (20.0 ml) and carbon tetrachloride (20.0 ml). It was refluxed 18 hours, cooled to RT, filtered, and the filtrate was concentrated under vacuum. Purified by flash column on silica gel by levigating with 10-60% EtOAc in hexanes to yield the title compound (0.34 g, 64%). MS (ES) 123.1 (M + 1) A X H NMR (400 MHz, CHC13) d 8.46 (m, 1 H), 8.09 (m, 1 H), 7.37 (m, 1 H).

Preparation 52 2-Fluoro-nicotinamide Thionyl chloride (40 ml) was added to 2-fluoro-nicotinic acid (2.0 g, 14.3 mmol), refluxed for 18 hours, cooled to RT, and concentrated under vacuum. Benzene (100 ml) was added to the residue and ammonia gas was bubbled in suspension for 3 hours. The flask was stopped, stirred for 18 hours, and concentrated. Water was added to the residue and extracted with EtOAc. EtOAc was washed with water, brine, then dried with Na 2 SO 4, and concentrated under vacuum to yield the title compound (0.6 g, 30%). MS (ES) 141.1 (M + 1) A X H NMR (400 MHz, CHC13) d 8.32 (d, 1 H, J = 4.5), 8.17 (, 1 H), 7.92 (brs, 1 H), 7.79 (brs, 1 H) 7.44 (m, 1H).

Preparation 53 C-Pirazin-2-yl-methylamine In a Parr bottle, pyrazin-2-carbonitrile was charged (1 g) in absolute ethanol (10 ml). 10% Pc / C (w / w, 0.4 g) was added and placed in a Parr Hydrogenation Apparatus under 50 psig of hydrogen at room temperature sixteen hours. The mixture was filtered through a pad of Celite. The material was purified on the SCX column. Crude raw material was used in the next step without further purification.

Preparation 54 C-Pyridazin-3-yl-methylamine Pyridazin-3-carbonitrile was hydrogenated using H2, NH3, MeOH, Raney Nickel at 40 ° C and 60 psi. Crude material was filtered to remove the catalyst. It was dissolved in MeOH and purified on an SCX column to produce basic material. Crude material was used in the amine coupling without further purification.

Preparation 55 2-Methoxy-cyclohexylamine A mixture of o-anisidine (5.0 g, 41 mmol) and rhodium on carbon (5% Rh, 5.0 g) was shaken in AcOH (65 ml) under H2 (60 psig) at 60 ° C for 6 h. The reaction mixture was filtered and the filtrate (75 ° C) was rotary evaporated. This material was dissolved in CHC13 (100 ml) and basified with saturated aqueous NaHCO3 (50 ml). The organic layer was dried (Na2SO4) and rotary evaporated (40 ° C) to yield 1.20 g of 2-methoxy-cyclohexylamine as a yellow oil.

Preparation 56 1- (4-Fluoro-phenyl) -piperidin-4-ylamine 4-Bromo-fluorobenzene (0.300 g, 1714 mmol), 4-Boc-amino-piperidine (0.411 g, 2.057 mmol), sodium tert-butoxide (0.230 g, 2.4 mmol), Tris (Dibenzylidenaceton) Dipaladium (0.249) were stirred. g, 0.257 mmol), 2- (Di-t-butylphosphinolbiphenol (0.1278 g, 0.4285 mmol) in toluene until the reaction was complete, The solution was diluted with EtOAc and filtered, the residue was concentrated and purified via The column was stirred with a mixture of EtOAc and hexane, the isolated material was stirred in TFA and the solvent was removed, the residue was diluted with methanol in the presence of hydroxy resin until the pH was basic, the solvent was decanted and concentrated to produce 0.115 g of the product (yield = 34.5%). Mass spectrum (m / e) 195.03 (M +).

Preparation 57 1-1- (4-Fluoro-phenyl) -pyrrolidin-3-ylamine The title compound was prepared by a similar method described for 1- (4-Fluoro-phenyl) -piperidin-4-ylamine above using I-2-diterbutylphosphinobiphenyl (0.108 g, 0.362 mmol) to isolate 0.136 g of solid material (Yield = 52%) Mass Spectrum (m / e): 181.0 (M ~).

Preparation 58 S) -1- (4-Fluoro-phenyl) -pyrrolidin-3-ylamine The title compound was prepared by a similar method described by 1- (4-Fluoro-phenyl) -piperidin-4-ylamine above using (S) -2-diterbutylphosphinobiphenyl (0.108 g, 0.362 mmol) to isolate 0.090 g of solid material (Yield = 34%) Mass Spectrum (m / e): 180.99 (M +).

Preparation 59 1- (4-Fluoro-phenyl) -azetidin-3-yl-amine The title compound was prepared by a similar method described for 1- (4-Fluoro-phenyl) -piperidin-4-ylamine above using tert-butyl azetidin-3-yl-carbamic acid ester (0.270 g, 0.186 mmol) isolate 0.115 g of solid material (Yield - 47%) Mass Spectrum (m / e): 168 (M +).

Preparation 60 C- (l-Phenyl-pi? Eridin-4-yl) -methylamine Prepare as in the methods described in J. of Med. Chem. 1999 vol. 42 (nol7) p3342-3355.

Preparation 61 [1- (4-Fluoro-phenyl) -azetidin-3-ylmethyl] -carbamic acid tert-butyl ester The title compound was prepared by a similar method described for [3- [(4-Fluoro-phenylamino) -methyl] -zetidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] ] -methanone using tert-butyl ester of azetidin-3-ylmethylcarbamic acid (215 mg, 1.15 mmol) to isolate 137 mg (42.3%) of light yellow foam. MS (m / e): 225.00 (M + 1-CH8).

Preparation 62 3- (tert-Butoxycarbonylamino-methyl) azetidine-1-carboxylic acid methyl ester The title compound was prepared by a similar method described for 3- [4- (3-phenyl-indole-1-sulfonyl) -benzoylamino] -zetidine-1-carboxylic acid methyl ester using tert-butyl ester of azetidin- 3-ylmethyl-carbamic acid (Beta Pharma: 559 mg, 3.00 mmol, 1 equivalent) to isolate 686 mg (93.6%) of colorless oil.

Preparation 63 Methyl ester of 3-aminomethyl-azetidine-l-carboxylic acid The title compound was prepared by a similar method described for (3-aminomethyl-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone using 3-methyl-3-methyl ester. (tert-butoxycarbonylamino-methyl) -azetidine-1-carboxylic acid (675 mg, 2.76 mmol) to isolate 399 mg (100%) of light yellow oil. MS (m / e): 144.98 (M + 1).

Preparation 64 [1- (4-Fluoro-phenyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester The title compound was prepared by a similar method described for N- [1- (4-fluoro-phenyl) -azetidin-3-yl] -4- (3-phenyl-indole-l-sulfonyl) -benzamide using 3- (tert-butoxycarbonylamino) pyrrolidine to isolate 341 mg (60.7%) of pale yellow crystalline solid. MS (m / e): 281.00 (M + l) Preparation 65 1- (4-Fluoro-phenyl) -pyrrolidin-3-llamine The title compound was prepared by a similar method described for (3-aminomethyl-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone using tert-butyl ester of the acid [1- (4-fluoro-phenyl) -pyrrolidin-3-yl] -carbamic acid (330 mg, 1.18 mmol) to isolate 204 mg (95.1%) of yellow oil. MS (m / e): 181.04 (M + 1).

Preparation 66 Methyl 5-cyano-nicotinic acid ester A solution of methyl 5-bromonicotinate (2.16 g, 10.0 mmol, 1 equivalent) and copper (I) cyanide (1.79 g, 20.0 mmol, 2.0 equivalent) is refluxed in reflux.

DMF anhydrous (10 ml) for 15 h. After allowing cooling, the reaction mixture was filtered through Celite®, rinsed with EtOAc (100 ml). A black precipitate formed in the filtrate. The filtrate was washed with salted H20 (3 x 100 ml). The organic layer was dried (anhydrous Na 2 SO 4) and rotary evaporated (40 ° C) to give 546 mg (33.7%) of product as a light yellow solid. This material was transferred to a column of silica gel (80 mm x 20 mm dia.) And levigated (20-35% EtOAc / hex) to yield 501 mg (30.9%) of 5-cyano- nicotinic as a whitish solid. MS (m / e): 163.07 (M + 1).

Preparation 67 5-Hydroxymethyl-n-trinonitrile Aluminum hydride and lithium (1.0M in THF; 1.5 mmol, 0.5 equivalents) for a period of 3 min to a solution of 5-cyano-nicotinic acid methyl ester (479 mg, 2.95 mmol 1 equivalent) in anhydrous THF (15 ml) and cooled to -78 ° C. After 1 h although still at -78 ° C, the reaction was quenched with H20 (60 μl), aqueous 5M NaOH (60 μl), and more H20 (180 μl). The reaction mixture was filtered through paper. The filtrate (40 ° C) was rotated to produce 369 mg of material as a yellow solid. This material was transferred to a column of silica gel (130mm x 25mm diameter) and levigated (2% MeOH / CH 2 Cl 2) to yield 180 mg of a mixture of ester, semiacetal, and aldehyde as a yellow solid and 45 mg (11%) of 5-hydroxymethyl-nicotinonitrile as a yellow solid. MS (m / e): 163.07 (M + 1).

Preparation 68 5-Chloromethyl-nicotinonitrile Thionyl chloride (1 ml) was added to a solution of 5-hydroxymethyl-nicotinonitrile (45 mg, 0.34 mmol, 1 equivalent) and anhydrous CH2C12 (1 ml). After 20 min, the reaction was basified with saturated aqueous NaHCO3 (12 mL). This mixture was extracted with Et20 (2x 5 ml). The combined organic layers (MgSO4) were dried anhydrous) and rotary evaporated (40 ° C) to yield 4.9 mg (9.6%) of 5-chloromethyl-nicotinonitrile as a yellow film. MS (m / z): 152.

Preparation 69 5-Aminomethyl-nicotinonitrile Dissolve 5-chloromethyl-nicotinonitrile (4.9 mg, 0.032 mmol) in NH3 of 2. OM in MeOH (1 mL). This solution was transferred to a pressure tube. The reaction solution was heated to aminomethyl-nicotinonitrile as a yellow oil. MS (m / e): 134.00 (M + 1).

Preparation 70 Tetrahydrofuran-3-ylmethyl methanesulfonic acid ester Triethylamine (6.0 ml, 4.4 g, 43 mmol, 2.1 equivalents) was added to a solution of tetrahydro-3-furanmethanol (2.0 ml, 2.1 g, 21 mmol, 1 equivalent) and methanesulfonic anhydride. (3.7 g, 21 mmol, 1.0 equivalent) in anhydrous CH2C12 (100 mL). After stirring for 20 h, the reaction solution was washed with aqueous 1M HCl (100 ml). The organic layer dried (Anhydrous MgSO4) and rotary evaporated (40 ° C) to produce 2. 77 g (74.0%) of the tetrahydro-furan-3-ylmethyl ester of methanesulfonic acid as a light yellow liquid.

Preparation 71 3-Azidomethyl-tetrahydrofuran Sodium azide (1.5 g, 23 mmol, 1.5 equivalents) was added to a solution of tetrahydro-furan-3-ylmethyl ester of methanesulfonic acid (2.76 g, 15.3 mmol, 1 equivalent) in anhydrous DMF (10 ml). The reaction mixture was heated at 50 ° C for 16 h. The reaction mixture was diluted with H20 (100 mL) and extracted with Et20 (2 x 50 mL). The combined organic layers were washed with H20 (2 x 50 ml), dried (anhydrous Na 2 SO 4), and rotary evaporated (40 ° C) to yield 1.20 g (61.6%) of 3-azidomethyl-tetrahydrofuran as a almost colorless liquid.

Preparation 72 (Tetrahydro-furan-3-yl) -methylamine A mixture of 3-azidomethyl-tetrahydrofuran (1.19 g, 9.36 mmol, 1 equivalent) and palladium on charcoal (10% Pd, 120 mg) in EtOH (20 ml) was stirred under H2 (1 atmosphere) for 18 h. The reaction mixture was filtered through Celite® and the filtrate (40 ° C) was evaporated by rotation to yield 777 mg (82.1%) of crude (tetrahydro-furan-3-yl) -methylamine as an almost colorless liquid.

Preparation 73 4-Aminomethyl-benzonitrile 4-Bromomethyl-benzonitrile (2.0 g, 0.010 mmol) was stirred in a sealed vessel in a 2N ammonia solution in methanol at 80 ° C until completion. The solvent is reduced in volume. The residue was dissolved in ethyl acetate and washed with 1N HCl. The aqueous layer was basified with 5N NaOH. The aqueous layer was extracted in dichloromethane. The organic layer was dried over MgSO4 and reduced in volume to isolate 0.223 g. Performance = 16.8%. Mass Spectrum (m / e): (M ").

Preparation 74 C- (Tetrahydro-pyran-2-yl) -methylamine 2- (Bromomethyl) tetrahydropyran (2.0 g, 11.16 mmol), sodium azide (1.088 g, 65.01 mmol), and DMF at 50 ° C were heated with stirring and until the reaction was complete. The reaction mixture was diluted with Et20 and washed with water once. The water layer was extracted with ether. Organic portions were combined and dried over MgSO4 and reduced in volume. Residual ethanol was diluted and introduced at 10% palladium (0.500 g) on carbon in the presence of hydrogen until the reaction was complete. The palladium was stirred over charcoal via filtration and concentrated to isolate 0.723 g. Yield = 56%.

Preparation 75 Methyl ester of 3-amino-pyrrolidine-l-carboxylic acid Methyl chloroformate (460 μl, 560 mg, 6.0 mmol, 3.0 equivalents) was added to a solution of 3- (tert-butoxycarbonylamino) pyrrolidine (TCI, 373 mg, 2.00 mmol, 1 equivalent) and triethylamine (1.1 ml, 800 mg 7.9 mmol, 3.9 equivalents) in anhydrous CH2C12 (4 mL). The emission of vigorous gas, a light exotherm, and precipitation may occur. After stirring for 30 min, the reaction mixture (60 ° C) was rotary evaporated. The resulting material was dissolved in MeOH to quench any residual chloroformate and the solution was rotary evaporated (60 ° C). Trifluoroacetic acid (5 ml) was added to this material causing the emission of the gas. The reaction solution was evaporated by rotation (40 ° C, subjected to 2 x azeotropy with MeOH). Resulting in a yellow oil was then dissolved in MeOH (30 ml) and hydroxide resin (Bio-Rad AG® 1-X8, 20-50 mesh, 9.3 g) was added to the amine free base. The mixture was filtered and the filtrate was evaporated by rotation (40 ° C, subjected to 2 × azeotropy with CH2C12) to yield 914 mg (300%) of crude product as a light brown oil. Mass spectrometry indicated the presence of the desired product. This oil was absorbed onto a SCX column (20 g) activated with 10% AcOH / MeOH. MeOH was pushed through the column to levigate any material without amine. The product was levigated with 2.0 M NH3 in MeOH to yield 269 mg (93.2%) of 3-amino-pyrrolidine-l-carboxylic acid methyl ester as a yellow oil.

Preparation 77 N- (4-Fluoro-benzyl) -4- (3-iodo-indol-l-sulfonyl) -benzamide Indole (2.93 g 0.025 mol) was dissolved in 10 ml of DMF. The solution was cooled in a water bath with ice. Potassium-t-butoxide (3.08 g, 0.0275 mol) and 10 ml of DMF were added. It was stirred in an ice bath for 22 minutes. Iodine (7.61 g, 0.03 mol) was added and stirred in a bath with ice for 32 minutes. The second shot of potassium-t-butoxide (3.08 g, 0.0275 mol) and 10 ml of DMF was added. The appropriate sulfonyl chloride, 4- (4-fluoro-benzylcarbamoyl) -benzenesulfonyl chloride, (9.01 g, 0.0275 mol) and 10 ml of DMF were added. It was stirred at room temperature for 16 hours. The reaction was quenched with 100 mL of water, and extracted with ethyl acetate (3Xl50ml). The organic products were washed with sodium metabisulphate (10 g in 100 ml of water), water (3 × 200 ml) and saturated brine (1 × 200 ml). The organics were concentrated and purified on silica gel using 20% ethyl acetate in heptane to obtain 6.96 g (yield = 52.2%) of the desired product as a colorless solid: 1 H NMR (DMSO): 9.2 (t, 1H ), 8.1 (m, 3H), 8.0 (m, 3H), 7.4 (m, 5H), 7.1 (m, 2H), 4.4 (d, 4H). MS (ES-) = 532.91 (M-1).

Preparation 78 N- (4-Fluoro-benzyl) -4- [3- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -indol-1-sulfonyl] -benzamide N- (4-Fluoro-benzyl) -4- (3-iodo-indol-l-sulfonyl) -benzamide (19g, 35.65 mmol), bis-pinnacolborane was added (10.86 g, 42.78 mmol), potassium acetate (10.49 g, 106.95 mmol), PdCl2 (dppf) 2 (2.92 g, 3.57 mmol) in DMF (125 mL). The mixture was heated at 100 ° C under nitrogen for 5 hours. The mixture was cooled to room temperature and quenched with ethyl acetate (200 ml) and water (200 ml). The mixture was filtered through Celite. The layers were separated and the organics washed with water (3X200ml) and a saturated brine solution (200ml). The organic products were dried over magnesium sulfate, filtered and concentrated to an oil which was crystallized with ether (200 ml). The white solid was filtered and dried in a vacuum oven at 50 ° C overnight to yield (5.6 g) as a white solid. Mp 158-160 ° C; XH NMR (DMSO): 9.2 (t, 1H), 8.1 (m, 3H), 8.0 (m, 3H), 7.4 (, 5H), 7.1 (m, 2H), 4.4 (d, 4H), 1.3 (s) , 12H). MS (ES) = 533.4 (M-1).

Preparation 79 4- (3-Cyclopentyl-indole-1-sulfonyl) -benzoic acid It was added to a stirring solution of 4- (3-Cyclopentyl-indole-1-sulfonyl) -benzoic acid methyl ester (2.0 g, 5.22 mmol) in THF (50 ml) and MeOH (25 ml), 5N NaOH ( 3 ml, 2.9 equivalents). The solution was stirred for 2 h at room temperature and the solvents were removed to produce a paste. The pulp was treated with IN HCl (25 mL) and a solid resulted. It was further diluted with water (50 ml). The solid was filtered, washed again with water, and dried (20 mm Hg, 60 ° C) to yield the pure title compound (1.63 g, 84%); aH NMR (DMSO-d6) d 8.06 (m, 4H), 7.93 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.53 (s, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 3.17 (m, 1H), 2.08 (m, 2H), 1.69 (m, 6H); MS (ESI) m / z 368 (m-H).

Preparation 80 4- (3-Chloro-indazole-1-sulfonyl) -N- (4-fluoro-benzyl) -benzamide Dissolve 3-chloro-lH-indazole (120 mg, 0.79 mmol) and 4- (4-fluoro-benzylcarbamoyl) -benzenesulfonyl chloride (114 mg, 0.35 mmol) in CH2C12 (2.0 ml) and treated with Et3N (50 1, 0.36 mmol). The solution was stirred for 1 h at RT, then diluted with additional CH2C12 (20.0 mL) and washed with saturated aqueous NaHCO3 (15 mL). The organic phase was dried, filtered and concentrated and the crude material was purified by flash chromatography (100% hexanes at 50% EtOAc / hexanes linear gradient) to yield the title compound (129 mg, 83%) as a white foam. MS (ES) + 443.9 (M + l) +, (ES-) 442.0 (Ml) X ^ H NMR (400 MHz, CDC13): d 8.17 (d, 1H, J = 8.3), 8.03 (d, 2H, J = 8.2), 7.83 (d, 2H, J = 8.9), 7.64 (m, 2H), 7.41 (t, 1H, J = 7.4), 7.27 (m, 2H), 7.01 (t, 2H, J = 8.9), 6.31 (br s , 1H), 4.57 (d, 2H, J = 5.9).

Preparation 81 2-Phenyl-azetidine 4-Phenyl-azetidin-2-one (1.0 g, 4.28 mmol) was dissolved in anhydrous THF (20 ml) and treated with 1.0 M lithium aluminum hydride solution (8.57 ml, 2.0 equivalents) at room temperature. It was stirred for 15 h, cooled to 0 ° C in an ice bath and quenched with 8.5 ml of 1.0 M NaOH then 8.5 ml of H20. The resulting solution was filtered through celite with additional EtOAc, dried with MgSO 4, filtered and evaporated to yield a milky white oil which solidifies on standing. 2-Phenyl-azetidine was used without further purification.

Preparation 82 4- (3-Iodo-indol-l-sulfonyl) -benzoic acid methyl ester 250 g of 4-sulfobenzoic acid were made in 750 ml of thionyl chloride. 0.5 ml of DMF was added, and the mixture was heated to reflux for 6 hours. 2 1 of toluene were added and the thionyl chloride was azeotropically removed. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to produce an oil which crystallized on standing. To obtain 222 g of 4-chlorosulfonyl-benzoyl chloride as a low melting solid. In a RBF of 22 1, 4-chlorosulfonyl-benzoyl chloride (990 g, 4.159 mol) was charged in 8.3 1 of THF and cooled to -78 ° C. Triethylamine (588 ml, 4,159 mol), methanol (168 ml, 4,159 mol), DMAP (5 g, 0.041 mol) and 4 1 THF were charged into an addition funnel.; this solution was added dropwise to the reaction to maintain the exotherm < -70 ° C, for 5 hours. After the addition was complete, the reaction was stirred in a cold bath overnight. The reaction was filtered and rinsed with 3X 500 mL of THF. The filtrate was concentrated under vacuum to yield a yellow solid. The solid was dissolved in 7 1 EtOAc and 7 1 HCl 1N. The organic layer was separated and washed with 5 l of brine. The organic products were dried over Na 2 SO 4, filtered and concentrated under vacuum to yield a white solid, 4-chlorosulfonyl-benzoic acid methyl ester. Yield = 93.1% (906 g).

In an RBF of 22 1, indole (181 g, 1545 mol) and 800 ml of DMF were charged. It cooled to < 10 ° C in a water bath with ice. The first potassium-t-butoxide grain (190.4 g, 1.70 mol) was added. Exotherm at 18.5 ° C. It was rinsed with 400 ml of DMF. It was stirred 30 minutes while cooled back to < 10 ° C. Iodine (470.6 g) was dissolved in 400 ml of DMF and charged to the addition funnel. This solution was added dropwise to the reaction for 30 minutes. The temperature was maintained < 10 ° C. Stirred to < 10 ° C for 2.5 hours. The second shot of potassium-t-butoxide (190.4 g, 1.70 mol) was added and rinsed with 400 ml of DMF. It was stirred for 30 minutes while it was cooled to 10 ° C and 4-chlorosulfonyl-benzoic acid methyl ester was added all at once. Exotherm at 28 ° C. It was rinsed with 400 ml of DMF. It cooled to < 10 ° C and then stirred at room temperature overnight. 6 1 of DI water was added at room temperature. The exotherm at 31 ° C and the reaction was thickened with solids. 5 1 EtOAc was added and stirred 15 min. The solids were filtered (which are the product). 315.1 g of white solid were obtained as the first culture. The filtrate was separated from the first culture, and the 2 X 31 aqueous layer of EtOAc was extracted. All organic products were combined and 2X 625 g of sodium acid sulfite in 4 1 of DI water and 2 X 3 1 of DI water and 1 X 31 of brine were washed. The organic products were dried by Na2SO4, filtered and rinsed with EtOAc. The organic products were removed under vacuum to yield a yellow-orange solid, the solid was rendered watery in 4% ether overnight to produce a second product culture of 240 g. The total yield = 81.4% (555.1 g). MS (El) m / z 440.9 (M + H).

Preparation 83 5-chloro-2-cyanopyridine It was added in a 22-neck 3-necked round bottom flask, equipped with overhead stirrer, reflux condenser, and thermometer, N, N-dimethylacetamide (DMAC, 6 1), 2,5-dichloropyridine (347.0 g, 2.34 g. mol), zinc cyanide (138.0 g, 1.17 mol), bis (diphenylphosphino) dipalladium II CH2C12 complex (DPPF, 20.8 g, 0.02 mol), and zinc powder (1.6 g, 0.02 mol). The reaction mixture was heated slowly to 160 ° C. When the temperature reaches 160 ° C, an exotherm (controllable) can result and the internal temperature can be raised to 180-185 ° C. The heat was removed from the dark solution and the mixture was cooled slowly to room temperature. The volumetric reaction mixture was extracted by taking 2 1 of the dark solution, diluting with brine (2 1), filtered over celite, and ethyl acetate (4 1) was added. The process was repeated 3 times to extract all the material, and the combined organic extracts were dried over magnesium sulfate. Careful concentration at 25-30 ° C will produce a dark liquid. (Note: the volatility of the product can be observed at a higher temperature so that the temperature with the concentration remained low at all stages.) The liquid was stirred and water (5 1) was added, resulting in a solid. After 1 h, it was filtered and again washed with water (2 1). The filter cake was dried to yield 215 g of crude product. The aqueous filtrate was extracted with ethyl ether (8 1). The organics were dried over magnesium sulfate and concentrated to yield 51 g of crude product. It was combined with the 215 g batch and purified by chromatography on silica gel (biotage 150, eluted with 5% ethyl acetate in hexanes increasing to 10% ethyl acetate in hexanes) to yield a white solid of the compound of the pure title (193 g, 59%); 1 H NMR (CDC13) d 8.68 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.7, 8.6 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H).

Preparation 84 2-Cyano-5-fluoropyridine It was added in a 5-necked 3-necked round bottom flask, equipped with overhead stirrer, reflux condenser, thermometer, and N 2, 5-chloro-2-cyanopyridine line (193.0 g, 1.39 mol) and 1-methyl. -2-pyrrolidinone (NMP, 21). The mixture was heated and stirred at 210-220 ° C for 4 h. The reaction mixture was cooled to room temperature, stirred overnight, and filtered. The filter cake was washed with ethyl ether (11). The filtrate was extracted with water (6 1) and ethyl ether (3 X 5 1). Combine the organic products and extract again with water (8 1) and dry over magnesium sulfate. Concentrated at 25-30 ° C to produce an oily semi-solid, 193 g. Chromatographed on flash silica gel (5% ethyl acetate in hexanes gradually increasing to 10% ethyl acetate in hexanes) to yield the title compound as a white solid. The solid was dissolved in ethyl ether, filtered and hexanes added. Concentrated at low volume to provide a primary culture of the pure title compound, 60 g. The crystallization process was repeated in the filtrate to provide a second crop of the highly pure title compound, 24.0 g. (The final filtrate was concentrated to a white solid of good quality product, and re-chromatographed, as above, to provide an additional 38.6 g of material). A total yield of the title compound of 122.4 g, 72% was obtained; aH NMR (CDC13) d 8.59 (d, J = 3.0 Hz, 1H), 7.75 (m, 1H), 7.55 (m, 1H) Preparation 85 (Dihydrochloride) 2-aminomethyl-5-fluoropyridine A mixture of 2-cyano-5-fluoropyridine was combined (63.2 g, 0.52 mol), 22.5 g of Raney nickel, and ethanol (1.5 L) saturated with ammonia and hydrogenated at 500 p.s.i. and 70 ° C for 16 h. The dark purple liquid was chromatographed on silica gel flash chromatography (methylene chloride / methanol / ammonia hydroxide 95: 4.5: 0.5) to produce, after concentration at 25-30 ° C, a yellow liquid from the desired pure free base, 25.0 g (44%); XH NMR (DMSO-) d 8.43 (d, J = 2.9 Hz, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 3.77 (s, 2H), 2.10 (br, 2H); MS (ESI) m / z 127 (m + H). It was added to a solution of the free base (20.0 g, 159.0 mmol) in 150 ml of 1,4-dioxane, 4N HCl in dioxane (150 ml, 3.8 eq.) And a white solid was separated immediately. The solid was diluted with ethyl ether (300 ml) and filtered. The product was dried at 20 mm Hg, 60 ° C, to yield the title compound pure dihydrochloride, 30.0 g (95%); XE NMR (DMSO- 5) d 8.61 (d, J = 2.9 Hz, 1H), 8.50 (brs, 3H), 7.82 (m, 1H), 7.62 (m, 1H), 7.50 (br, 1H), 4.18 (m, 2H); MS (ESI) m / z 127 (m + H, free base).

Preparation 87 N-pyridin-2-yl-N '-styryl-hydrazine Pyridin-2-yl-hydrazine and phenyl-acetaldehyde were reacted under the conditions of the literature (Azaindoles I. Preparation of 7-azaindoles by thermal indolization of 2-pyridylhydrazones Canadian Journal of Chemistry (1966), 44 (21) , 2455-9) to produce N-pyridin-2-yl-N '-styryl-hydrazine (10 g, 100% yield of crude material). Mass spectrum (m / e): 211.96 (MH +).

Preparation 88 3-phenyl-lH-pyrrolo [2, 3-b] pyridine The N-pyridin-2-yl-N '-styryl hydrazine was reacted according to published literature conditions (Azaindoles I. Preparation of 7-azaindoles by thermal indolization of 2-pyridylhydrazones Canadian Journal of Chemistry ( 1966), 44 (21), 2455-9) to produce 3-phenyl-lH-pyrrolo [2, 3-b] pyridine (2.5 g, 45% yield) as a dark solid. Mass spectrum (m / e): 194.96 (MH +).

Preparation 91 4- [3- (1-Hydroxy-cyclohexyl) -indol-1-sulfonyl] -benzoic acid methyl ester Via an addition funnel the 2M EtOEt solution of cyclopropyl magnesium bromide (2.16 g, 6.23 ml, 12.46 mmol, 1.1 eq) was added slowly to the solution of THF -78 ° C (30 ml) of methyl ester. of 4- (3-iodo-indol-l-sulfonyl) -benzoic acid (5 g, 11.33 mmol, 1.00 eq.). It was stirred for 2 hours and then warmed to 0 ° C. It was stirred for 0.5 hours. The mixture was again cooled to -10 ° C and then a solution of THF (3 ml) of cyclohexanone (1298 g, 13.03 mmol, 1.15 eq.) Was slowly added. It was stirred for 15 min and warmed to room temperature. It was stirred for 1.5 days. The reaction was quenched with saturated aqueous ammonium chloride, the organics were removed on the rotoevaporator, and EtOAc was added to the crude mixture. The product was extracted in organics, the organics were separated, dried over MgSO4, and concentrated in a rotoevaporator to produce the crude product as an oil. Purified by silica gel chromatography to yield 4- [3- (1-hydroxy-cyclohexyl) -indol-1-sulfonyl] -benzoic acid methyl ester (948 mg, 20% yield).

Preparation 92 4- (3-Cyclohexyl-indol-l-sulfonyl) -benzoic acid methyl ester Under N2 / triethylsilane (676 mg, .929 ml, . 82 mmol, 2.6 eq. ) followed by trifluoroacetic acid (4.08 g, 2.7 ml, 35.79 mmol, 16.0 eq.) to a solution of CH2C12 (20 ml) of 4- [3- (1-hydroxy-cyclohexyl) -indol-1- methyl-methyl ester sulfonyl] -benzoic acid (925 mg, 2.24 mmol, 1 eq.). It was stirred for 1.5 hours and then the volatiles were removed in the rotoevaporator. EtOAc was added to the crude mixture and worked up with saturated aqueous sodium bicarbonate. The product was extracted in organics, the organics were separated, dried over MgSO4, and concentrated in rotoevaporator to produce the crude product as a rose oil. Purified by silica gel chromatography to yield the 4- (3-cyclohexyl-indole-1-sulfonyl) -benzoic acid methyl ester (775 mg, 87% yield) as a white solid. Mass spectrum (m / e): 397.99 (MH +).

Preparation 93 4- (3-Cyclohexyl-indole-l-sulfonyl) -benzoic acid 5N sodium hydroxide (1.17 ml, 3 eq.) Was added to a solution of 4- (3-cyclohexyl-indole-1-sulfonyl) -benzoic acid methyl ester (775 mg, 1.95 mmol, 1 eq) dissolved in a mixture of 10 ml of THF and 5 ml of MeOH. It was stirred for 1.5 hours. The solvent was removed in the rotoevaporator and IN HCl was added. The solid that broke off from the solution was dissolved in EtOAc. The product was extracted in organics, the organics were separated, dried over MgSO4, and concentrated in rotoevaporator to produce 4- (3-cyclohexyl-indole-1-sulfonyl) -benzoic acid (646 mg, 86% yield) as a white solid.

Preparation 94 4- [3- (3, 3-difluoro-cyclopentyl) indol-1-sulfonyl] -benzoic acid methyl ester Potassium tert-butoxide (368 mg, 3.28 mmol, 1.1 eq.) Was added to a solution of dioxane (3 mL) of 3- (3, 3-difluoro-cyclopentyl) -lH-indole (660 mg, 2.98 mmol, 1.0 eq) under N2. The solution was stirred for 5 minutes. 4-Chlorosulfonyl-benzoic acid methyl ester (117 mg, 0.497 mmol, 1.1 eq) was added. The reaction was stirred for 4 hours at room temperature. The reaction of the solvent was stirred and purified by silica gel chromatography to yield 4- [3- (3, 3-difluoro-cyclopentyl) -indol-1-sulfonyl] -benzoic acid methyl ester (466 mg, 37%). % of performance).

Preparation 95 4- [3- (3, 3-difluoro-cyclopentyl) -indol-1-sulfonyl acid] Aqueous sodium hydroxide (5N, 0.72 ml, 3 eq.) To a solution of 4- [3- (3,3-difluoro-cyclopentyl) -indol-1-sulfonyl] -benzoic acid methyl ester (500 mg, 1.20 mmol, 1 eq) in 5 ml of THF , 2.5 ml of MeOH. The reaction was stirred at room temperature for 2 hours. The solvent was removed in the rotoevaporator and IN HCl and EtOAc were added. The products were extracted in organic, the organics were separated, and then the organics were dried with MgSO4. The drying agent was filtered off, and the organics were removed in rotoevaporator to produce 4- [3- (3,3-difluoro-cyclopentyl) -indol-1-sulfonyl] -benzoic acid (450 mg, 92% yield). ) which was used without further purification.

Preparation 96 3-piperidin-l-yl-l-triisopropylsilanyl-lH-indole Piperidine (1.20 mL, 12.9 mmol) was dissolved in THF (10 mL) and treated with lithium bis (trimethylsilyl) -amide (1.0M in THF, 11.2 mL, 11.2 mmol). To the above solution, 3-bromo-l-triisopropylsilanyl-1H-indole (TCI-US, 3.04 g, 8.63 mmol), (2'-dicyclohexyl-phosphanyl-biphenyl-2-yl) -dimethyl-amine (88 mg, 0.22 mmol), and Pd2dba3 »CHCl3 (225 mg, 0.22 mmol). The red solution was heated at 70 ° C for 4 hours after cooling to RT and concentrated. The crude material was purified by flash chromatography, using a linear gradient of 100% hexanes to 40% EtOAc / hexanes to give the title compound (837 mg, 27%). MS (ER +) 357.2 (M + 1) +. XH NMR (400 MHz, CDC13): d 7.61 (d, 1H, J = 8.4), 7.41 (d, 1H, J = 8.4), 7.07 (m, 2H), 6.68 (s, 1H), 3.03 (m, 4H), 1.79 (m, 4H), 1.65 (septet, 3H, J = 7.7), 1.58 (m, 2H), 1.12 (d, 18H, J = 7.1).

Preparation 97 3-piperidin-l-yl-lH-indole Add -_Bu4NF (1.0M in THF, 3.2 mL, 3.2 mmol), to a solution of 3-piperidin-1-yl-1-triisopropylsilanyl-1H-indole (835 mg, 2.34 mmol) in THF (10 mL). The red solution was stirred at RT for 1 h, then diluted with EtOAc (40 mL) and washed with saturated NaHCO 3 (20 mL). The organic solution was dried, filtered and concentrated, then the crude material was purified by flash chromatography, using a linear gradient of 100% hexanes to 40% EtOAc / hexanes. The title compound (347 mg, 74%) was obtained as a gray solid. MS (ER +) 201.1 (M + 1) A X H NMR (400 MHz, CDC 13): d 7.65 (d, 1 H, J = 8.1), 7.59 (br s, 1 H), 7.29 (d, 1 H, J = 8.4) , 7.16 (t, 1H, J = 7.5), 7.06 (t, 1H, J = 7.9), 6.70 (s, 1H), 3.03 (m, 4H), 1.80 (m, 4H), 1.59 (m, 2H) .

Preparation 98 4-fluoro-3-methoxy-benzylamine 4-Fluoro-3-methoxy-benzonitrile (2 g) was added, 0.01 mol), 10% palladium on carbon (0.400 g) and glacial acetic acid (120 ml) to a pressure vessel. The pressure vessel was purged with nitrogen, the reaction mixture was pressurized with hydrogen (415 Kpa), the vessel was sealed and the reaction was stirred. After 8 hours the stirring was stopped, the excess hydrogen was vented from the vessel and purged with nitrogen. The reaction mixture was filtered to remove the palladium on 5% carbon and return the filtrate for product isolation. The crude solution was concentrated, redissolved in CH2C12 (80 mL) and washed with 5N NaOH (35 mL). The aqueous and organic phases were separated and the aqueous extracted with additional CH2C12 (20 ml). The organic solutions were combined, dried, filtered and concentrated to give the crude material 2.08 g (100%). The title compound as the main product (Rf = 0.12, 10% MeOH / CH2C12) was used without further purification. MS (ER +) 156.1 (M + 1) A X H NMR (400 MHz, CDC13): d 7.01 (dd, 1H, J = 8.2, 11.4), 6.95 (dd, 1H, J = 2.1, 8.4), 6.80 (m , 1H), 3.89 (s, 3H), 3.82 (s, 2H), 1.54 (br s, 2H).

Preparation 99 Chloride of 4- (4-fluoro-3-methoxy-benzylcarbamoyl) 4-Chlorosulfonyl-benzoyl chloride (3.18 g, 13.3 mmol) was dissolved in THF (25 mL) and cooled to -78 ° C. A pre-mixed solution of 4-fluoro-3-methoxybenzylamine (1.91 g, 12.3 mmol), Et3N (1.64 mL, 11.8 mmol) and DMAP (150 mg, 1.23 mmol) in THF (25 mL) was added slowly. to the previous cooled solution for 1 hour. The resulting mixture was stirred at -78 ° C for 1 hour, then warmed to RT and stirred for 4 hours. All solids were removed by filtration and washed with THF (5 mL). The filtrate was concentrated and the crude material was redissolved in EtOAc (30 mL) and washed with 1N HCl (30 mL). The aqueous and organic layers were separated and the aqueous phase was extracted with additional EtOAc (30 mL). The organic solutions were combined, dried, filtered and concentrated. The crude material was purified by flash chromatography, using a linear gradient of 100% hexanes to 40% EtOH / hexanes, to give the title compound as a white solid (1.36 g, 28%). MS (ER ") 356.1 (-l) A X H NMR (400 MHz, CDC13): d 8.11 (d, 2H, J = 8.3), 8.00 (d, 2H, J = 8.8), 7.05 (dd, 1H, J = 8.2, 11.1), 6.96 (dd, 1H, J = 1.9, 8.0), 6.86 (m, 1H), 6.44 (br s, 1H), 4.61 (d, 2H, J = 5.7), 3.88 (s, 3H) ).

Preparation 100 Cyclopentyl- (2-fluoro-phenyl) -metanone 2-Fluorobenzonitrile (5.0 g, 41.04 mmol) in 80 ml of THF was stirred with a THF solution of 2 molar cyclopentyl magnesium bromide (20.51 ml, 41.01 mmol) and CuBr (0.100 g, 0.697 mmol) for 15 hours at 60 ° C under argon gas. A 15% solution of sulfuric acid was added to the reaction at 0 ° C and stirred for 15 hours. The reaction mixture was extracted three times with diethyl ether. The organic layers were combined and dried over MgSO4 and concentrated. The residue was purified via column chromatography using the mixture of ethyl acetate and hexanes; to give 3.085 grams. Yield 40% EM (ER) = 192.15 (M + 1) +.

Preparation 101 3-cyclopentyl-lH-indazole Cyclopentyl- (2-fluoro-phenyl) -methanone (2.5 g, 13.005 mmol) was dissolved in hydrazine (20 ml), heated at 130 ° C for 72 hours. The mixture was cooled to 0 ° C. The precipitate was filtered and washed with cold water to give the title compound: 2171 g (yield = 89%) EM ER + 187.12: MSES-185.22.

Preparation 102 4- (3-Cyclopentyl-indazol-1-sulfonyl) -benzoic acid methyl ester 3-Cyclopentyl-lH-indazole (2168 g, 11,640 mmol) was combined with triethylamine (3.526 g, 34.92 mmol) in 50 mL of dichloromethane. Chlorosulfonyl-benzoic acid methyl ester (4.085 g, 17,460 mmol) in 50 ml dichloromethane was dissolved and added dropwise to a solution at 0 ° C. The reaction was stirred for 12 hours. The reaction was diluted and washed with NaHCO3. The organic layer was dried over MgSO4 and concentrated. The residue was purified via column chromatography with a mixture of ethyl acetate and hexanes to isolate 2.046 g (yield = 48.5%) of the title compound: MS ER + 385.3.

Preparation 103 4- (3-Cyclopentyl-indazole-1-sulfonyl) -benzoic acid 4- (3-Cyclopentyl-indazole-1-sulfonyl) -benzoic acid methyl ester (2.045 g, 5.325 mmol) in 50 mL of THF was combined. 3 ml of 5N NaOH was added and allowed to stir for 15 hours. The reaction was made acidic with HCl and extracted into diethyl ether. The organic layer was dried over MgSO4 and concentrated to isolate 1243 g (yield = 63%) of the title compound: MS ER + 369.47; EM ER- 369.46 Preparation 104 (S) -1- (4-fluoro-phenyl) -pyrrolidin-3-ylamine NH JKX Tert-butyl ester of (S) -pyrrolidin-3-yl-carbamic acid (1741 mmol), l-bromo-4-fluorobenzene (1.45 mmol), Pd2dba (0.217 mmol), NaOtBu were combined (2.03 mmol), 2-di-t-butylphosphinolbiphenyl (0.362 mmol) in 30 ml of toluene, and stirred at 80 ° C. The solution was diluted with ethyl acetate and filtered. The solution was concentrated. The residue was purified via column chromatography with a mixture of ethyl acetate and hexanes and a mixture of methanol and trifluoroacetic acid was added and stirred for 1 hour at 0 ° C. The reaction was concentrated and dissolved in methanol in the presence of hydroxy resin until the pH was 10. The solution was filtered and concentrated to isolate 0.136 of the title compound, yield = 52 MS ER- = 182.0 Preparation 105 Azetidin-3-yl (4-fluoro-phenyl) -amine A procedure similar to l- (4-fluoro-phenyl) -pyrrolidin-3-ylamine was used to give 0.053 g (yield = 21%) of the title compound. EM ER not observed.

Preparation 106 C- (tetrahydro-pyran-2-yl) -methylamine C- (Tetrahydro-pyran-2-yl) -methylamine was combined with sodium azide and heated at 50 ° C for 15 hours in 30 ml of DMF. The reaction was diluted with dichloromethane and washed with NaHCO3. The organic layer was treated with MgSO4 and concentrated. The residue was dissolved in 30 ml of ethanol with palladium on carbon in the presence of hydrogen gas until the reaction was complete. The reaction mixture was filtered. The solvent was concentrated to yield 1.32 g of the title compound (yield = 54.9%) EM ER + 115.95.

Preparation 107 4- (3-Cyclopent-1-enyl-indol-1-sulfonyl) -benzoic acid methyl ester In a 12 L RBF, 4- (3-iodo-indol-1-sulfonyl) -benzoic acid methyl ester (620 g, 1,406 mmol), cyclopentene (958 g, 14.06 mol), potassium acetate (414 g) were charged. , 4.218 mol), tetrabutylammonium chloride (391 g, 1,406 mmol), palladium acetate (15.8 g, 0.0703 mol) and DMF (6.2 L). The mixture was heated at 60 ° C for sixteen hours, cooled and filtered through Hyflo. The filter cake was washed with ethyl acetate (5L). Additional ethyl acetate (4L) and DI water (12L) were added. It was stirred for 30 minutes, the layers were separated and the organic layer was washed with brine (6 L). The organic layer was dried over sodium sulfate, filtered and the paste was rinsed with ethyl acetate (2 L). The solvents were removed under vacuum to give 609 g of a dark oil. The oil was dissolved in methylene chloride (1L) and filtered through silica gel (6 kg). The silica plug was washed with MTBE (20L) to levigate the product. The MTBE layer was concentrated under vacuum to give 535 g of an oil (yield = 99.8%) of the title compound.

Preparation 108 4- (3-Cyclopentyl-indol-1-sulfonyl) -benzoic acid methyl ester In a 3 gallon (11.37 liter) autoclave, 4- (3-cyclopent-1-enyl-indole-l-sulfonyl) -benzoic acid methyl ester (475 g), ethyl acetate (2.5 L), ethanol was charged. absolute (2.5 L) and 10% Pd-C (45 g, w / w), under 35 psi of hydrogen at room temperature for 5 hours. The crude reaction was filtered over Hyflo. The filtrate was concentrated under vacuum to give a light yellow solid (465 g) of the title compound.

Preparation 109 4- (3-Cyclopentyl-indole-1-sulfonyl) -benzoic acid In a 12 L RBF, 4- (3-cyclopentyl-indole-1-sulfonyl) -benzoic acid methyl ester (465 g, 1.213 mol) and THF (4.7 L) were charged. 5N NaOH (485 ml) was added dropwise at room temperature. The solution was stirred at room temperature overnight. The pH of the reaction was brought to 1 with conc. HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (4L). The combined organic layers were dried over sodium sulfate, filtered and rinsed with ethyl acetate. The organics were concentrated under vacuum to give a whitish solid (401 g, yield = 89.5%) of the title compound.

Preparation 110 Tetrahydro-pyran-4-carboxylic acid amide Into a 5L flask, methyltetrahydropyran-4-carboxylate (500 mL, 3.75 mol) and concentrated aluminum hydroxide (1.3 L) were charged and the reaction was stirred at room temperature for 48 hours. The reaction was filtered and the white solid was dried in a vacuum oven at 60 ° C overnight to obtain 36.33 g of white solid of the title compound.

Preparation 111 C- (tetrahydro-pyran-4-yl) -methylamine Into a 2L flask, tetrahydro-pyran-4-carboxylic acid amide (51 g, 0.395 mol) and THF (1.3L) were charged and the reaction was cooled in an ice bath. LAH (30 g, 0.791) was added per portion. The reaction was stirred at 10 ° C for 16 hours and quenched by the dropwise addition of DI water (30 ml), 15% NaOH (30 ml), and DI water (90 ml). The reaction was stirred at room temperature for 16 hours. The salts were filtered and the filtrate was concentrated under vacuum to give 36.79g of the clear oil of the title compound.

Preparation 112 Acid 4-. { [4- (3-phenyl-indole-1-sulfonyl) -benzoylamino] -methyl} - benzoic 4- (3-Phenyl-indole-1-sulfonyl) -benzoic acid (1324 mmol) was combined with N-hydroxy-succinamide (NHS-1457 mmol), and EDC (1324 mmol) and stirred in 20 ml of dichloromethane by 15 hours. The reaction condensed to produce a solid. 0.613 g was isolated (yield = 97.6%). 1.05 mmol of the residue was reacted with 4-amino-methyl-benzoic acid (1.05 mmol) in 3 ml of dichloromethane for 15 hours. The reaction mixture was diluted and washed with IN HCl. Dichloromethane was treated with MgSO 4 and concentrated. A mixture of 4- (3-phenyl-indole-1-sulfonyl) -benzoic acid and the compound 0.258 g (48%) was isolated: MS ER + 5.10-77 MS ER-509.21.

Example 1 N- (4-Fluoro-benzyl) -4- (3-phenyl-pyrrolo [3,2-c] pyridin-1-sulfonyl) -benzamide A solution of THF 5 ml of 3-phenyl-lH-pyrrolo [3,2-c] pyridine (500 mg, 2.57 mmol, 1 eq.) Was added to a solution of THF 4 ml of KotBu (303 mg, 2.70 mmol , 1.05 eq.), Under N2 atmosphere. The reaction was stirred for 10 minutes and then a 5 ml THF solution of 4- (4-fluoro-benzylcarbamoyl) -benzenesulfonyl chloride (844 mg, 2.57 mmol, 1 eq.) Was added. The reaction was stirred for 16 hours, the solvent was removed on a rotary evaporator, and purified by chromatography on silica gel to give N- (4-fluoro-benzyl) -4- (3-phenyl-pyrrolo [3.2]. -c] pyridine-1-sulfonyl) -benzamide (982 mg, 79% yield). Mass spectrum (m / e): 485.96 (MH +).

Example 2 N- (4-Fluoro-benzyl) -4- [3- (3-oxo-cyclopentyl) -indol-1-sulfonyl] -benzamide A solution of DMF 3 ml of 3- (lH-indol-3-yl) -cyclopentanone (500 mg, 2.57 mmol, 1 eq.) Was added to a solution of DMF 3 ml of NaH (155 mg, 60% strength). weight, 3.86 mmol, 1.1 equiv.) under N2 atmosphere. The reaction was stirred for 15 minutes and then a solution of DMF 5 ml of 4- (4-fluoro-benzylcarbamol) -benzenesulfonyl chloride (1.27 g, 3.86 mmol, 1.1 eq.) Was added. The reaction was stirred for 48 hours, the solvent was stirred on a rotary evaporator and purified by chromatography on silica gel to give N- (4-fluoro-benzyl) -4- [3- (3-oxo-cyclopentyl) - indole-1-sulfonyl] -benzamide (375 mg, 22% yield). Mass spectrum (m / e): 490.53 (MH +).

Example 3 N- (4-Fluoro-benzyl) -4- (3-propyl-indole-1-sulfonyl) -benzamide 60% NaH in mineral oil (0.080 g, 2.0 mmol) was added to a stirred solution of 3-propyl-indole (0.266 g, 1.67 mmol) in dry THF (25 mL) under N2. The reaction mixture at room temperature for 45 minutes. 4- (4-Fluoro-benzylcarbamoyl) -benzenesulfonyl chloride (0.547 g, 1.67 mmol) was added per portion at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into a two-phase mixture of EtOAc (150 mL) and saturated sodium NaHCO 3 solution (50 mL). The organic layer was separated, washed with brine, separated and dried (MgSO4). The filtrate was filtered and evaporated. The residue was purified on the chromatron using a 4 mm plate and levigating with a hexane-EtOAc gradient system to give 0.262 g (34%) of N- (4-fluoro-benzyl) -4- ([3-propyl-indole-l-sulfonyl] -benzamide) Mass spectrum (m / e) (M + l) 451.1.

Example 5 N- (4-Fluoro-benzyl) -4-pyrrolo [2, 3-b] pyridin-1-sulfonyl) -benzamide MeCN (2 ml) was added to a flask under N2 containing 4- (4-fluoro-benzylcarbamoyl) -benzenesulfonyl chloride (50 mg, 0.152 mmol), IH-pyrrolo [2, 3-b] pyridine (18 mg, 0.152 mmol), 4-pyrrolidin-1-yl-pyridine (2 mg, 0.167 mmol), and triethylamine (17 mg, 0.167 mmol). The reaction was heated at 80 ° C for 16 hours. The solution was cooled to room temperature, MeCN was removed in a rotary evaporator. The crude material was purified on silica gel to give 45 mg (73% yield) of N- (4-fluorobenzyl) -4- (pyrrolo [2, 3-b] piperidin-1-sulfonyl) -benzamide. Mass spectrum (m / e): 410.1 (M +). The following sulfonamides were prepared in Table 1 using methods similar to those noted in the reference examples.

Table 1 Example 53 N- (4-Fluoro-benzyl) -4- (3-piperidin-l-yl-indazol-l-sulfonyl) benzamide 4- (3-Chloro-indazol-1-sulfonyl) -N- (4-fluoro-benzyl) -benzamide (91 mg, 0.20 mmol) was dissolved in piperidine (1.0 mL) and stirred at 90 ° C. The solution was diluted with EtOAc (30 ml) and washed with 1 N HCl (15 ml) and saturated NaHCO 3 (15 ml). The organic solution was dried, filtered and concentrated and the residue was purified by flash chromatography, using a linear gradient of 100% hexanes to 50% EtOAc / hexanes, to give the title compound as a light yellow foam (7 mg , 7%). MS (ES) 493.0 (M + 1) +, 491.2 (M-1) -.

Example 54 N- (4-Fluoro-benzyl) -4- (3-morpholin-4-yl-indazol-l-sulfonyl) benzamide 4- (3-Chloro-indazol-1-sulfonyl) -N- (4-fluoro-benzyl) -benzamide (91 mg, 0.20 mmol) was dissolved in morpholine (1.0 ml) and stirred at 100 ° C overnight . The solution was diluted with EtOAc (30 ml) and washed with 1 N HCl (11 ml), water (10 ml) and saturated NaHCO 3 (10 ml). The organic solution was dried, filtered and concentrated and the residue was purified by flash chromatography, using a linear gradient of EtOAc / hexanes from 20% to 80%, to give the title compound as a white foam (17 mg, 34%). . MS (ES) 495.0 (M + 1) +, 493.1 (M-1) -.

Example 55 I N- (4-Fluoro-benzyl) -4- [3- (3-hydroxy-cyclopentyl) -indol-1-sulfonyl] -benzamide Sodium borohydride (23 mg, 0.601 mmol) was added to a solution at 0 ° C of N- (4-fluoro-benzyl) -4- [3- (3-oxo-cyclopentyl) -indol-1-sulfonyl] - benzamide (295 mg, 0.601 mmol) in MeOH (7 ml) under N2. It was stirred for 30 minutes and then warmed to room temperature. It was stirred for 18 hours. A small amount of water was added to quench the reaction and then remove the MeOH in a rotoevaporator. EtOAc and water were added and the product was extracted into organics. They were separated, and the organics were dried over MgSO4. The organics were condensed in rotoevaporator and then purified by silica gel chromatography to give N- (4-fluoro-benzyl) -4- [3- (3-hydroxy-cyclopentyl) -indol-1-sulfonyl] -benzamide- (205 mg, 69% yield) as a light orange solid. Mass Spectrum (m / e): 493.01 (MH +).

Example 56 4- [3- (2, 3-Dihydro-furan-3-yl) -indol-1-sulfonyl] -N- (4-fluorobenzyl) -benzamide 3,4-Dihydrofuran (0.70 g, 0.76 mL, 0.01 mol) was added to N- (fluoro-benzyl) -4- (3-iodo-indol-1-sulfonyl) -benzamide (0.534 g, 0.001 mol). ) followed sequentially by Pd (0ac) 2 (0.024 g, 0.075 mmol), tetrabutyl ammonium chloride (0.283g, 0013 mol), and DMF (16.0 mL). Sodium acetate (0.246 g, 003 mol) was added and the resulting mixture was stirred and heated at 50 ° C for 8 hours. The reaction mixture was poured into a DMF-H20 mixture. The EtOAc layer was separated and extracted several times with H20. It was washed with brine, dried and filtered and chromatographed on the chromatron by levigating with EtOAc-hexanes (3: 7) to give 0.040 g of the title compound as a viscous gum. Mass Spectrum (m / e) M (+ l) 477; (M-1) 475. EXAMPLE 57 N- (4-Fluoro-benzyl) -4- [(3-tetrahydro-furan-3-yl) -indol-1-sulfonyl] -benzamide 4- [3- (2, 3-Dihydro-furan-3-yl) -indol-1-sulfonyl] -N- (4-fluoro-benzyl) -benzamide (0.095 g, 0.10 mmol) was added to absolute EtOH ( 25 mL) and 5% P / C 0.0029 g and hydrogenated on a PARR shaker overnight at 60 pounds per square inch (42,180 kg / cm 2). The catalyst was filtered and the solvent was evaporated giving 0.071 g of oil. It was chromatographed on the ISCO using a gradient system of EtOAc-hexane (0-100%) to give a viscous oil, which was solidified to a glass of 0.050 g. Mass spectrum (m / e) (M + l) 479.144; Found (M + l) 479.1457.

Example 60 (4-Fluoro-benzyl) -4- (3-phenyl-2,3-dihydro-indol-1-sulfonyl) -benzamide 3-phenyl-2,3-dihydro-1H-indole (Yamamoto, Y et al., Bull Chem. Soc. Jpn 44, 1971, 541-545) (0.158, 0.81 mmol) 4- (4-fluoro-benzylcarbamoyl) -benzenesulfonyl chloride (0.266 g, 0.81 mmol), Et3N (0.161 g, 0.23 mL, 1.5 mmol) and DMAP 0 (0.011 g), 09 mmol) to CH2C12 (25 mL) and stirred at room temperature under N2 overnight. The reaction was diluted to 150 mL with CH2C12 and poured into saturated NaHCO3 (50 mL). The organic layer was separated and extracted with 1M HCl (2x75 mL). It was washed with brine, separated, dried (MgSO), filtered and the filtrate evaporated. The residue was chromatographed on the ISCO using a gradient system EtOAc-hexane (0-100%) to give 0.167 g of the title compound. Mass spectrum (m / e) (M + l) 487.1492; Found: 487.1479. 0 Example 60a Isomer 1 Separated on a QUiracel OD column (0.46 x 255 cm) at a flow rate of 1.0 mL / min, .255 nM levigating with 2/3 EtOH / heptane and 20 μL of injection to give .060 g of the desired enantiomer.

TA = 5.45 minutes.

Example 60b Isomer Was separated on a Chiracel OD column (0.46 x 255 cm) at a flow rate of 1.0 mL / min, 255 nM by levigating with 2 / 3EtOH / heptane and 20 μL of injection to give 0.061 g of the desired enantiomer. TA = 7.20 min.

Example 61 N- (4-Fluoro-benzyl) -4- [3- (tetrahydro-pyran-4-yl) -indol-1-sulfonyl] -benzamide It was added to a 1L 3-neck ball flask previously dried overnight at 120 ° C, hot-mounted with a top disc stirrer, N2 line, temperature probe and drip funnel, 4- (3-) acid. tetrahydro-pyran-4-yl) -indol-1-sulfonyl) -benzoic acid (15.0 g, 38.94 mmol) and anhydrous THF (200 mL), the solution was stirred and cooled to 0 ° C under N2. N-methylmorpholine (4.3 mL, 39.09 mmol) was added immediately via syringe, followed by 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 6.8 g, 38.80 mmol) in portions as a solid. The mixture was stirred for 1 hour at 0 ° C and treated with a solution of 4-fluorobenzylamine (4.9 mL, 42.89 mmol) in anhydrous THF (50 mL) via dropping funnel for 10 minutes. The resulting mixture was warmed to room temperature, stirred for 3 hours, cooled down again to 0 ° C, and quenched with IN HCl (150 mL). Ethyl acetate (150 mL) was added and the layers separated (a small amount of brine was added to separate the layers more efficiently). The organic layer was washed with brine (150 mL), dried over sodium sulfate and concentrated to an oil. The oil was dissolved in methylene chloride and added to an instant 65M biotage cartridge. It was levigated with hexanes / ethyl acetate 3: 1, followed by hexanes / ethyl acetate 3: 2 to provide isolation of the main product as a foam. The foam was treated with MTBE and re-concentrated to a paste. After standing at room temperature, crystallization of the material occurs. It was recrystallized from ethyl acetate / hexanes to provide a solid. It was resuspended in MTBE (400 mL) and stirred at room temperature for 3 more hours. The solid was filtered and subsequently washed with MTBE, dried (20 mm Hg 55 ° C, to give the title compound homogeneous (14.5 g, 76%); 1 H NMR (DMSO-de) d 9.24 (t, J = 6.0 Hz, 1H), 8.10 (m, 2H), 7.98 (m, 3H), 7.67 (d, J = 1 .1 Hz, 1H), 7.58 (s, 1H), 7.32 (m, 5H), 7.12 (t, J = 8.8 Hz, 1H), 4.42 (d, J = 5.5 Hz, 2H), 3.96 (m, 2H), 3.50 (t, J = 11.5 Hz, 2H), 3.02 (m, 1H), 1.85 (m, 2H), 1.71 (m, 2H), MS (ESI) m / z 493 (m + H), MS / CL, 100% DAD.

Example 63 (3-aminomethyl-azetidin-1-yl) - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone Trifluoroacetic acid (5 mL) was added to [1- [4- (3-phenyl-indole-1-sulfonyl) -benzoyl] -zetidin-3-ylmethyl] -carbamic acid tert-Jutyl ester (853 mg, 1.56 mmol ) causing a lot of gas evolution. The reaction solution was rotary evaporated (40 ° C, forming 2 × azeotropes with MeOH). The resulting yellow oil was dissolved in MeOH (10 mL) and hydroxide resin (Bio-Rad AG® 1-X8, 20-50 mesh, 5 g) was added to the free base of the amine. The mixture was filtered and the filtrate was rotationally evaporated (40 ° C, 3 × azeotrope was formed with CH2C12) to give 664 mg (95.3% (3-aminomethyl-azetidin-1-yl) - [4- (3-phenyl- indole-1-sulfonyl) -phenyl] -methanone as a whitish foam. (m / e): 446.02 (M + l).

Example 64 N-Azetidin-3-yl-4- (3-phenyl-indole-1-sulfonyl) -benzamide The title compound was prepared by a method similar to that described for (3-aminomethyl-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone using tert-Jutyl ester. 3- [4- (3-phenyl-indole-l-sulfonyl) -benzoylamino] -azetidine-carboxylic acid (792 mg, 1.49 mmol) to give 568 mg (88.4%) of a whitish foam. MS (m / e): 431.92 (M + 1); 430.03 (M-1).

Example 65 (I-3-amino-pyrrolidin-1-yl) - [4- (3-phenyl-indole-l-sulfonyl) phenyl] -metanone The title compound was prepared by a method similar to that described for 3- (aminomethyl-azetidin-1-yl) - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone using the ternary ester. [1-1- [4- (3-Phenyl-indole-l-sulfonyl) -benzoyl] -pyrrolidin-3-yl] -carbamic acid jbutilic (655 mg, 1.20 mmol) to give 474 mg (88.6%) of a white foam. ES (m / e): 445.95 (M + l).

Example 66 ((S) -3-amino-pyrrolidin-1-l) - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone The title compound was prepared by a similar method described by (3-aminomethyl-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone using acidic tert-alkyl ester [(S) -1- [4- (3-phenyl-indole-l-sulfonyl) -benzoyl] -pyrrolidin-3-yl] -carbamic acid (903 mg, 1.65 mmol) to give 674 mg (91.4%) of a white foam. MS (m / z): 445.95 (M + 1).

Example 67 (3-amino-azetidin-1-yl) - [4- (3-phenyl-indol-l-sulfonyl) -phenyl] -metanone The title compound was prepared by a method similar to that described by (3-aminomethyl-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone using tert-butyl ester of the [1- [4- (3-Phenyl-indole-1-sulfonyl) -benzoyl] -zetidin-3-yl] -carbamic acid (325 mg, 0.611 mmol) to give 239 mg (90.6% of a white foam. (m / e); 431.97 (M + l).

Example 70 4- (3-phenyl-indole-l-sulfonyl) -N-pyrazin-2-ylmethyl-benzamide ml of dry DMF was added to a N 2 flask containing 4- (3-phenyl-indole-l-sulfonyl) -benzoic acid (500 mg, 1.33 mmol, 1.0 eq.), L- (3-dimethylaminopropyl hydrochloride. ) -3-ethylcarbodiimide (279 mg, 1.46 mmol, 1.1 equivalents), dimethyl-pyridin-4-yl-amine (16 mg, .132 mmol, .1 eq.), And C-pyrazin-2-yl-methylamine ( 217 mg, 1.99 mmol, 1.5 eq.). It was stirred for 18 hours at room temperature. The solvent was removed on a rotary evaporator and purified by chromatography on silica gel to give 4- (3-phenyl-indole-1-sulfonyl) -N-pyrazin-2-ylmethyl-benzamide (127 mg, 20% yield ). Mass spectrum (m / e): 468.95 (MH +). Example 71 N- (4-cyano-benzyl) -4- [(3-tetrahydro-pyran-4-yl) -indol-1-sulfonyl] -benzamide 4- (3-Tetrahydro-pyran-4-yl) -indol-1-sulfonyl) -benzoic acid (0.200 g, 0.518 mmol) was stirred with EDC [1892-57-5] (0.118 g, 0.662 mmol) 4- aminomethyl-benzonitrile (0.082 g, 0.662 mmol) in dichloromethane until completion. The reaction was diluted and washed with IN HCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified via flash column chromatography with a mixture of methanol and dichloromethane or EtOAc and dichloromethane to isolate 0.102 g of solid material (yield = 41%). Mass spectrum (m / e): 498.04 (M-).

Example 72 (2-phenyl-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone 4- (3-Phenyl-indole-1-sulfonyl) -benzoic acid was combined (125 mg, 0.33 mmol) and 2-phenyl-azetidine (100 mg, 0.75 mmol, in excess) in dichloromethane (1.0 mL) and triethylamine (0.300 mL, 2.15 mmol, excess) and benzotriazole hexafluorophosphate-1- was added. iloxitris (dimethylamino) phosphonium (BOP reagent) (150 mg, 0.33 mmol) at room temperature. It was stirred for 30 minutes, the whole reaction was loaded directly onto a pre-packed silica gel column and purified by flash column chromatography (EtOAc / Hexanes) to give 149 mg of (2-phenyl-azetidin-1-yl) - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone as a glassy solid (92%). LRMS: MH + 493.08.

The following sulfonamides of Table 2 were prepared using methods similar to those indicated in the reference examples.

Table 2 1. The purified compound was dissolved in a minimum amount of tetrahydrofuran, cooled to 0 ° C and treated with 1-2 equivalent of anhydrous HCl in THF and the solvents were evaporated to give the final HCl salts.

Example 158 Resolution of Cis-N- (2-Hydroxy-cyclohexyl) -4- (3-phenyl-indole-1-sulfonyl) -benzamide The title compound was separated by chiral chromatography (prep ChiralPak AD, 100% EtOH, 14 ml / min, ChiralPak Analytical AD 100% EtOH, 1.0 ml / min. Retention time of Isomer 1 (analytical) 8.35 min., LRMS: 475.06. Retention time of Isomer 2 (analytical) 11.85 min., LRMS: 475.05.

Example 159 Resolution of Trans-N- (2-Hydroxy-cyclohexylmethyl) -4- (3-phenyl-indole-1-sulfonyl) -benzamide The title compounds were separated by chiral chromatography (prep ChiralPak AD, 100% EtOH, 14 ml / min, analytical ChiralPak AD, 100% EtOH, 1.0 ml / min.

Retention time of Isomer 1 (analytical) 6.75 min., LRMS: 489.10. Retention time of Isomer 2 (analytical) 9. 55 min., LRMS: 489.11.

Example 161 (3-Hydroxy-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) phenyl] -metanone L-Benzhydryl azetidin-3-ol (250 mg, 1.04 mmol) was dissolved in methanol (3.0 mL) and added to Pd (OH) 2 under nitrogen. The reaction vessel was degassed and purged with 60 psi H2 (g). The degassed / H2 purge cycle was repeated again. It was allowed to stir under 60 psi of H2 for 15 hours. The reaction was released and filtered through celite with additional methanol. The methanol was evaporated to provide azetidin-3-ol as a liquid which was used without further purification. 4- (3-Phenyl-indole-1-sulfonyl) -benzoic acid (200 mg, 0.53 mmol) and azetidin-3-ol (50 mg, 0.68 mmol, excess) in dichloromethane (1.0 ml) and triethylamine (0.500) were combined. ml, 3.58 mmol, excess) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexfluorophosphate (BOP reagent) was added. (300 mg, 0.66 mmol, excess) at room temperature. Stirred for 30 minutes, the reaction was loaded directly onto a pre-packed silica gel column and purified by flash chromatography (EtOAc / Hexanes) to provide 167 mg of (3-Hydroxy-azetidin-1-yl) - [ 4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone as a white foam (73%). LRMS: MH + 432.97.

EXAMPLE 162 1- [4- (3-Phenyl-lndol-1-sulfonyl) -benzoyl] -zetidin-3-yl ester of methanesulfonic acid The title compound was prepared using l-benzydril-azetidin-3-yl ester of methanesulfonic acid in the same procedure as above.

Example 163 1- [4- (3-Phenyl-indol-1-sulfonyl) -benzoyl] -zetidin-3-yl ester of dimethyl carbamic acid (3-Hydroxy-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone (95 mg, 0.219 mmol), triethylamine (0.200 ml, 1.43 mmol, excess ) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in dichloromethane (1.0 ml) and treated with N, N-dimethylcarbamoyl chloride (0.050 ml) at room temperature. Stirred for 15 hours, loaded directly onto a pre-packed silica gel column and purified by flash column chromatography (EtOAc / Hexanes) to provide 82 mg of l- [4- (3-phenyl-indole) ester. 1-sulfonyl) -benzoyl] -zetidin-3-yl of dimethylcarbamic acid as a white foam (74%). LRMS: MH + 503.97.

Example 164 N- [1- (4-Fluoro-phenyl) -azetidin-3-ylmethyl] -4- (3-phenyl-indole-1-sulfonyl) -benzamide Trifluoroacetic acid (2 ml) was added to [1- (4-fluoro-phenyl) -azetidin-3-ylmethyl] -carbamic acid tert-butyl ester (135 mg, 0.482 mmol) which causes the emission of a lot of gas. The reaction solution was rotary evaporated (40 ° C, 3 × azeotrope was formed with CH2C12). This material was dissolved in anhydrous CH2C12 (3 mL). 4- (3-Phenyl-indole-1-sulfonyl) -benzoic acid (200 mg, 0.53 mmol, 1.1 equiv), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 140 mg, 0.73 mmol) was added. , 1.5 equiv), and 4- (dimethylamino) pyridine (DMAP, 270 mg, 2.3 mmol, 4.7 equiv). After stirring for 16 hours, the reaction solution was transferred to a column of silica gel (80 mm x 20 m dia.) And levigated (EtOAc / hex 10-45%) to provide 31 mg (12%) of N- [1- (4-fluoro-phenyl) -azetidin-3-ylmethyl] -4- (3-phenyl-indole-1-sulfonyl) -benzamide as a light yellow foam. MS (m / e): 539.99 (M + 1); 538.16 (M-l).

Example 165 3- [(4-Fluoro-phenylamino) -methyl] -zetidin-1-yl] - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -metanone L-bromo-4-fluorobenzene (220 μl, 350 mg, 2.0 mmol, 2.0 equiv) was added to a mixture of (3-aminomethyl-azetidin-1-yl) - [4- (3-enyl-indole-l- sulfonyl) -phenyl] -methanone (446 mg, 1.00 mol, 1 equiv), tris (dibenzylidene ketone) dipalladium (0) (23 mg, 0.025 mmol, 0.025 equiv), 2- (di-tert-butyl-phospho-) bifenil (15 mg, 0.057 mmol, 0.050 equiv), and sodium tert-oxide (120 mg, 1.2 mmol, 1.2 equiv) in toluene anhydride (4 ml) and heated at 100 ° C for 19 hours. After cooling, the reaction mixture was transferred through a 0.45 μm filter screener to a column of silica gel (125 x 25 mm dia.) And was levigated (EtOAc / hex 10-100%) to provide 98 mg (18%) of [3- [(4-fluoro-phenylamino) -methyl] -zetidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone as a foam light yellow. 1 H NMR indicates the purity of the desired product. MS (m / e): 540.07 (M + 1); 538.19 (M-l).

Example 166 [1-3- (4-Fluoro-phenylamino) -pyrrolidin-1-yl] - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -metanone The title compound was prepared in a manner similar to the method described for [3- [(4-Fluoro-phenylamino) -methyl] -azetidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) phenyl] -methanone using (I-3-Amino-pyrrolidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone (334 mg, 0.750 mmol) to isolate 35 mg (8.7%) of a light yellow foam. MS (m / e): 540.01 (M + 1).

Example 167 [(S) -3- (4-Fluoro-phenylamino) -pyrrolidin-1-yl] - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -metanone The title compound was prepared by a similar method described for [3- [(4-Fluoro-phenylamino) -methyl] -zetidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] ] -methanone using ((S) -3-Amino-pyrrolidin-1-yl) - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone (334 mg, 0.750 mmol) to isolate 59 mg (15%) of light yellow foam. MS (m / e): 540.02 (M + 1).

EXAMPLE 170 [3- [(6-Fluoro-pyridin-2-ylamino) -methyl] -zetidin-1-yl] - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -metanone 2,6-difluoropyridine (55 μl, 70 mg, 0.61 mmol, 2.0 equiv) was added to a solution of (3-aminomethyl-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) phenyl] -metanone (134 mg, 0.301 mmol, 1 equiv) and triethylamine (120 μl, 87 mg, 0.86 mmol, 2.9 equiv) in 1,4-dioxane (3 ml) and heated at 80 ° C for 16 hours . The mass spectrum did not show the desired product. More triethylamine (120 μL) and 2,6-difluoropyridine (110 μL) were added. After 32 hours at 80 ° C, LC / MS showed a small amount of the desired product. More triethylamine (200 μl) and 2,6-difluoropyridine (110 μl) was added. After 38 hours, more triethylamine (200 μl) and 2,6-difluoropyridine (110 μl) were added. After 100 hours, the reaction was transferred to a column of silica gel (80 mm x 20 mm dia.) And levigated (50-60% EtOAc / hex) to provide 65 mg (40%) of [3- [(6-fluoro-pyridin-2-ylamino) -methyl] -zetidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone as a white foam. MS (m / e): 541.02 (M + 1); 539.17 (M-l).

Example 171 [4- (3-Phenyl-indole-l-sulfonyl) -phenyl] - [3- (pyrimidin-2-ylaminomethyl) -azetidin-1-yl] -metanone The title compound was prepared by a similar method for [3- [(6-Fluoro-pyridin-2-ylamino) -methyl] -zetidin-1-yl] - [4- (3-phenyl-indole-1-sulfonyl ) -phenyl] -methanone • using (3-aminomethyl-azetidin-1-yl) - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone (134 mg, 0.301 mmol) to isolate 56 mg (36%) of a whitish foam. MS (m / e): 524.01 (M + 1).

Example 172 1, l-Dimethyl-3- [1- [4- (3-phenyl-indole-l-sulfonyl) -benzoyl]-azetidin-3-ylmethyl] -urea Example 173 1, l-Dimethyl-3- [1- [4- (3-phenyl-indole-l-sulfonyl) -benzoyl] azetidin-3-ylmethyl] -thiourea Dimethylthiocarbamoyl chloride (350 mg, 2. 8 mmol, 12 equiv) to a suspension of (3-aminomethyl-azetidin-1-yl) - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone (101 mg, 0.227 mmol, 1 equiv. ) and triethylamine (130 μl, 94 mg, 0.93 mmol, 4.1 equiv) in CH2C12 anhydride (3 ml). After stirring for 17 hours, the reaction was transferred to a column of silica gel (80 mm x 20 mm dia.) And levigated / 20-100% EtOAc / hex.; 2% MeOH / CH 2 Cl 2) to provide 15 mg (12%) of 1,1-dimethyl-3- [1- [4- (3-phenyl-indole-1-sulfonyl) -benzoyl] -zetidin-3-ylmethyl ] -urea as a white foam. The starting dimethylthiocarbamoyl chloride contains some dimethylcarbamoyl chloride. The column of silica gel was levigated with more polar solvent (20% MeOH / CH 2 Cl 2) to give thiourea along with triethylamine hydrochloride. This material was dissolved in CH2C12 and washed with saturated aqueous NaHCO3. The organic layer was dried (anhydrous MgSO 4) and rotary evaporated (40 ° C) to provide 30 mg (25%) of 1,1-dimethyl-3- [1- [4- (3-phenyl-indole l-sulfonyl) -benzoyl] -azetidin-3-ylmethyl] -thiourea as a tan foam.

Example 174 3- [(4-Fluoro-benzylamino) -methyl] -zetidin-1-yl] - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -metanone 4-Fluorobenzaldehyde (26 μl, 31 mg, 0.25 mmol, 1.0 equiv) was added to a solution of (3-aminomethyl-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl) ] -methanone (112 mg, 0.251 mmol, 1 equiv) in MeOH (1 ml). After a few minutes, white precipitation was observed. After 1 hour, H20 was added and the reaction mixture was extracted with CHC13 (3x). The organic layers were combined, dried on a rotary evaporator (40 ° C) to give 120 mg of imine as a colorless film. The imine was dissolved in anhydrous THF (2 ml) and sodium triacetoxyborohydride (80 mg, 0.38 mmol, 1.5 equiv) was added. After 19 hours, the reaction mixture was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with EtOAc. (5 ml). The organic layer was dried (anhydrous MgSO 4) and rotary evaporated (40 ° C). The resulting colorless oil was transferred to a column of silica gel (60 mm x 12 mm dia.) And levigated (2% MeOH / CH 2 Cl 2) to provide 54 mg (39%) of [3- [(4-fluoro) -benzylamino) -methyl] -azetidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone as a white foam. MS (m / e): 553.96 (M + 1).

Example 175 N- [1- (4-Fluoro-phenyl) -azetidin-3-yl] -4- (3-phenyl-indole-1-sulfonyl) -benzamide L-bromo-4-fluorobenzene (110 μl, 180 mg, 1.0 mmol, 2.0 equiv) was added to a mixture of N-azetidin-3-yl-4- (3-phenyl-indole-1-sulfonyl) -benzamide ( 216 mg, 0.501 mmol, 1 equiv), tris (dibenzylidene ketone) dipalladium (0) (12 mg, 0.012 mmol, 0.025 equiv), 2- (di-tert-jylphosphino) biphenyl (8 mg, 0.03 mmol, 0.05 equiv), and tert -butoxide sodium (58 mg, 0.60 mmol, 1.2 equiv) in anhydrous toluene (2 ml). The reaction mixture was heated at 100 ° C for 14 hours. After cooling, the reaction mixture was diluted with CH2C12 and transferred along a 0.45 μm filter disc to a column of silica gel (80 mm x 20 m day) and levigated (EtOAc / hex at 10 ° C). -35%) to provide 63 mg (24%) of N- [1- (4-fluoro-phenyl) -azetidin-3-yl] -4- (3-phenyl-indole-l-sulfonyl) -benzamide as a solid.

EXAMPLE 176 3- [4- (3-Phenyl-indol-l-sulfonyl) -benzoylamino] -zetidine-1-carboxylic acid methyl ester Methyl chloroformate (60 μl, 73 mg, 0.78 mmol, 3.1 equiv) was added to a suspension of N-azetidin-3-yl-4- (3-phenyl-indole-1-sulfonyl) -benzamide (108 mg, 0.250 g). mmol, 1 equiv) and triethylamine (140 μl, 100 mg, 1.0 mmol, 4.0 equiv) in anhydrous CH2C12 (3 ml). A vigorous gas emission was observed. After stirring for 4 hours, the reaction solution was rotary evaporated. The resulting material was transferred to a column of silica gel (80 mm x 20 mm dia.) And levigated (EtOAc / hex 20-60%) to provide 84 mg (69%) of methyl ester of 3- [4] acid. - (3-phenyl-indole-l-sulfonyl) -benzoylamino] -azetidine-1-carboxylic acid as a whitish foam. MS (m / e): 489.96 (M + 1); 488.09 (M-l).

Example 177 [1-1- [4- (3-Phenyl-indole-l-sulfonyl) -benzoyl] -pyrrolidin-3-yl] -carbamic acid methyl ester The title compound was prepared by a similar method for 3- [4- (3-phenyl-indole-1-sulfonyl) -benzoylamino] -zetidine-1-carboxylic acid methyl ester using (1-3-amino-pyrrolidin- 1-yl) - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone (111 mg, 0.249 mmol) to isolate 98 mg (78%) of a white foam. MS (m / e): 503.98 (M + 1); 502.09 (M-l).

Example 178 [(S) -1- [4- (3-phenyl-indol-l-sulfonyl) -benzoyl] -pyrrolidin-3-yl] -carbamic acid methyl ester The title compound was prepared by a similar method described for 3- [4- (3-phenyl-indole-1-sulfonyl) -benzoylamino] -azetidine-1-carboxylic acid methyl ester using ((5) -3-amino -pyrrolidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone (111 mg, 0.249 mmol) to isolate 97 mg (77%) of a white foam. MS (m / e): 504.00 (M + 1); 502.09 (M-l).

Example 179 [1- [4- (3-Phenyl-indole-l-sulfonyl) -benzoyl] -zetidin-3-yl-methyl] -carbamic acid methyl ester The title compound was prepared by a similar method described for 3- [4- (3-phenyl-indole-1-sulfonyl) -benzoylamino] -azetidine-1-carboxylic acid methyl ester using (3-aminomethyl-azetidin-1) -yl) - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone (111 mg, 0.249 mmol) to isolate 99 mg (79%) of a white foam. MS (m / e): 504.02 (M + 1); 502.15 (M-1).

Example 180 [1- [4- (3-Phenyl-indole-1-sulfonyl) benzoyl] -zetidin-3-yl] -carbamic acid methyl ester The title compound was prepared by a similar method described for 3- [4- (3-phenyl-indole-1-sulfonyl) -benzoylamino] -zetidine-1-carboxylic acid methyl ester using (3-amino-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone (111 mg, 0.249 mmol) to isolate 99 mg (79%) of white foam. MS (m / e): 489.99 (M + 1); 488.04 (M-1).

Example 183 N- (4-Fluoro-benzyl) -4- (3-pyridin-3-yl-indol-l-sulfonyl) -benzamide hydrochloride N- (4-fluoro-benzyl) -4- (3-iodo-indole-l-sulfonyl) -benzamide 300 mg, 0.56 mmol, 1 equiv), 3-tributylstanilpyridine (Frontier Scientific®; 90%; 230 mg (0.90) = 210 mg, 0.56 mmol, 1.0 equiv), and tetrakis- (triphenylphosphine) palladium (0) (100 mg, 0.087 mmol, 0.15 equiv) in deoxygenated toluene (3 ml) and heated to 100 ° C by 18 hours. The reaction solution was transferred to a column of silica gel (125 mm x 25 mm dia.) And levigated (EtOAc / hex. 0-70%) to provide 73 mg (27%) of the free amine as an orange oil. This material was dissolved in MeOH (5 ml) and 12 M aqueous HCl (2 drops) was added. This solution was rotary evaporated (40 ° C) to provide 78 mg (27%) of N- (4-fluoro-benzyl) -4- (3-pyridin-3-yl-indole-1-sulfonyl) hydrochloride) -benzamide as brown glass. EM (m / e): 485. 95 (M + l); 484.10 (M-1).

Example 184? - (4-Fluoro-benzyl) -4- (3-pyridin-2-yl-indole-1-sulfonyl) -benzamide hydrochloride The title compound was prepared by a method similar to Example 183 using 2-tributylstanilpyridine (Frontier Scientific®, 85%; 250 mg [0.85] = 210 mg, 0.58 mmol, 1. 0 equiv) to isolate 109 mg (37%) of yellow glass. MS (m / e): 485.96 (M + 1); 484.10 (M-1).

Example 185 N- (4-Fluoro-benzyl) -4- [3- (6-methoxy-pyridin-3-yl) -indol-1-sulfonyl] -benzamide N- (4-Fluoro-benzyl) -4- [3- (4, 4, 5, 5-tetramethyl- [1, 3,2] -dioxaborolan-2-yl) -indol-1-sulfonyl] - benzamide (0.534 g, 1.0 mmol), 5-Bromo-2-methoxy pyridine (0.155 mL, 1.2 mmol) and PdCl2 (dppf) .CH2C12 (0.088 g, 0.07 mmol) in dry DMF (40 mL). 2 M Na2CO3 (1.40 mL, 2.8 mmol) was added and heated under N2 at 100 ° C for 4 hours. It was stirred at room temperature. The reaction mixture was poured into EtOAc-H20, separated, extracted several times with H20 and washed with brine. The EtOAc was dried (MgSO4) and filtered through celite®. Evaporated and chromatographed using EtOAc of a 0-100% hexane-EtOAc gradient to give 0.347 g (67%) of the desired compound. MS (M + 1) 516; (M-1) 514.

Example 186 N- (4-Fluoro-benzyl) -4- [3- (6-fluoro-pyridin-3-yl) -indol-1-sulfonyl] -benzamide N- (4-Fluoro-benzyl) -4- [3- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -indol-1-sulfonyl] -benzamide was combined (150 mg, 0.28 mmol), 5-Bromo-2-fluoro-pyridine (0.05 ml, 0.56 mmol), CsF (212 mg, 1.4 mmol) and Pd (Ph3P) (32 mg, 0.028 mmol) in 1.0 ml DMF and 0.100 ml of water. The reaction vessel was discarded and placed under a nitrogen atmosphere. The resulting reaction was heated to 90 degrees for 12 hours. The reaction was loaded directly on silica gel and purified by flash chromatography (EtOAc / Hexanes) to provide 98 mg of a white foam (70%) LRMS: MH + 504.02.

Example 187 4- [3- (5-Chloro-thiophen-2-yl) -dole-1-sulfonyl] -N- (4-fluorobenzyl) -benzamide N- (4-Fluoro-benzyl) -4- [3- (4, 4, 5, 5-tetramethyl- [1,3,2] -dioxaboralan-2-yl) -indol-1-sulfonyl] - benzamide (0.534 g, 1.0 mmol), 2-bromo-5-chloro-thiophene (0.012 ml, 1.1 mmol), PdCl2 (dppf), CH2C12 (.051g, .069 mmol) and KOAc (0.294g, 3.0 mmol) in dry DMF (22.0 ml) under hot N2 and stirred at 100 ° C for 16 hours. It was cooled to room temperature and poured into a mixture of EtOAc-H20. The EtOAc was separated and extracted several times with H20, washed with brine and dried (MgSO4). It was filtered and evaporated to an oily residue. The product was purified by chromatography using EtOAc of a hexane-EtOAc gradient to give 0.209 g (40%) of a viscous oil. TOF EM (M-l) 523.0332.

Example 188 4- (3-Clclopropyl-lndol-l-sulfonyl) -N- (4-fluoro-benzyl) -benzamide N- (4-Fluoro-benzyl) -4- (3-iodo-indol-l-sulfonyl) -benzamide (0.50 g, 0.94 mmol), cyclopropylboronic acid (0.24 g, 2.8 mmol), tricyclohexylphosphine was combined (0.05 g, 0.18 mmol), potassium phosphate (0.70 g, 3.30 mmol), and palladium acetate (0.02 g, 0.09 mmol) in a mixture of toluene (15 mL) and water (0.4 mL). It was heated at 100 ° C under nitrogen for 18 hours, filtered through celite and the solids were washed with EtOAc. The EtOAc was washed with saturated NaHCO 3 (30 mL), then dried with Na 2 SO 4 and concentrated under vacuum. The flash column was purified on silica gel by levigating with 0-50% EtOAc in hexane to give the title compound (0.25 g, 60%). MS (RE) 449.2 (M + 1) +, 447.4 (M-1) -.

Example 189 N- (4-Fluoro-benzyl) -4- (3-thiophen-3-yl-indole-l-sulfonyl) - N- (fluoro-benzyl) -4- (3-iodo-indole-l-sulfonyl) -benzamide (0.534 g, 1.1 mmol), thiophene-3-boronic acid (0.154 g, 1.25 mmol), PdCl2 (dppf) was combined ) .CH2C12 (0.10 mmol) and Na2C03 2N (1.32 mL) l, 2.64 mmol) respectively, in dry DMF (40 mL) under N2. It was stirred and heated at 81 ° C under N2 for one and one-half hour. It was cooled to room temperature and stirred overnight. The reaction was poured into EtOAc (150 mL) and extracted with H20 (3 x 150 L). It was washed with brine, the organic layer was separated and dried (MgSO4). It was filtered through celite and the filtrate was evaporated in a rotary evaporator.

Chromatograph using a gradient of 0-100% EtOAc-hexane-EtOAc to give 0.352 g (71%) of the desired compound as an off white solid (ER +) (M + 1) 491.0; (M-l) 490.10.

Example 190 4- [3- (2-chloro-phenyl) -indol-1-sulfonyl] -N- (4-fluoro-benzyl) benzamide N- (4-Fluoro-benzyl) -4- (3-iodo-indol-l-sulfonyl) -benzamide (268 mg, 0.50 mmol), 2-chlorophenylboronic acid (78.2 mg, 0.50 mmol), PdCl2 (dppf) was added. ) .CH2C12 (41 mg, 0.05 mmol) and Na2CO3 2M (0.55 mL, 1.1 mmol) respectively, to DMF (15.0 mL) at room temperature under N2. The reaction was heated to 100 ° C for 16 hours. The reaction was cooled to room temperature and poured into a mixture of H20-EtOAc (200 mL / 100 mL). The EtOAc was separated, extracted several times with H20 and washed with brine. Dried (MgSO), filtered and evaporated the filtrate. The crude material was purified on silica gel using a gradient hexane-EtOAc system to give 0.155 g (60% yield) of 4- [3- (2-chloro-phenyl) -1-indole-1-sulfonyl] - N- (4-fluoro-benzyl) -benzamide: Mass spectrum (m / e) (Ml) 517.0787.

Example 191 N- (4-Fluoro-benzyl) -4- [3- (2-fluoro-pyridin-3-yl) -indol-1-sulfonyl] -benzamide N- (4-Fluoro-benzyl) -4- (3-iodo-indol-l-sulfonyl) -benzamide (300 mg, 0.56 mmol), 2-fluoro-3-boronic acid-pyridine (140 mg, 1.12 g) was combined mmol), CsF (170 mg, 1.12 mmol) and Dichlorobis (triphenylphosphine) palladium (100 mg, 0.14 mmol) in dioxane (2.0 mL) and water (0.200 mL). The reaction was evacuated and placed under a nitrogen atmosphere. The resulting reaction was heated in a grade 80 oil bath for 15 hours. The reaction was cooled and filtered through a short pad of silica gel are additional ethyl acetate. Evaporated and purified by flash column chromatography (EtOAc / hexanes) to give 141 mg of a whitish foam (50%). LRMS: MH + 503.2. The following sulfonamides were prepared in Table 3 using methods similar to those indicated in the reference examples.

Table 3 1. The purified compound was dissolved in a minimum amount of tetrahydrofuran, cooled to 0 ° C and treated with 1-2 equivalents of anhydrous HCl in THF, the solvents were evaporated to give the final HCl salt.

Example 214 N- (4-Fluoro-benzyl) -4- (3-pyrip? Idin-2-yl-indole-l-sulfonyl) -benzamide A mixture of N- (4-fluoro-benzyl) -4- [3- (4,4,5,5-tetramethyl- [1, 3, 2] -dioxoborolan-2-yl) -indol-1- was stirred. sulfonyl] -benzamide (0.200 g, 0.374 mmol), 2-bromo-pyrimidine (0.282 g, 1872 mmol), tetrakis (triphenylphosphine) palladium (0) (0.043 g, 0.0374 mmol), cesium fluoride (0.282 g, 1872 mmol) ) in dioxane, until the reaction reaches termination at 90 ° C. The reaction was concentrated and purified via column chromatography using a mixture of EtOAc and hexanes to give 0.049 g of a solid material (yield = 27%): Mass spectrum (m / e): 485.09 (M ~).

Example 215 N- (4-Fluoro-benzyl) -4- (3-pyrimidin-5-yl-indole-l-sulfonyl) The title compound was prepared by a similar method of N- (4-fluoro-benzyl) -4- (3-pyrimidin-2-yl-indole-l-sulfonyl) -benzamide using 5-bromo-pyrimidine (0.118 g, 0.748 mmoles), to isolate 0.070 g of a solid (yield = 95%). Mass spectrum (m / e): 486.1 (M +).

Example 216 N- (4-Fluoro-benzyl) -4- (3-pyrimidin-5-yl-indole-1-sulfonyl) -benzamide: chloride N- (4-Fluoro-benzyl) -4- (3-pyrimidin-5-yl-indole-1-sulfonyl) -benzamide (0.041 g, 0.084 mmol) was stirred in dioxane with IN HCl until completion and the solvent was removed to isolate 0.026 g (yield = 61%).

Example 217 N- (4-Fluoro-benzyl) -4- (3-pyrazin-2-yl-indole-l-sulfonyl) DMF was degassed with N2 for 30 minutes. 2-Tributylastanyl piperazine (0.214 g, 0.58 mmol), N- (4-fluoro-benzyl) -4- (3-iodo-indol-l-sulfonyl) -benzamide 0.300 g, was added. 0. 56 mmol) and tetrakis (triphenylphosphine) Pd (0) (0.100 g, 0.86 mmol) to DMF (5.0 mL). It was heated and stirred at 100 ° C under N2 through 16 hours. The reaction mixture was poured into H20-EtOAc. The EtOAc layer was separated and extracted several times with H20, washed with brine, dried (MgSO4) and filtered through celite. The solvent was stirred in a rotary evaporator to give an oil. Chromatograph on the chromatron using a 1 mm plate and levigate with 1% CH30H-CHC12 to give the title compound. Mass spectrum (m / e) (M + H) 487. 1240; found: 487.1220.

Example 218 N- (4-Fluoro-benzyl) -4- (3-phenyl-indole-1-sulfonyl) -benzamide In a 100 ml RBF, 4- (3-phenyl-indole-1-sulfonyl) -benzoic acid (2.5 g, 6.62 mmol) and THF (25 ml) were combined. The solution was cooled in an ice water bath and 4-methylmorpholine (0.73 ml, 7.29 mmol) was added, followed by the dropwise addition of CDMT (1.16 g, 7.29 mmol). The solution was stirred in a bath of ice water for one hour. A solution of 4-fluorobenzylamine (0.83 ml, 7.29 mmol) in THF (8 ml) was added dropwise to the reaction at 0 ° C. The solution was stirred at 0 ° C for five hours and quenched with IN HCl (50 ml). The reaction was extracted with MTBE (2x50 ml), filtered and washed with saturated aqueous sodium chloride solution (50 ml). The organics were dried over magnesium sulfate, filtered and concentrated to give N- (4-fluoro-benzyl) -4- (3-phenyl-indole-1-sulfonyl) -benzamide (2.43 g) as a white solid. HPLC = 95.5%, MS (ESI) m / z observed 485.1334 calculated 485.1335 (M + H). 4 g of N- (4-fluoro-benzyl) -4- (3-phenyl-indole-1-sulfonyl) -benzamide was dissolved in 15 mL of absolute ethanol. As the sample became wet, it was sonic and observed crystallization. A powder diffraction pattern was collected in these crystals. The crystals were characterized by having a melting onset starting at 140 ° C.

Example 219 4- (3-Cyclopentyl-indole-1-sulfonyl) -N- (tetrahydro-pyran-4-yl) -benzamide A solution of 4- (3-cyclopentyl-indole-1-sulfonyl) -benzoic acid (19.0 g, 51.43 mmol) in anhydrous THF (250 mL) was stirred, cooled to 5 ° C, N-methylmorpholine (5.8) was added. mL, 52.72 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.0 g, 51.34 mmol). The mixture was stirred at 0-5 ° C for 1 hour, a solution of 4-aminotetrahydro-pyran (5.8 g, 57.36 mmol) in dry THF (75 mL) was added via a dropping funnel. The mixture was brought to room temperature, stirred for 3 hours and cooled again down to 5 ° C. The mixture was stirred and 1N HCl (250 mL) was added, the resulting solution was added to a separatory funnel, and extracted with ethyl acetate (250 mL). The layers were separated, the organic layer was washed with brine (250 mL), and the aqueous layers were combined and extracted with ethyl acetate (250 mL). The organics were combined and washed with saturated aqueous sodium bicarbonate (400 mL) and the organic layer was dried over sodium sulfate. It was concentrated to give a foam, dissolved in minimal methylene chloride, and an instant 65M biotage cartridge was added. It was levigated with hexanes / ethyl acetate 3: 2 to provide the main product as a foam and dried (20 mm Hg, 40 ° C), to give a white powder of pure product (20.3 g, 87%); MS (ESI) m / z 453 (m + H).

EXAMPLE 220 4- (3-cyclopentyl-indole-sulfonyl) -N- (tetrahydro-pyran-4-ylmethyl) -benzamide A stirred solution of 4- (3-cyclopentyl-indole-1-sulfonyl) -benzoic acid (19.0 g, 41.53 mmol) in anhydrous THF (250 mL) was stirred, cooled to 5 ° C under N2 and added N- methylmorpholine (5.8 mL, 52.72 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.0 g, 51.34 mmol). The mixture was stirred for 1 hour and a solution of 4-aminomethyltetrahydropyran (6.6 g, 57.34 mmol) in dry THF (75 mL) was added per dropping funnel. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was cooled to 5 ° C, IN HCl (250 mL) was added and the resulting solution was partitioned with ethyl acetate (250 mL). The organic layer was extracted with aqueous sodium bicarbonate (250 mL), brine (250 mL), and dried over sodium sulfate. It was concentrated to give a foam, dissolved in minimal methylene chloride and added to an instant 65M cartridge. It was levigated with hexanes / ethyl acetate 3: 2 to give the main product as a solid, filtered from hexanes and dried (20 mm Hg, 40 ° C), to give the homogeneous white solid (20.5 g, 85% ); MS (ESI) m / z 467 (m + H).

Example 221 4- (3-cyclopentyl-indole-1-sulfonyl) -N- (4-fluoro-benzyl) -benzamide A 500-mL 5-necked ball flask equipped with an upper disc shaker, temperature probe, dropping funnel, and N 2 coating with 4-3-cyclopentyl-indole-1-sulfonyl) -benzoic acid (7.8) was charged. g, 21.1 mmol) in anhydrous THF (100 mL). The solution was cooled and stirred at 0 ° C and N-methylmorpholine (NMM, 2.4 mL, 21.8 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 3.7 g, 21.1) were added. mmol). The mixture was stirred for 1 hour at 0 ° C and a solution of 4-fluorobenzylamine (2.7 mL, 23.6 mmol) in anhydrous THF (30 mL) was added for 10 minutes via a dropping funnel. The resulting suspension was brought to room temperature and stirred for 3 hours. The mixture was cooled to 0 ° C and treated with IN HCl (100 mL). Ethyl acetate (100 mL) was added and the layers separated. The organic layer was dried over sodium sulfate and concentrated to a residue which was kept on its side at this point. The reaction was repeated exactly as summarized above using 4- (3-cyclopentyl-1-indole-1-sulfonyl) -benzoic acid (8.8 g, 23. 82 mmol), NMM 82.7 mL, 24.5 mmol), CDMT (4.2 g) , 23.9 mmol), 4-fluorobenzylamine (3.1 mL, 27.1 mmol) and anhydrous THF (160 mL). After the reaction and lifting as previously described, the CLAR profile of the crude organic residue (similar, but less pure) (hexanes / ethyl acetate 3: 2) was obtained, with that of the initial reaction. Chromatography independently of the two organic extracts (biotage 65M, 5% ethyl acetate in toluene), provided, in both cases, separation of the main component. The appropriate fractions were combined at this point and concentrated to a white foam. The foam was dried (20 mm Hg, 40 ° C) to provide a white powder (14.6 g, 68%); MS (ESI) m / z 477 (m + h). 20 mg of 4- (3-cyclopentyl-indole-1-sulfonyl) -N- (4-fluoro-benzyl) -benzamide was dissolved in isopropyl ether, although a minor amount of the oil remains at the bottom. It is stirred vigorously until evaporation occurs and a white powder forms: the beginning of the melting is at 113 ° C.

Example 222 N- (5-Fluoro-pyridin-3-ylmethyl) -4- (3-phenyl-indole-1-sulfonyl) -benzamide A solution of 242.7 mg / mL of N- (5-fluoro-pyridin-3-ylmethyl) -4- (3-phenyl-indole-1-sulfonyl) -benzamide in methanol was made. The solution was allowed to evaporate to dryness: beginning of the melting point at 131 ° C.

Example 223 (N- (5-fluoro-pyridin-2-ylmethyl) -4- (3-f-enyl-indol-1-sulfonyl) -benzamide A stirred mixture of 4- (3-phenyl-indole-1-sulfonyl) -benzoic acid (5. 0 g, 13.25 mmol) and 2-aminomethyl-5-fluoropyridine (dihydrochloride) (2.9 g, 14.57 mmol) was added. anhydrous methylene chloride (60 mL), EDCI (3.8 g, 19.82 mmol) and 4-DMAP (6.0 g, 49.10 mmol). The resulting solution was stirred overnight at room temperaturewas concentrated to a pad and partitioned between ethyl acetate (100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated to an oil. The oil was dissolved in methylene chloride and 65 biotage was added to a cartridge. It was levigated with 1: 1 ethyl acetate / hexanes to provide isolation of 3- (N- (5-fluoro-pyridin-2-ylmethyl) -4- (3-phenyl-indole-1-sulfonyl) -benzamide as a solid, 5.7 g (89%): 2 H NMR (DMSO-ds) d 9.32 (t, J = 5.9 Hz, 1 H), 8.46 (d, J = 2.9 Hz, 1 H), 8.20 (d, J = 8.3 Hz, 2H), 8.12 (s, 1H), 8.03 (m, 3H), 7.82 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 6.8 Hz, 2H), 7.62 (dt, J = 2.9, 8.8 Hz, 1H), 7.50 (t, s 7.3 Hz, 2H), 7.39 (m, 4H), 4.50 (d, J = 5.9 Hz, 2H); MS (ESI) m / z 486 (m + H).

Example 224 (N- (5-fluoro-pyridin-3-ylmethyl) -4- (3-phenyl-indole-l-sulfonyl) - A stirred mixture of 4- (3-phenyl-indole-1-sulfonyl) -benzoic acid (5.0 g, 13.25 mmol), and 2-aminomethyl-4-fluoropyridine was added. (2.9 g, 14.57 mmol) in anhydrous methylene chloride (60 L), EDCI (3.8 g, 19.82 mmol) and 4-DMAP (6.0 g, 49.10 mmol). The resulting solution was stirred overnight at room temperature and concentrated to an oil. The oil was partitioned between ethyl acetate (100 ml), water (100 ml) and brine (100 ml). The aqueous layers were combined and extracted again with methylene chloride (100 ml) and the organics were dried over sulfate. They were concentrated to produce an oil and dissolved in methylene chloride and added to a biotage 65 cartridge. It was levigated with 3: 2 ethyl acetate / hexanes gradually increased to 4: 1 ethyl acetate / hexanes to produce the main product as a foam which was found to be homogeneous 3 (N- (5-fluoro-pyridin-3-ylmethyl) -4- (3-phenyl-indole-1-sulfonyl) -benzamide 5.6 g (87%); 1 H NMR ( DMSO- 6) d 9.28 (t, J = 5.9 Hz, 1H), 8.44 (d, J = 2.9 Hz, 1H), 8.39 (s, 1H), 8.19 (d, J = 8.8 Hz, 2H), 8.12 ( s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 7.3 Hz, 2H), 7.60 (m, 1H), 7.49 (t, J = 7.3 Hz, 2H), 7.39 (m, 3H), 4.48 (d, J = 5.9 Hz, 2H), MS (IER) m / z 486 ( m + H).

Example 226 N- (4-Fluoro-benzyl) -4- (3-phenyl-pyrrolo [2,3-b] pyridin-1- 3-Phenyl-1H-pyrrolo [2, 3-b] pyridine (178 mg, 0.915 mmol, 1.0 eq) was added slowly as a solution of DMF (2 ml) to a flask under potassium ter-butoxide containing N2 ( 108 mg, 0.961 mmol, 1.05 eq) in 1 ml of DMF solution. The solution was stirred for 5 minutes. 4- (4-Fluoro-benzylcarbamoyl) -benzenesulfonyl chloride (300 mg, 0.915 mmol, 1.0 eq) was slowly added as a solution of DMF (3 mL). The reaction was stirred for 18 hours at room temperature. The reaction of the solvent was removed and purified on gel chromatography to yield N- (4-fluoro-benzyl) -4- (3-phenyl-pyrrolo [2,3-b] pyridin-1-sulfonyl) -benzamide (82 mg, 18% yield). Mass spectrum (m / e): 485.94 (MH +).

Example 228 N- (4-Fluoro-benzyl) -4- [3- (2-piperidin-1-yl-acetyl) -indol-1-sulfonyl] -benzamide 1- (1H-indol-3-yl) -2-piperidin-1-yl-ethanone (199 mg, 0.821 mmol, 1.0 eq) was slowly added as a solution of DMF (2 ml) to a flask under sodium hydride containing N (36 mg, 60% by weight of oil, 0.903 mmol, 1.1 eq) in 2 ml of DMF solution. The solution was stirred for 5 minutes. 4- (4-Fluoro-benzylcarbamoyl) -benzenesulfonyl chloride (296 mg, 0.903 mmol, 1.1 eq) was slowly added as a solution of DMF (3 ml). The reaction was stirred for 18 hours at room temperature. The reaction was removed from the solvent and purified on gel chromatography to yield N- (4-fluoro-benzyl) -4- [3- (2-piperidin-1-yl-acetyl) -indol-1-sulfonyl] -benzamide (249 mg, 57% yield). Mass spectrum (m / e): 534 (MH +).

Example 229 4- (3-cyclohexyl-indole-1-sulfonyl) -N- (4-fluoro-benzyl) -benzamide 4-Fluoro-benzylamine (72 mg, .574 mmol, 1.1 eq) was added followed by triethylamine (343 mg, .472 ml, 3.39 mmol, 6.5 eq) to a solution of CH2C12 (8 ml) of 4- (3 -cyclohexyl-indole-1-sulfonyl) -benzoic acid (200 mg, .521 mmol, 1 eq). Benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (231 mg, 0.521 mmol, 1 eq) was added and stirred at room temperature for 16 hours. The solvent was removed on a rotoevaporator and crude was purified by silica gel chromatography to yield 4- (3-cyclohexyl-indole-1-sulfonyl) -N- (4-fluoro-benzyl) -benzamide (232 mg, 99% of performance). Mass spectrum (m / e): 490.92 (MH +).

Example 230 4- (3-cyclohexyl-indole-1-sulfonyl) -N- (tetrahydro-pyran-4-ylmethyl) -benzamide Using a similar procedure as for 4- (3-cyclohexyl-indole-1-sulfonyl) -N- (4-fluoro-benzyl) -benzamide to yield 275 mg (100% yield) of the title compound. Mass Spectrum (m / e): 480.97 (MH +).

Example 231 4- (3-cyclohexyl-indole-1-sulfonyl) -N- (tetrahydro-pyran-4-yl) -benzamide Using a similar procedure as for 4- (3-cyclohexyl-indole-1-sulfonyl) -N- (4-fluoro-benzyl) -benzamide to yield 198 mg (71% yield) of the title compound. Mass Spectrum (m / e): 466.94 (MH +).

Example 232 4- [3- (3, 3-difluoro-cyclopentyl) -indol-1-sulfonyl] -N- (tetrahydro-pyran-4-yl) -benzamide About 2 ml of CH2C12 solution of tetrahydro-pyran-4-ylamine (62 mg, 0. 0610 mmol, 1.1 eq) and triethylamine (365 mg, 3.6 mml, 6.5 eq) were added to about 2 ml of CH2C12 acid solution 4- [3- (3, 3-difluoro-cyclopentyl) -indol-1-sulfonyl] benzoic acid. Benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (245 mg, 0.555 mmol, 1.0 eq) was added and the reaction was stirred at room temperature for 18 hours. The volatiles were removed in rotoevaporator and purified by silica gel chromatography, followed by SCX ion chromatography to produce 4- [3- (3,3-difluoro-cyclopentyl) -indol-1-sulfonyl] -N- (tetra idro-pyran-4-yl) -benzamide (240 mg, 89% yield). Mass spectrum (m / e): 489.71 (MH +).

Example 233 4- [3- (3, 3-difluoro-cyclopentyl) -indol-1-sulfonyl] -N- (tetrahydro-pyran-4-ylmethyl) -benzamide Using a similar procedure as for 4- [3- (3, 3-difluoro-cyclopentyl) -indol-1-sulfonyl] -N- (tetrahydro-pyran-4-yl) -benzamide using C- (tetrahydro-pyran-4) -yl) -methylamine in place of tetrahydro-pyran-4-ylamine to produce 4- [3- (3, 3-difluoro-cyclopentyl) -indol-1-sulfonyl] -N- (tetrahydro-pyran-4-ylmethyl) ) -benzamide (280 mg, 100% yield). Mass Spectrum (m / e): 503.98 (MH +).

Example 234 N- (4-Fluoro-3-methoxy-benzyl) -4- (3-piperidin-1-iA-indol-1-sulfonyl) -benzamide hydrochloride KotBu (211 mg, 1.88 mmol) was added to a solution of 3-piperidin-1-yl-1H-indole (299 mg, 1.49 mol) in dioxane (15 ml). The yellow solution was stirred at RT for 30 min, then treated with 4- (4-fluoro-3-methoxy-benzylcarbamoyl) -benzenesulfonyl chloride (560 mg, 1.56 mmol). The solution was stirred at RT for a further 2 h, then diluted with EtOAc (50 ml) and washed with saturated NaHCO 3 (25 ml). The organic phase was removed and the aqueous layer was extracted with additional EtOAc (50 ml). The organic solutions were combined, dried over Na 2 SO, filtered, and concentrated. The crude material was purified by flash chromatography (3X) using an oversized silica column and a gradient of 100% hexanes at 4% EtOAc / hexanes. The fractions containing pure material were concentrated then redissolved in CH2C12 (100 ml) and treated with 4M HCl / dioxane (0.5 ml). The off-white precipitate was filtered and dried under vacuum to yield the title compound as a white powder (417 mg). MS (ES +) 522.1 (M + 1) +, (ES ") 520.2 (M-1)". X H NMR (DMSO-dff): d 9.19 (m, 1 H), 8.03 (d, 2 H, J = 8.4), 7.97 (, 1 H), 7.95 (d, 2 H, J = 8.4), 7.61 (d, 1 H, J = 7.5), 7.37 (t, 1H, J = 7.6), 7.26 (t, 2H, J = 7.5), 7.06-7.13 (m, 2H), 6.81 (m, 1H), 6.12 (br s, 1H) , 4.39 (d, 2H, J = 5.7), 3.78 (s, 3H), 3.06 (s, 4H), 1.72 (s, 4H), 1.56 (s, 2H).

Example 240 4 { [4- (3-phenyl-indole-1-sulfonyl) -benzoylamino] -methyl} -N, N-dimethyl-benzamide . The 4-acid was combined. { [4- (3-phenyl-indole-l-sulfonyl) -benzoylamino] -methyl} -benzoic acid (0.489 mmol) with dimethylamine (0.587 mmol), and EDC (0.733 mmol) in 5 mL of dichloromethane and stirred for 15 hours. The reaction was diluted and washed with IN HCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified via column chromatography with a mixture of ethyl acetate and dichloromethane to isolate 0.40 g (15.2%) of the title compound: MSES + 537.95; MSES- 536.08.

General Example 241 EDC Coupling The amine (0.809 mmol), benzoic acid, for example, 4- (3-cyclopentyl-indazole-l-sulfonyl) -benzoic acid (0.539 mmol), EDC (0.809 mmol) in 5 ml of dichloromethane and stirred for 15 hrs. The reaction mixture was diluted and washed with 1N HCl. The organic material was dried over MgSO4 and concentrated. The residue was purified via column chromatography using a mixture of ethyl acetate and dichloromethane. The following compounds were prepared essentially following General Example 241.

General Example 248 Bop Couplings The amine (0.525 mmol), BOP (0.421 mmol), triethylamine (1.05 mmol), and the appropriate benzoic acid (0.350 mmol) were combined and stirred in 5 mL dichloromethane for 4 hrs. The reaction was concentrated and purified via column chromatography using a mixture of ethyl acetate and dichloromethane. The following compounds were prepared essentially following General Example 248.

General Example 253 EDC-DMAP The amine (0.300 mmol), the appropriate benzoic acid (0.300 mmol), DMAP (300 mmol), and EDC (0.450 mmol) in 5 mL dichloromethane were combined and stirred until the reaction was full. The reaction was diluted and washed with 1N HCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified via column chromatography with a mixture of ethyl acetate and dichloromethane. The following compounds were prepared essentially following General Example 253.

Example 257a 4- (3-Cyclopentyl-indole-1-sulfonyl) -N- (tetrahydro-pyran-2-ylmethyl) -benzamide Isomer 1 The racemate was separated from 4- (3-cyclopentyl-indole-l-sulfonyl) -N- (tetrahydro-pyran-2-ylmethyl) -benzamide on a Chiralpak AD column of 8x29 cm with 100% 3A (anhydrous ethanol) used as the mobile phase, flow rate of 300 ml / min, and UV detection at 220 nm. It was analyzed on a Chiralpak AD-H column of 4.6x150 mm with 100% 3A as the mobile phase, flow rate of 0.6 ml / min, and UV detection at 219 nm to produce the isolation of isomer 1 which was levigated at 12.6 min. MS ES + 466.98, MS ES-465.07.

Example 257b 4- (3-Cyclopentyl-indole-1-sulfonyl) -N- (tetrahydro-pyran-2-ylmethyl) -benzamide Isomer 2 The racemate was separated from 4- (3-cyclopentyl-indole-l-sulfonyl) -N- (tetrahydro-pyran-2-ylmethyl) -benzamide on a Chiralpak AD column of 8x29 cm with 100% 3A (anhydrous ethanol) as the mobile phase, flow rate of 300 ml / min, and UV detection at 220 nm. It was analyzed on a Chiralpak AD-H column of 4.6x150 mm with 100% 3A as the mobile phase, flow rate of 0.6 ml / min, and UV detection at 219 nm to produce the isolation of isomer 2 which was levigrated at 18.8 min. EM ES + 467.0, MS ES- 465.1.

Example 259 4- (3-cyclopentyl-indole-l-sulfonyl) -N-pyridin-3i-ethyl-benzamide Hunigs base (0.148 g, 0.200 ml, 1.11 mmol) was added to a stirred mixture of 4- (3-cyclopentyl-indole-l-sulfonyl) -benzoic acid (0.188 g, 0.50 mmol), PyBOP (0.0.288 g). , 0.50 mmol) and 3-amino-pyridine (0.063 g, 0.59 mmol) in dry CH2C12 (10 ml) under N2. The reaction was stirred overnight at room temperature and evaporated on the rotary evaporator. The residue was chromatographed on the ISCO system using a 40 g column and a gradient hexane-EtOAc system (0-100%) to yield 0.048 g of the title compound as white foam: Mass Spectrum (m / e) ( M + H) 460.1697; found 460.1681.

Example 260 4- (3-cyclopentylindol-1-sulfonyl) -N- [1-1- (tetrahydrofuran-2-yl) methyl] benzamide I- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 98 mg, 0.51 mmol, 1.5 equivalents) and 4- (dimethylamino) pyridine hydrochloride (DMAP, 70 mg, 0.57 mmol, 1.7 equivalents) were added to a solution of 4- (3-cyclopentylindol-1-sulfonyl) benzoic acid (126 mg, 0.341 mmol, 1 equivalent) and I- (-) - tetrahydrofurfurylamine (Aldrich; 140 μL, 140 mg, 1.4 mmol, 4.0 equivalent) in anhydrous CH2C12 ( 1 ml). After stirring for 16 h, the reaction solution was transferred to a column of silica gel (80 mm x 20 mm diameter) and levigated (10-45% EtOAc / hexanes) to yield 24 mg (16%). of 4- (3-cyclopentylindol-1-sulfonyl) -N- [1-1- (tetrahydrofuran-2-yl) methyl] benzamide as a white foam. MS (m / e): 452.96 (M + 1); 451.14 (M-l).

Example 261 4- (3-phenylindol-1-sulfonyl) -N- (tetrahydrofuran-3-ylmethyl) benzamide Benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (2.2 g, 5.0 mmol, 1.5 equivalents) was added to a solution of 4- (3-phenyl-indole-l-sulfonyl) -benzoic acid (1.23 g, 3.26 mmol, 1 equivalent), (tetrahydro-furan-3-yl) -methylamine (331 mg, 3.27 mmol, 1.0 equivalent), and triethylamine (2.3 ml, 1.7 g, 17 mmol, 5.0 equivalents) in anhydrous CH2C12 (12 ml). After 1 hour, the reaction solution was subjected to rotary evaporation and the resulting residue transferred to a column of silica gel (235 mm x 35 mm in diameter) and levigated (50-90% EtOAc / Hexanes). This produced 486 mg (32.4%) of rac-4- (3-phenyl-indole-l-sulfonyl) -N- (tetrahydro-furan-3-ylmethyl) -benzamide as a yellow foam. MS (m / e): 460.96 (M + l); 459.04 (M-1).

Example 261a 4- (3-phenylindol-1-sulfonyl) -N- (tetrahydrofuran-3-ylmethyl) benzamide Isomer 1 The enantiomers of rac-4- (3-f-enyl-indole-1-sulfonyl) -N- (tetrahydro-furan-3-ylmethyl) -benzamide (470 mg) were separated using a Chiralpak AD-H column (4.6 x 150 mm) with 95% EtOH / MeOH at 0.6 ml / min. The peak was collected at 9.8 min followed by rotary evaporation to yield 154 mg (32.8%) of the 1-4 (3-f-enylindol-1-sulfonyl) -N- (tetrahydrofuran-3-ylmethyl) benzamide isomer. MS (m / e): 460.96 (M + 1); 459.03 (M-l).

Example 261b 4- (3-f-enyl indol-1-sulfonyl) -N- (tetrahydrofuran-3-ylmethyl) benzamide Isomer 2 The enantiomers of rac-4- (3-phenyl-indole-1-sulfonyl) -N- (tetrahydro-furan-3-ylmethyl) -benzamide (470 mg) were separated using a Chiralpak AD-H column (4.6 x 150 mm) ) with 95% EtOH / MeOH at 0.6 ml / min. The peak was collected at 12.6 min followed by rotary evaporation to yield 156 mg (33.2%) of the 2- (3-phenylindol-1-sulfonyl) -N- (tetrahydrofuran-3-ylmethyl) benzamide isomer. MS (m / e): 460.96 (M + 1); 459.04 (M-1).

Example 265 (3-hydroxymethyl-azetidin-1-yl) - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] methanone Azetidin-l, 3-dicarboxylic acid mono-tert-butyl ester (300 mg, 1.50 mmol) was dissolved in THF (5.0 mL) and treated with lithium aluminum hydride (1.0M in ether, 3.0 mL, 3.0 mmol). ). It was stirred for 18 hours, cooled with 3.0 ml of 1.0 M NaOH, diluted with ether, filtered through celite and evaporated. The tert-butyl ester of 3-hydroxymethyl azetidine-l-carboxylic acid was treated with 10 ml of trifluoroacetic acid for 20 minutes in an evaporator. This material was used without further purification. 4- (3-Phenyl-indole-1-sulfonyl) -benzoic acid (100 mg, 0.26 mmol) and the resulting azetidin-3-yl-methanol in dichloromethane (1.0 ml) and triethylamine (0.100 ml, 0.717 mmol) were combined. , excess) and benzotriazole-1-yloxytris (dimethylamin) phosphonium hexafluorophosphate (BOP Reagent) (150 mg, 0.33 mmol, excess) was added at room temperature. Stirred for 30 minutes, evaporated and loaded the entire reaction directly onto the pre-packed silica gel column and purified by flash chromatography (EtOAc / Hexanes) to yield 41 mg of (3-hydroxymethyl azetidin-1-yl) ) - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone as a white solid (35%). EMBR: MH + 447.2.

Example 266 4- (3-Cyclopentyl-indole-1-sulfonyl) -N- (tetrahydro-pyran-4-ylmethyl) -benzamide In a 12 L RBF, 4- (3-cyclopentyl-indole-1-sulfonyl) -benzoic acid (400 g, 1084 mol) and THF (3.6 L) were charged and the solution was cooled to 5 ° C, and added 4-methylmorpholine (121 g, 1192 mol). CDMT (209 g, 1192 mol) was added over a period of 5 minutes and stirred for 1 hour at 5 ° C. A solution of 4-aminomethyltetrahydropyran (150 g, 1300 mol) and THF (500 ml) was added dropwise over a period of 1 hour at 5 ° C. The cooling bath was removed and the reaction was stirred for 75 minutes. The solution was cooled to 10 ° C and quenched with 1N HCl (4 1). Ethyl acetate (2.5 1), DI water (2 L) were added and the aqueous layer was again extracted with ethyl acetate (2 L). The organic layers were washed with saturated sodium bicarbonate (3 L), brine (3 L), dried over sodium sulfate, filtered and concentrated under vacuum to yield 575 g of an oil / foam. The crude material was purified by filtration through silica plug and formed into a slurry in methanol (2 L) for 2 hours. The slurry was cooled to 5 ° C, stirred for 2 hours, filtered, rinsed with methanol (0.5 L) and dried at 45 ° C in a vacuum oven to provide 485 g of a white solid (yield = 96%) of the title compound that showed two fusions one at 136-138 ° C and a second at 153-155 ° C.

Example 267 4- (3-cyclopentyl-indole-1-sulfonyl) -N- (4-fluoro-benzyl) -benzamide In a 22 L RBF, 4- (3-cyclopentyl-indole-1-sulfonyl) -benzoic acid (435 g, 1177 mol) and THF (4 L) were charged and the solution was cooled to 5 ° C, and added 4-methylmorpholine (131 g1,295 mol). CDMT (227 g, 1295 mol) was added in one portion and stirred for 1 hour at 5 ° C. A solution of 4-fluorobenzylamine (162 g, 1295 mol) and THF (500 ml) was added dropwise over a period of 1 hour at 5 ° C. The cooling bath was stirred and the reaction was stirred 120 minutes. The solution was cooled to 10 ° C and quenched with 1N HCl (4 1). Ethyl acetate (3 1), DI water (3 L) were added and the aqueous layer was again extracted with ethyl acetate (3 L). The organic layers were washed with saturated sodium bicarbonate (3 L), brine (3 L), dried over sodium sulfate, filtered and concentrated under vacuum to yield 575 g of an amber oil / foam. The crude material was purified by filtration through silica plug and formed into a slurry in methanol (2 L) for 17 hours. The slurry was cooled to 5 ° C, stirred for 1 hour, filtered, rinsed with methanol (0.75 L) and dried at 45 ° C in a vacuum oven to provide 450g of a white solid (yield = 80.2). %) of the title compound having a single melt ranging from 118 ° C to 121 ° C; X H NMR (DMSO) d 9.2 (t, 1 H), 8.1 (m, 2 H), 7.95 (m, 2 H), 7.9 (d, 1 H), 7.6 (d, 1 H), 7.5 (s, 1 H), 7.3 ( m, 4H), 7.1 (t, 2H), 4.4 (dd, 2H), 3.1 (t, 1H), 2.05 (m, 2H), 1.7 (m, 6H). % Theory C 68.0484, H 5.2876, N 5.8781,% Found C 68.01, H 5.13, N 5.

Example 268 4- (3-cyclopentyl-indole-1-sulfonyl) -N-pyridin-3-yl-methyl-benzamide A mixture of 4- (3-cyclopentyl-indole-1-sulfonyl) -benzoic acid (0.188 g, 0.50 mmol), PyBOP (0.0.288 g, 0.50 mmol), and 3-amino-pyridine (.063 g) was stirred. , 0.59 mmol) in dry CH2C12 (10 ml) under N2, Hunigs base (0.148 g, 0.200 ml, 1.11 mmol) was added. It was stirred overnight at room temperature and evaporated on the rotary evaporator. The residue was chromatographed on the ISCO using a 40 g column and a gradient system of hexane-EtOAc (0-100%) to yield 0.048 g of the title compound as a white foam. Mass spectrum (m / e) (M + H) 460.1697; found 460.1681.

Example 269 4- (3-cyclopentyl-indole-1-sulfonyl) -n-isobutyl-benzamide A mixture of 4- (3-cyclopentyl-indole-1-sulfonyl) -benzoic acid (0.163 g, 0.44 mmol), PyBOP (0.226 g, 0.51 mmol), and isobutylamine (0.038 g, 0.52 mmol) in dry CH2C12 was stirred. (10 ml) under N2, Hunigs base (0.148 g, 0.11 mmol) was added. The reaction was stirred overnight at room temperature and evaporated on the rotary evaporator. The residue was chromatographed on the ISCO using a 40 g column and a gradient system of hexane-EtOAc (0-100%) to yield 0.110 g of the title compound as a white foam. Mass spectrum (m / e) (M + H) 425.1899; found 460.1925.

Example 270 N- (4-Fluoro-benzyl) -4- (3-isopropyl-indole-l-sulfonyl) benzamide A mixture of 3-isopropyl indole in dry DMF (20 ml) under N2 was stirred, 1.0 M potassium t-butoxide (1.2 ml, 1.2 mmol) was added dropwise. The resulting solution was stirred for 30 minutes at room temperature. 4- (4-Fluoro-benzylcarbamoyl) -benzenesulfonyl chloride (0.360 g, 1.1 mmol) was added dropwise and the resulting mixture was stirred overnight. The reaction mixture was poured into a mixture of EtOAc-H20. The EtOAc layer was separated, extracted with H20, washed with brine and dried (MgSO4). It was filtered and evaporated to produce the crude product. The residue was chromatographed on the ISCO by levigating with hexane-EtOAc to yield a white solid (0.150 g). Mass spectrum (m / e) (M + H) 451.1492; found 451.1488.

Example 271 N-Cyclopropylmethyl-4- (3-isopropyl-indole-1-sulfonyl) -benzamide A mixture of 4- (3-isopropyl-indole-l-sulfonyl) -benzoic acid (0.181 g, 0.53 mmol), PyBOP (0.243 g, 0.55 mmol), and cyclopropylmethyl amine (0.064 g, 0.59 mmol) in was stirred. CH2C12 (20 ml) and Hunigs base (0.28 ml, 1.62 mmol) under N2. The resulting mixture was stirred overnight at room temperature. The reaction was extracted with H20, washed with brine, dried (MgSO), filtered, evaporated and chromatographed using hexane-EtOAc (0-100%) to yield 0.183 g of the title compound as an off-white solid. . Mass spectrum (m / e) (M + H) 397.1586.

Example 272 4- (3-cyclopentyl-2,3-dihydro-indol-1-sulfonyl) -N- (4-fluorobenzyl) -benzamide 4- (3-Cyclopentyl-indole-1-sulfonyl) -N- (4-fluoro-benzyl) -benzamide (0.152 g, 0.319 mmol) was added dropwise to a stirred mixture of NaCNBH (0.96 g, 1.52 mmol) in ATF from 0 to 5 ° C under N2. The mixture was stirred for 15 minutes at 0-5 ° C, allowed to warm to room temperature and some .096 g of additional NaCNBH3. The resulting yellow solution was stirred for 2 h at room temperature, diluted with H20 (13.0 ml) and stirred overnight. The reaction mixture was poured into EtOAc (100 mL). The EtOAc was separated, extracted with H20, 5% NaHCO3 and washed with brine. The EtOAc was separated, dried (MgSO 4), filtered and evaporated to yield a crystal. Chromatograph on the chromatron by levigating with EtOAc-hexane 3: 7 to yield 0.60 g of the title compound: Mass spectrum (m / e) (M + H) 479.1805; found 479.1788.

Example 273 N- (4-Fluoro-benzyl) -4- (3-methyl-2,3-dihydro-indol-1-sulfonyl) benzamide N- (4-Fluoro-benzyl) -4- (3-methyl-indole-l-sulfonyl) -benzamide (0.106 g, 0.25 mmol) was added dropwise to a stirred mixture of NaCNBH3 (0.074 g, 1.2 mmol) in ATF (5.0 ml) from 0 to 5 ° C under N2. The mixture was stirred for 15 minutes at 0-5 ° C, allowed to warm to room temperature and stirred for 1 h, NaCNBH3 (0.074 g, 1.2 mmol) was added and the reaction was stirred for 2 h, diluted with H20. (13.0 ml) and was prepared as described in the previous example. Chromatographed and levigated with EtOAc-hexane (0-50%) to yield 0.075 g of the title compound: Mass spectrum (m / e) (M + H) 425.1335; found 425.1341.

Example 274 N- (4-Fluoro-benzyl) -4- (3-phenyl-2,3-dihydro-indol-l-sulfonyl) -benzamide 3-Phenyl-2,3-dihydro-1H-indole (0.233 g, 1.19 mmol), 4- (4-fluoro-benzylcarbamoyl) -benzenesulfonyl chloride (1 equivalent), Et3N (0.50 mL, 0.36 g, 3.57 g) were stirred. mmol), DMAP (0.015 g, 0.123 mmol) in CH2C12 (45 ml) overnight under N2. The CH2C12 was diluted to 150 ml and poured into a saturated solution of NaHCO3 (50 ml) and stirred for 15 minutes. The organic layer was separated and washed with H20 (100 ml), extracted with IN HCl (2 x 75 ml), washed with brine, separated and dried (MgSO4). It was filtered and evaporated followed by chromatography on the ISCO using a 40 g silica gel column and was levigated with EtOAc-hexane (90-100%) to yield 0.33 g of the racemic compound.

Example 274a N- (4-Fluoro-benzyl) -4- (3-phenyl-2,3-dihydro-indol-l-sulfonyl) benzamide, Isomer 1 N- (4-fluoro-benzyl) -4- (3-phenyl-2,3-dihydro-indole-1-sulfonyl) -benzamide was separated via chromatographic separation in chiral OD (90.46x25 cm column) (EtOAc- hexane 90-100%), 1.0 ml / min to produce (isomer 1) (0.60 g), retention time 5.45 min.

Example 274b N- (4-Fluoro-benzyl) -4- (3-phenyl-2,3-dihydro-indol-l-sulfonyl) benzamide, Isomer 2 The separation of Example 274a was continued via chromatographic separation on chiral OD (90.46x25 cm column) (90-100% EtOAc-hexane), 1.0 ml / min to produce (2-isomer) (0.61 g), retention time 7.21 min.

Example 275 4- [3- (3-cyano-phenyl) -indol-1-sulfonyl] -N- (4-fluoro-benzyl) benzamide Se) -4-. { 3- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaboralan-2-yl) -indol-1-sulfonyl} -benzamide (0.267 g, 0.50 mmol), 3-bromobenzonitrile (0.160 g, 0. 55 mmol), PdCl2 (dppf) .CH2C12 (0.032 g, 0.39 mmol) and 2N Na2CO3 (0.50 ml, 1.0 mmol) and heated in dioxane (20 ml) at 81 ° C under N2 for 6 h. The reaction was concentrated and the residue was chromatographed on the ISCO using a column of 12 g silica gel and levigating with hexane-EtOAc (0-100%) to yield the title compound as a light tan foam (0.100 g). ). Mass spectrum (m / e) (M + H) 510.1288; found 510.1283.

Example 276 N- (4-Fluoro-benzyl) -4- (3-thiazol-2-yl-indole-l-sulfonyl) -benzamide N- (4-Fluoro-benzyl) -4- was stirred. { 3- (4, 4,5, 5-tetramethyl- [1,3,2] dioxaboralan-2-yl) -indol-1-sulfonyl} -benzamide (0.267 g, 0.50 mmol), 2-bromothiazole (0.090 g, 0.55 mmol), PdCl2 (dppf) .CH2C12 (.032 g, .039 mmol) and 2N Na2CO3 (0.25 mL, 0.50 mmol) and warmed in dioxane (20 ml) at 99 ° C under N2 for 14 h. The reaction mixture was concentrated to dryness and the residue was chromatographed on the ISCO using a 12 g silica gel column and levigating with hexane-EtOAc (5-100%) to afford the title compound as a white solid. Mass spectrum (m / e) (M + H) 492.0852; found 492.0848.

Example 277 4- (3-cyclopentyl-indole-1-sulfonyl) -N- (5-fluoro-pyridin-2-ylmethyl) -benzamide The mixture of 4- (3-cyclopentyl-indole-1-sulfonyl) -benzoic acid (0.767 g, 0.21 mmol), C- (5-fluoro-pyridin-2-yl) -methylamine (0.041 g, 0.25 mmol) was stirred. ), and EDC (0.063 g, 0.33 mmol) in dry CH2C12 (15 ml) under N2 and DMAP (0.061 g, 0.50 mmol) was added. The resulting mixture was stirred at room temperature for 72 h. The reaction mixture was diluted to 50 ml with CH2C12, washed with H20, 1 N NaOH, and brine consecutively. The organic layer was dried (MgSO 4), filtered and evaporated to yield 0.189 g of the crude product. It was subjected to ISCO chromatography using a 12 g column and levigating with Hexane-EtOAc (0-100%) to yield the title compound (0.60 g) as a foam: Calculated for: C H FN O; C, 65.39; H, 5.066; N, 8.79.

Found: C, 65.50; H, 5.26; N, 8.61.

Example GTP 35S binding assays of CBl and CB2 The GTP 35S assays of CBl and CB2 were performed essentially as described in DeLapp et al. in buffer pH 7.4 containing 20 mM HEPES, 100 mM NaCl and 5 mM MgCl (NaCl was omitted from the rat brain membrane assay) in a final volume of 200 μl in 96-well Costar plates at 25 ° C. 100 μl of membrane preparation (25 μg of protein per well for cell membranes Sf9 of CBl or CB2, 15-18 μg per well for rat cerebellar membranes) containing the appropriate concentration of GDP (1 μM GDP for CB1 Sf9 cell membranes, 0.05 μM for CB2 Sf9 cell membranes, 25 μM GDP for cerebellar membrane assays). rat) were added to each well followed by the addition of 50 μl of buffer + test compounds or controls and then the plates were incubated for 30 minutes. Then 50 μl of GTPγ 35S were added to a final concentration of 400 pM in each well and the plates were incubated for another 30 minutes. After this, 20 μl of 0.27% Nonidet P-40 were added with a 30 minute incubation before the addition of 20 μl / well of a dilutionanti-Gal antibody (1-3) final 1/400 to 1/100 (Rabbit antibody to conjugated BSA peptide KNNLKECGLY) with a 60 minute incubation. 50 μl of SPA beads (PVT; anti-rabbit antibody) resuspended in 20 ml of assay buffer then added to each well. After 180 min, the plates were centrifuged at 900 g for 10 min and the G protein binding radioactivity was measured using a Wallac plate counter. DeLapp NW. McKinzie JH. Sawyer BD. Vandergriff A. Falcone J. McClure D. Felder CC. Determination of link of [35S] Guanosin-5 '-O- (3-thio) triphosphate mediated by cholinergic muscarinic receptors in membranes of Chinese hamster ovary cells and rat striatum using an anti-G protein scintillation proximity assay. Journal] Journal of Pharmacology & Experimental Therapeutics. 289 (2): 946-55, May 1999. In this test, the IC 50 of the compounds of the formula (I) is less than or equal to 5 μM. The utilities of the present compounds in the treatment or prevention of diseases or disorders can be demonstrated in models of animal diseases that have been reported in the literature. The following are examples of such models of animal diseases: a) suppression of food intake and resultant weight loss in rats (Life Sciences 1998, 63, 113-117); b) reduction of admission of sweet foods in marmosets (Behavioral, Pharm, 1998, 9, 179-181); c) reduction of admission of ethanol and sucrose in mice (Psychopharm, 1997, 132, 104-106); d) increased motor activity and place conditioning in rats (Psychopharm, 1998, 135, 324-332, Psychopharmacol 2000, 151: 25-30); e) Spontaneous locomotor activity in mice (J. Pharm. Exp. Ther. 1996, 277, 586-594); and f) reduction of self-administration in opiate in mice (Sci. 1999, 283, 401-404). The administration of the compound of the structural formula I to practice the present methods of therapy is carried out by administering an effective amount of the compound of the structural formula I to the patient in need of such treatment or prophylaxis. The need for prophylactic administration according to the methods of the present invention is determined via the use of well-known risk factors. The effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions of which the patient suffers, the chosen route of administration, other drugs and treatment which the patient may require concomitantly, and other factors to the judgment of the doctor. The magnitude of the prophylactic or therapeutic dose of a compound of formula I, of course, will vary with the nature of the severity of the condition to be treated and with the particular compound of formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range is in the range of about 0.001 mg to about 100 mg per kg of body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. For use where a composition for intravenous administration is employed, a suitable dosage range is from about 0.001 mg to about 25 mg (preferably 0.01 mg to about 1 mg) of a compound of formula I per kg of body weight per day and for cytoprotective use of from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of formula I per kg of body weight per day. In the case where an oral composition is employed, a suitable dosage range is, for example, from about 0.01 mg to about 100 mg of a compound of the formula I per day, preferably from about 0.1 mg to about 10 mg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0 or 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. For the treatment of eye diseasesOphthalmic preparations for ocular administration comprising 0.001-1% by weight, solutions or suspensions of the compounds of the formula I can be used in an acceptable ophthalmic formulation. Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of the formula I and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical composition, is proposed to include a product comprising the active ingredient, preferably present in pharmaceutically effective amounts, and the inert ingredients (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which it results, directly or indirectly, from the combination, complexing or aggregation of some two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition made by mixing a compound of the formula I and pharmaceutically acceptable excipients. Any suitable route of administration can be employed to provide a mammal, especially a human, with an effective dosage of a compound of the present invention. For example, they can be used oral, rectal, topical, parenteral, ocular, pulmonary, nasa and the like. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, suppositories and the like. The pharmaceutical compositions of the present invention comprise a compound of the formula as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In particular, the term "pharmaceutically acceptable salts" refers to salts prepared from non-toxic pharmaceutically acceptable bases or acids including inorganic bases or acids and organic bases or acids. The compound can be presented in crystalline form or can be incorporated into the pharmaceutical composition as an amorphous solid. Alternatively, the compound can be made partially or completely amorphous by the manufacturing process. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (inhalation by aerosol), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions that are treated and the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmacy art. For administration by inhalation, the compounds of the present invention are conveniently supplied in the form of a spray presentation of aerosolized container or pressurized nebulizers. The compounds can also be supplied as powders which can be formulated and the powder composition can be inhaled with the aid of a powder inhalation device by insufflation. Preferred delivery systems for inhalation are aerosol for metered dose inhalation (MDI), which can be formulated as a solution or suspension of a compound of formula I in suitable propellants, such as fluorocarbons or hydrocarbons and aerosol for inhalation of powder dry (IPS), which can be formulated as a dry powder of a compound of the formula I with or without additional excipients. Suitable topical formulations of a compound of the formula I include transdermal devices, aerosols, creams, ointments, lotions, powdered powders, and the like. Topical preparations containing the active drug component can be mixed with a variety of carrier materials well known in the art such as, for example, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil , myristyl propionate PPG2, and the like. To be administered in the form of a transdermal delivery system, dosing administration, of course, will be continuous rather than intermittent throughout the dosing regimen. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as cholesterol, sterilamine or phosphatidylcholines. The compounds of the present invention can also be coupled with soluble polymers as target drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylasparamidefeon, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, for example, polylactic acid, polypepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates and copolymers of cross-linked or amphipathic blocks of hydrogels. The compounds of the present invention can also be supplied as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. In practical use, the compounds of the formula I can be combined as the active ingredient in intimate admixture with or solubilization in a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous). In the preparation of the compositions for oral dosage form, any of the usual pharmaceutical media can be employed, such as, for example, water, glycols, simple oils, chemically modified or fractionated glycerides, polyoxyethylene-polyoxypropylene copolymers, alcohols, agents of active surface, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred envelopes liquid preparations. The carrier may possess special properties to control or modify the release and subsequent absorption profile of the drug substance, the properties include but are not limited to self-emulsification, or controlled disintegration, dissolution or solubilization in vivo. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in this case solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated by standard non-aqueous or aqueous techniques. In addition to the common dosage forms described above, the compounds of formula I can also be administered by delivery devices and / or controlled release media such as those described in US Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719. The pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, lozenges or tablets each containing a predetermined amount of the active ingredient, such as a powder or granules or as a solution or suspension in an aqueous liquid. , a 'non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions can be prepared by any of the pharmacy methods but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly or intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more secondary ingredients. Compressed tablets can be prepared by compressing in a suitable machine, the active ingredient in a flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, dispersing agent or active surface. The molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Hard or soft gelatin capsules can be prepared either by filling with granule or dry powder formulations or by filling with a liquid formulation compatible with the capsule shell. Desirably, each tablet contains from 0.01 to 500 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3.0, 5.0, 6.0, 10.0, 15.0, 25.0, 50.0, 75, 100, 125, 150, 175, 180, 200, 225, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. And each tablet or capsule contains from about 0.01 to 500 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3.0, 5.0, 6.0, 10.0, 15.0, 25.0, 50.0, 75, 100, 125, 150, 175, 180, 200, 225 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The exemplification of the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. In addition, the exemplification of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for producing a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier. The dose can be administered in a single daily dose or the total daily dosage can be administered in divided doses of two, three or four times daily. In addition, based on the properties of the individual compound selected for administration and / or the characteristics of the dosage form (ie, modified release), the dose may be administered less frequently, eg, weekly, twice a week, monthly, etc. The unit dosage may be correspondingly higher for less frequent administration. When administered via transdermal routes or through a continuous intravenous solution, the dosage administration, of course, will be continuous rather than intermittent throughout the dosing regimen. The following are examples of representative pharmaceutical dosage forms for the compounds of formula I: Injectable Suspension (I.M.) mg / mL Compound of formula I 10 Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 Benzalkonium Chloride 1.0 Water for injection at a total volume of 1 ml Tablet mg / tablet Compound of the formula I 25 Microcrystalline cellulose 415 Povidona 14.0 Pregelatinized starch 43.5 Magnesium Stearate 2.5 500 Capsule (Dry Fill) g / capsule Compound of the formula I 25 Lactose Powder 573.5 Magnesium Stearate 1.5 600 Capsule (Liquid Filler) mg / capsule Compound of the formula I 25 Peanut oil 575 600 Capsule (Semi-solid, Self-Emulsifying Filler) mg / capsule Compound of the formula I 25 Gelucire 44/14 575 600 Capsule (Liquid Filling, Self-Emulsifying) mg / capsule Compound of the formula I 25 Sesame Oil 125 Cremophor RH40 300 Peceol 150 600 Aerosol Per can Composite formula I 24 mg Lecithin, NF Liq. Conc. 1.2 mg Trichlorofluoromethane, NF 4.025 g Dichlorodifluoromethane, NF 12.15 g The examples of the above dosage form are representative. The amount of the compound present in the compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention can be determined by a person skilled in the art.

Claims

CLAIMS A compound of formula I Formula I characterized in that: V. is a 6,5-bicyclic ring selected from the group consisting of: R1 is selected from the group consisting of: (a) hydrogen (b) alkylcarbonyl optionally substituted with heterocyclyl, (c) heterocyclylcarbonyl optionally substituted with alkyl or acetyl (d) alkyl or haloalkyl, (e) cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino and dialkylamino, (f) heterocyclyl selected from the group consisting of: 15 (g) aryl optionally substituted with halo, alkyl, alkoxy, cyano, amino, alkylamino or dialkylamino, and (h) heteroaryl selected from the group consisting of: R 2 is hydrogen, alkyl, heterocyclyl or together with R 1 and the carbon to which they are attached, form a saturated ring substituent selected from the group consisting of: (a) cycloalkyl, and (b) heterocyclyl selected from the group consisting of: tetrahydrofuranyl, tetrahydropyranyl and piperidinyl optionally N-substituted with alkyl, acetyl or aryl, X is -NR13R3 or V-A R3 is selected from the group consisting of: (a) hydrogen, (b) alkyl optionally substituted with one or two substituents independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, alkylamino and dialkylamino, (c) cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of hydroxy, alkoxy, halo, amino, alkylamino and dialkylamino, (d) heterocyclyl selected from the group consisting of: (e) cycloalkyalkyl selected from the group consisting of: 15 ^. "a. ^ C "H, ^? RH5 s ^ C "H ^ P ^ R5 (f) heterocyclylalkyl selected from group 20 consisting of: 25 (g) arylalkyl selected from the group consisting of: (h) heteroaryl selected from the group consisting of K /) / is a heterocyclic ring selected from R 4 is hydrogen, phenyl, halophenyl, acyl or alkoxycarbonyl; R5 is hydrogen, hydroxy or alkoxy; each of R6 and R7 is independently selected from hydrogen, halo, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, dialkylaminocarbonyl, aryl and aryloxy; R8 is hydrogen, hydroxyalkyl, acyl, oxo, aryl, pyridinyl, alkyl-S02-0-, Rb-NH-CH2-, arialkyl or Rc2N-CO-0; R9 is hydrogen, hydroxy, hydroxyalkyl, acyl, halo, dihalo, oxo, aryl, haloarylalkyl, pyridinyl, alkyl-S02-0-, Ra-NH-, Rb-NH-CH2-, arialkyl, or Rc2N-C0-0-; R10 is hydrogen, alkyl, alkoxycarbonyl, aryl or haloaryl; R11 is hydrogen, alkyl or aryl; R12 is hydrogen or aryl; R13 is hydrogen or alkyl; R 14 is hydrogen, alkyl, aryl or acyl; Ra is hydrogen, alkoxycarbonyl or halophenyl; R b is hydrogen, alkoxy, phenyl, halophenyl, halophenyl, halopyridinyl, pyrimidinyl, alkoxycarbonyl, dialkylaminocarbonyl or dialkylaminothiocarbonyl; and Rc is hydrogen or alkyl; and all salts, solvates, optical and geometric isomers, and crystalline forms thereof with the proviso that the compound of formula (I) is different from [4- (2,3-dihydro-indol-1-sulfonyl) -phenyl) ] - (4-phenyl-piperazin-1-yl) -methanone, [4- (2,3-dihydro-indol-1-sulfonyl) -phenyl] -morpholin-4-yl-methanone and [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] -piperidin-1-yl-methanone.
2. A compound of formula I Formula I characterized in that: \ X > is a 6, 5-bicyclic ring selected from the group consisting of: Y R1 is selected from the group consisting of: (a) hydrogen (b) alkylcarbonyl optionally substituted with heterocyclyl, (c) heterocyclylcarbonyl optionally substituted with alkyl or acetyl (d) alkyl or haloalkyl, (e) cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino and dialkylamino, 10 (f) heterocyclyl selected from the group consisting of: (g) aryl optionally substituted with halo, alkyl, alkoxy, cyano, amino, alkylamino or dialkylamino, and (h) heteroaryl selected from the group consisting of: 25 R2 is hydrogen, alkyl, heterocyclyl or together with R1 and the carbon to which they are attached, form a saturated ring substituent selected from the group consisting of: (a) cycloalkyl, and (b) heterocyclyl selected from the group consisting of: tetrahydrofuranyl , tetrahydropyranyl and piperidinyl optionally N-substituted with alkyl, acetyl or aryl, R3 is selected from the group consisting of: (a) hydrogen, (b) alkyl optionally substituted with one or two substituents independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, alkylamino and dialkylamino, (c) optionally substituted cycloalkyl with one or two substituents independently selected from the group consisting of hydroxy, alkoxy, halo, amino, alkylamino and dialkylamino, (d) heterocyclyl selected from the group consisting of: (e) cycloalkylalkyl selected from group 15 consisting of: CH? -y R ° (F) heterocyclylalkyl selected from the group consisting of: 25 (g) arylalkyl selected from the group consisting of: (h) heteroaryl selected from the group consisting of a heterocyclic ring selected from R 4 is hydrogen, phenyl, halophenyl, acyl or alkoxycarbonyl; R5 is hydrogen, hydroxy or alkoxy; each of R6 and R7 is independently selected from hydrogen, halo, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, dialkylaminocarbonyl, aryl and aryloxy; R8 is hydrogen, hydroxyalkyl, acyl, oxo, aryl, pyridinyl, alkyl-S02-0-, Rb-NH-CH2-, arialkyl or Rc2N-CO-0; R9 is hydrogen, hydroxy, hydroxyalkyl, acyl, halo, dihalo, oxo, aryl, haloarylalkyl, pyridinyl, alkyl-S02-0-, Ra-NH-, Rc2N-CO-0-; R10 is hydrogen, alkyl, alkoxycarbonyl, aryl or haloaryl; R11 is hydrogen, alkyl or aryl; R12 is hydrogen or aryl; R13 is hydrogen or alkyl; R 14 is hydrogen, alkyl, aryl or acyl; Ra is hydrogen, alkoxycarbonyl or halophenyl; R b is hydrogen, alkoxy, phenyl, halophenyl, halophenyl, halopyridinyl, pyrimidinyl, alkoxycarbonyl, dialkylaminocarbonyl or dialkylaminothiocarbonyl; and Rc is hydrogen or alkyl; and all salts, solvates, optical and geometric isomers, and crystalline forms thereof with the proviso that the compound of formula (I) is different from [4- (2,3-dihydro-indol-1-sulfonyl) -phenyl) ] - (4-phenyl-piperazin-1-yl) -methanone, [4- (2,3-dihydro-indol-1-sulfonyl) -phenyl] -morpholin-4-yl-methanone and [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] -piperidin-1-yl-methanone.
3. The compound according to claim 1 or claim 2, characterized in that: G- -X > X 'is a 6,5-bicyclic ring selected from the group consisting of: R1 is selected from the group consisting of: (a) hydrogen, (b) alkylcarbonyl optionally substituted with heterocyclyl, (c) heterocyclylcarbonyl optionally substituted with alkyl or acetyl, (d) methyl, propyl, t-butyl or trifluoromethyl, (e) cycloalkyl optionally substituted with oxo, hydroxy, methoxy, difluoro or methyl, (f) heterocyclyl selected from the group consisting of: X? kV XG > K - (g) phenyl optionally substituted with halo, methyl, methoxy, cyano or dimethylamino, and (h) heteroaryl selected from the group consisting of: R2 is hydrogen, methyl, ethyl or together with R1 and the carbon to which they are attached, form a saturated ring substituent selected from the group consisting of: (a) cycloalkyl, and (b) heterocyclyl selected from the group consisting of: tetrahydropyranyl and N-methylpiperidin-4-yl; R3 is selected from the group consisting of: (a) hydrogen, (b) (C? -C2) alkyl optionally substituted with (C? -C2) alkoxy, (c) (C4-Cg) cycloalkyl optionally substituted with one or two substituents independently selected from hydroxy, methoxy, amino, alkylamino and dialkylamino, (d) heterocyclyl selected from the group consisting of: (e) cycloalkylalkyl selected from the group consisting of: (f) heterocyclylalkyl selected from the group consisting of: (g) arylalkyl which is; and (h) heteroarylalkyl selected from the group consisting of: K ^ ~) "^ is a heterocyclic ring selected from the group consisting of: R 4 is hydrogen, phenyl, fluorophenyl, t-butyloxycarbonyl or methoxycarbonyl; R5 is hydrogen, hydroxy or methoxy; each of R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, fluoro, chloro, trifluoromethyl, cyano, methoxy, amino, monomethylamino, dimethylamino, methoxycarbonyl and dimethylaminocarbonyl; R8 is hydrogen, hydroxyalkyl, acyl, oxo, aryl, pyridinyl, alkyl-S02-0, Rb-NH-CH2-, arylalkyl or (CH3) 2N-CO-0-; R9 is hydrogen, hydroxy, hydroxymethyl, acetyl, fluoro, difluoro, oxo, phenyl, benzyl, pyridinyl, CH3-S02-0-, Ra-NH-, Rb-NH-CH2-, 0 (CH3) 2N-CO-0; R10 is hydrogen or alkyl; R11 is hydrogen or alkyl; R 12 is hydrogen or phenyl; R13 is hydrogen or methyl; R14 is hydrogen, methyl, phenyl or acetyl; Ra is hydrogen, methoxycarbonyl, t-butyloxycarbonyl or fluorophenyl; and Rb is hydrogen, methoxy, phenyl, phenylalkyl, fluorophenylalkyl, fluorophenyl, pyridinyl, fluoropyridinyl, pyrimidinyl, methoxycarbonyl, t-butyloxycarbonyl, dimethylaminocarbonyl or dimethylaminothiocarbonyl.
4. The compound according to claim 1, 2 6 3, characterized in that GA is selected from the group consisting of:
5. The compound according to claim 1, 2, 3 or 4, characterized in that
6. The compound according to claim 1, 2, 3 or 4, characterized in that
7. The compound according to claim 4, 5 'or 6, characterized in that R1 is aryl optionally substituted with halo, alkyl, alkoxy, cyano, amino, alkylamino or dialkylamino.
8. The compound according to claim 7, characterized in that R1 is phenyl.
9. The compound according to claim 4, 5 or 6, characterized in that R1 is cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, oxo, hydroxy alkoxy, amino, alkylamino and dialkylamino.
10. The compound according to claim 9, characterized in that R1 is cyclopentyl.
11. The compound according to claim 4, 5 or 6, characterized in that R1 is heterocyclyl selected from the group consisting of:
12. The compound according to claim 11, characterized in that R1 is tetrahydrofuran.
The compound according to any of claims 1 to 12, characterized in that R 3 is heterocyclylalkyl selected from the group consisting of:
14. The compound according to claim 13, characterized in that R3 is
15. The compound according to any of claims 1 to 12, characterized in that R 3 is heterocyclyl selected from the group consisting of:
16. The compound according to claim 15, characterized in that R3 is
17. The compound according to any of claims 1 to 12, characterized in that R 3 is cycloalkylalkyl selected from the group consisting of: CH ".Ff r.u -R" ^^ YHAR A Z? ^
18. The compound according to claim 17, characterized in that R3 is
19. The compound according to any of claims 1 to 12, characterized in that R3 is alkyl optionally substituted with one of two substituents independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, alkylamino and dialkylamino.
20. The compound according to claim 19, characterized in that R3 is tx.
21. The compound according to any of claims 1 to 12, characterized in that R3 is arylalkyl selected from the group consisting of:
22. The compound according to claim 21, characterized in that R3 is
23. The compound according to any of claims 1 to 12, characterized in that R 3 is heteroarylalkyl selected from the group consisting of:
24. The compound according to claim 23, characterized in that R3 is:
25. A compound according to any of claims 1 to 24, characterized in that the compound is: N- (4-Fluoro-benzyl) -4- (3-phenyl-indole-l-sulfonyl) -benzamide, N- (5- Fluoro-pyridin-3-ylmethyl) -4- (3-phenyl-indole-1-sulfonyl) -benzamide, 4- (3-phenyl-indole-1-sulfonyl) -N- (tetrahydro-pyran-4-ylmethyl) -benzamide, 4- (3-Cyclopentyl-indole-l-sulfonyl) -N- (4-fluorobenzyl) -benzamide, N- (4-Fluoro-benzyl) -4- [3- (tetrahydro-pyran-4-yl ) -indol-1-sulfonyl] -benzamide, N-Cyclopropylmethyl-4- (3-phenyl-indole-1-sulfonyl) -benzamide, 4- (3-Cyclopentyl-indole-1-sulfonyl) -N- (tetrahydro- pyran-4-yl) -benzamide, or 4- (3-cyclopentyl-indole-l-sulfonyl) -N- (tetrahydro-pyran-4-ylmethyl) -benzamide.
26. A compound according to any of claims 1 to 25, characterized in that the compound is: 4- (3-cyclopentyl-indole-l-sulfonyl) -N- (4-fluorobenzyl) -benzamide.
27. A pharmaceutical composition characterized in that it comprises a compound according to any of claims 1 to 26, or [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1) -yl) methanone, [4- (2, 3-dihydro-indol-1-sulfonyl) -phenyl] -morpholin-4-yl-methanone or [4- (2,3-dihydro-indol-l-sulfonyl) - phenyl] -piperidin-1-yl-methanone in an amount effective to antagonize the stimulation of the CB-1 receptor, and a pharmaceutically acceptable carrier, diluent or excipient.
28. A pharmaceutical composition characterized in that it comprises a compound according to any of claims 1 to 26, or [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) ) methanone, [4- (2, 3-dihydro-indol-1-sulfonyl) -phenyl] -morpholin-4-yl-methanone, [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] -piperidin-1-yl-methanone or [4- (3-fluoro-phenyl) -piperidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone in an effective amount to reduce the neurotransmission of endocannabinoid through CB-1 receptors, and a pharmaceutically acceptable carrier, diluent or excipient.
29. A pharmaceutical composition characterized in that it comprises a compound according to any of claims 1 to 26, or [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1) -yl) methanone, [4- (2, 3-dihydro-indol-1-sulfonyl) -phenyl] -morpholin-4-yl-methanone, [4- (2,3-dihydro-indol-l-sulfonyl) - phenyl] -piperidin-1-yl-methanone or [4- (3-fluoro-phenyl) -piperidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone and a pharmaceutically acceptable carrier, diluent or excipient.
30. A method for treating a condition which is treatable by reducing stimulation of the CB-1 receptor, characterized in that it comprises administering to a mammal in need therefor, a composition according to any of claims 27, 28 or 29.
31. The method according to claim 30, characterized in that the mammal is a human.
32. The method according to claim 30 or claim 31, characterized in that the condition is psychosis, memory deficit, cognitive disorder, migraine, neuropathy, neuroinflammatory disorder, stroke, head trauma, anxiety disorder, stress, depression, epilepsy, Parkinson's disease, schizophrenia, substance abuse disorder, obesity and an eating disorder associated with excessive food intake.
33. The method according to claim 32, characterized in that the condition is obesity.
34. A compound according to claim 1 or Formula (I), [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) methanone, [ 4- (2,3-dihydro-indol-1-sulfonyl) -phenyl] -morpholin-4-yl-methanone, [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] -piperidin-1 -yl-methanone or [4- (3-fluoro-phenyl) -piperidin-1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -metanone, for use in therapy.
35. Use of a compound according to any of claims 1 to 26, [4- (2,3-dihydro-indol-1-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) methanone, [4- (2, 3-dihydro-indol-l-sulfonyl) -phenyl] -morpholin-4-yl-methanone, [4- (2,3-dihydro-indol-l-sulfonyl) -phenyl] -piperidine- 1-yl-methanone or [4- (3-fluoro-phenyl) -piperidin-1-yl] - [4- (3-phenyl-indole-1-sulfonyl) -phenyl] -methanone, for the manufacture of a medicament to treat a condition which is treatable by reducing stimulation of the CB-1 receptor.
36. The use according to claim 35, wherein the condition is psychosis, memory deficit, cognitive disorder, migraine, neuropathy, neuroinflammatory disorder, stroke, head trauma, anxiety disorder, stress, depression, epilepsy. , Parkinson's disease, schizophrenia, substance abuse disorder, obesity or eating disorder associated with excessive food intake.
37. The use according to claim 36, wherein the condition is obesity.
38. A method for treating a condition selected from the group consisting of psychosis, memory deficit, cognitive disorder, migraine, neuropathy, neuroinflammatory disorder, stroke, head trauma, anxiety disorder, stress, depression, epilepsy, disease of Parkinson's, schizophrenia, substance abuse disorder, obesity or eating disorder associated with excessive food intake, characterized in that it comprises: administering to a mammal in need thereof, a compound according to any of claims 1-26, [4 - (2,3-dihydro-indol-l-sulfonyl) -phenyl] - (4-phenyl-piperazin-1-yl) methanone, [4- (2,3-dihydro-indol-1-sulfonyl) -phenyl] -morpholin-4-yl-methanone, [4- (2, 3-dihydro-indol-1-sulfonyl) -phenyl] -piperidin-1-yl-methanone or [4- (3-fluoro-phenyl) -piperidine- 1-yl] - [4- (3-phenyl-indole-l-sulfonyl) -phenyl] -methanone.
39. The method according to claim 38, characterized in that the condition is obesity.
40. A compound of formula (lia) characterized in that: Y is halogen, cyclopent-1-enyl or cyclopentyl and R17 is alkyl.
41. A compound according to claim 40, characterized in that Y is iodine.
42. A compound according to claim 40 or claim 41, characterized in that R17 is methyl.
43. A compound according to claim 40, or claim 42, characterized in that Y is cyclopent-1-enyl.
44. A compound according to claim 40 or claim 42, characterized in that Y is cyclopentyl.